CN103687862A - Improved process for preparing penicillins and intermediate compounds - Google Patents
Improved process for preparing penicillins and intermediate compounds Download PDFInfo
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- CN103687862A CN103687862A CN201180072474.1A CN201180072474A CN103687862A CN 103687862 A CN103687862 A CN 103687862A CN 201180072474 A CN201180072474 A CN 201180072474A CN 103687862 A CN103687862 A CN 103687862A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/76—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with hetero rings directly attached to the carboxamido radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/10—Modification of an amino radical directly attached in position 6
- C07D499/12—Acylation
Abstract
Disclosed is an improved process for the preparation of isoxazolyl penicillins of formula (I), wherein X1 and X2 can be independently selected from the group comprising hydrogen, chlorine or fluorine, and its pharmaceutically suitable salts. The process is economic in -situ synthetic method without isolation of any intermediate.
Description
Technical field
Generally speaking the present invention is the preparation of relevant isoxazolyl penicillin (isoxazolyl penicillins), and be more particularly original position (in-situ) preparation of the acyl chlorides (acid chloride) of relevant 3-phenyl-5-methyl-Isoxazole derivative, it produces with intermediate form in the preparation process of isoxazolyl penicillin derivative.
Background technology
Isoxazolyl penicillin has the activity of antagonism susceptibility gram positive bacteria infection.They are narrow territory beta-lactam antibiotic (beta-lactam antibiotics), belong to penicillin family and are widely used in antimicrobial formulation.
Medicine industry faces significant challenge often at exploitation compounds process for production thereof, i.e. efficiency and cost-benefit balance in technical scale.Therefore, preparing the pharmaceutical compound of the suitable purity of tool and productive rate, is particularly isoxazolyl penicillin, is often technical challenging task.
In the prior art, many methods have been probed into the manufacture of isoxazolyl penicillin derivative, for example Oxazacillin (oxacillin), gram husky XiLin (cloxacillin), dicloxacillin (dicloxacillin) or Flucloxacillin (flucloxacillin).Generally speaking, the preparation method of isoxazolyl penicillin is multistage method, it is involved in the first reactions steps prepares intermediate, that is the carbonyl chloride (carbonyl chloride) of 3-phenyl-5-methyl-4-isoxzzole-carboxylic acid derivative, in second step, carry out subsequently the condensation reaction of this intermediate.The intermediate that in reaction mixture, separated first step forms also carries out crystallization under organic solvent exists.This crystalline compounds is further dissolved in ester class and reacts with 6-amidopenicillanic acid.
The main challenge facing in this method process is its cost benefit.Due to the chemical process of multi-step, the industrial-scale production of those compounds needs more investment.This type of multistage method relates to the production of intermediate, adds subsequently organic solvent to carry out purifying and crystallization flow process.Filtration and crystallization flow process are method huge and consuming time.The separated also crystallization of this intermediate compound reaction mixture.The pure crystalline substance of this intermediate is dissolved in to organic solvent to start the synthetic final step of isoxazolyl penicillin.Because of the separation of this intermediate and the use of complicated purification method, so class multistage method must increase production cost.
Another shortcoming of this type of multistage method is this intermediate, that is the carbonyl chloride of 3-phenyl-5-methyl-4-isoxzzole-carboxylic acid derivative, for high corrosion compound and tendency are reacted with the moisture existing in atmosphere.Therefore, this intermediate productive rate in its purifying and crystallisation process declines, because it is converted into its corresponding acid with the moisture reaction being present in atmosphere.In addition, the solubleness in the solvent that this intermediate is used in purification process can further reduce productive rate, is that some is still dissolved in mother liquor and cannot when repeatedly extracting, reclaims because of this intermediate.Therefore, purifying and crystallization requirements of process optimum reaction condition, it should reduce any modulated environment of temperature and pressure that contacts and maintain with moisture.
Another shortcoming of the isoxazolyl penicillin derivative preparation method of this quasi-tradition is to using hexane as the organic solvent for intermediate crystallization.As known in document, hexane is flammable compound and potential environmentally hazardous substance.With hexane purifying intermediate, have the difficulty in processing, because it is flammable essence.
In the traditional industry scale of isoxazolyl penicillin, production method must be paid high fund cost, because it often need to use machine/apparatus, that is but be not limited to horizontal filter plate filter (sparkler filter), whizzer/stirring filtration device (agitated nutch filter), drying machine and solvent Distallation systm.Need further illustrate, if use the method with reference to prior art, need to use all or most of above-mentioned machine/apparatus, thereby increase the required expense of a large amount of productions of carrying out appointed product.In this mandatory declaration, improved place is not limited to factor as herein described.
Therefore, this field still has improved demand for the efficient and cost-benefit method for preparing isoxazolyl penicillin derivative.
Summary of the invention
The object of this invention is to provide a kind of the improving one's methods of isoxazolyl penicillin derivative for the preparation of thering is formula (I).
X wherein
1with X
2can be independently selected from the group including but not limited to hydrogen, chlorine or fluorine, and applicable salt pharmaceutically.
Another object of the present invention is to provide a kind of cost benefit method for the preparation of having the isoxazolyl penicillin derivative of formula (I).
The present invention is that relevant a kind of for the preparation of the improving one's methods of isoxazolyl penicillin derivative, it relates to original position and prepares intermediate, that is has the acyl chlorides of 3-phenyl-5-methyl-Isoxazole derivative of formula (III),
X wherein
1with X
2can be independently selected from the group including but not limited to hydrogen, chlorine or fluorine, further add ethyl acetate and exist lower and 6-amidopenicillanic acid to carry out condensation reaction in alkali, subsequently with saturated salt solution-treated and crystallization; Filter the reaction mixture of gained; And be dried in the modulated environment of temperature.
Accompanying drawing explanation
Fig. 1 shows according to the filtering process figure of a specific embodiment of the present invention.
Fig. 2 shows according to the drying process figure of another specific embodiment of the present invention.
Embodiment
Each aspect of the present invention, produces a kind ofly for the preparation of the improving one's methods of isoxazolyl penicillin derivative, and details are as follows.
The present invention is relevant a kind of the improving one's methods of isoxazolyl penicillin for the preparation of having formula (I), and it relates to original position and prepares intermediate, that is has the acyl chlorides of 3-phenyl-5-methyl-Isoxazole derivative of formula (III).Defined " original position " word refers to and carries out two or multiple reaction sequence and need not be separated in any intermediate producing in the process of this reaction sequence herein.An aspect of of the present present invention relates to a kind of method for original position manufacture with the compound of formula (I), and it comprises:
A) acyl chlorides of preparation formula (III) be dissolved in ester class,
B) solution of acid chloride from step (a) is added to the basic solution of 6-amidopenicillanic acid, subsequently saturated saline solution is added,
C) with 2 ethyl hexanoic acid sodium (sodium-2-ethyl hexanoate) crystallization,
D) filter, subsequently washing; And
E) under the environment of controlled temperature system, wetted material is dry.
In a specific embodiment of the present invention, for the ester class of step (a), be selected from but be not limited to ethyl acetate, methyl acetate or its mixture or any acetic ester not mixed with water.
If without other statements, the specific group that takes from the different cationic Oxazacillins of tool, gram husky XiLin, dicloxacillin or Flucloxacillin that comprises of " salt of isoxazolyl penicillin derivative " as used herein word, for example, basic metal or alkaline earth metal cation, as sodium, potassium or magnesium, be preferably sodium.This salt can utilize salinization (salifying) compound, such as but not limited to 2 ethyl hexanoic acid sodium, and obtains.
In preferred embodiment of the present invention, the sodium salt of derivative that is selected from the isoxazolyl penicillin of the group that comprises Oxazacillin, gram husky XiLin, dicloxacillin or Flucloxacillin is that original position preparation is from parent material benzaldehyde derivative, to produce the acyl chlorides of corresponding 3-phenyl-5-methyl-Isoxazole derivative with formula (III).This formula (III) compound is to be directly dissolved in ester class, ethyl acetate preferably, and need not carry out its separation, purifying or crystallization.Basic solution and acyl chlorides intermediate with 6APA carry out condensation reaction.Or, also can reaction mixture separate type (III) compound, and move to subsequently reaction vessel, make it be dissolved in ester class, be preferably ethyl acetate, with 6APA, carry out condensation reaction subsequently.The separated organic layer of reaction mixture.Subsequently, the extract merging with strong brine washing, and 2 ethyl hexanoic acid sodium is added to produce the sodium salt of isoxazolyl penicillin, its filter subsequently and drying process to obtain aseptic and oral, purified isoxazolyl penicillin derivative.
This intermediate, that is there is the acyl chlorides of 3-phenyl-5-methyl-Isoxazole derivative of formula (III), be under ester class exists, to carry out condensation reaction with 6APA, wherein step (a) is that original position is carried out.In this respect of the present invention, formula (III) compound is purifying and be separated into white crystal compound not.Compared to in-situ method, with traditional method, prepare compound (I) and do not obtain expected results, be because of due to the shortcomings such as used solvent and intermediate output are few.Each compound that need not separated produce in conjunction with multiple reaction step in addition, has its advantage economically.
Of the present invention improve one's methods be better than being in reaction process of traditional method need not be in separated intermediate of any stage, that is react in original position mode, this is highly beneficial on commercial size.This can reduce fund cost, because exempted the equipment/machine cost for intermediate purifying completely.
This intermediate is comprised of highly reactive acyl chlorides functional group, and it is very easy to change into acid during the moisture in atmosphere in contact.Reactive intermediate like this, when its separation and purifying, has produced the very big shortcoming that changes into acid, thereby affects productive rate and the purity of final product.Personnel's easy to understand present method of the common technology of this area tool has considerable advantage, and wherein this intermediate is without separated and make reaction directly enter next reactions steps.
In addition, described in specific embodiment, this intermediate need not any purifying flow process, and it relates to and uses poisonous and highly flammable organic solvent as hexane.Extensively be used to manufacture in the method for isoxazolyl penicillin, hexane is considered to be best suited for the solvent of this intermediate of purifying.Compare, realize in-situ method of the present invention and gets rid of use hexane completely because omitting purification step, and react and directly enter immediately reactions steps subsequently, that is be first dissolved in ester class before carrying out condensation reaction with 6-APA.Therefore, method of the present invention is not more had a contaminative and compared with environmental protection.
In detailed description of the present invention, there are many specific embodiments, so that the understanding completely of various specific embodiments of the present invention to be provided.Yet various equivalent modifications will recognize, specific embodiments of the invention can not have one or more specific implementations, or have other equipment, system, assembly, method, composition, material, part, and/or implement in the situation of its analogue.
Formula of the present invention (I) compound can, by comprising prepared by ordinary method of the prior art, specifically be followed the description of containing herein.Some method for the manufacture of formula of the present invention (I) compound is with following reacting flow chart explanation.Additive method is illustrated in experiment chapters and sections.The partial reaction initial compounds and the embodiment that in schema, describe are to prepare as explanation herein.
Schema I
In another specific embodiment of the present invention, the filtration for the preparation of isoxazolyl penicillin derivative and drying means described in the schema of Fig. 1 and Fig. 2 promote output usefulness widely.The filtration and the drying means that use are herein a kind of temperature sensitivity flow process, because it may make final product, under high temperature, decompose.According to the present invention, sterilizing filter (sterile filter) is that it is essential by sterile product for maintaining the sterile state of pharmaceutical compound.The filtration of final product is to carry out in the stirring filtration device (agitated nutch filter) in vacuum.The solution of solvent extraction gained is placed in inert gas environment.In the indoor vacuum that applies, make mother liquor separation and leave throw out.With solvent wash throw out to get rid of any other impurity.This moistening throw out is crude product, it is further placed in to the modulated environment of temperature and is dried.
Under the high temperature of decompression, utilize lasting stirring mechanism that moistening throw out is exposed to mechanical stress, thereby make residual solvent autoreaction medium volatilization and produce pure in fact isoxazolyl penicillin derivative.Meanwhile, recyclable by the solvent of system recoveries, so this flow process is the method compared with environmental protection.In addition, owing to being under reduced pressure dried, drying temperature and stir the suction strainer time and maintain low value wherein, the mass property that makes final product promotes as purity.Or, can be separated with the moistening throw out stirring after filtration device filters, and can utilize methods such as vacuum-drying, tray drying to reach drying purpose.Those filtrations and drying process have its efficiency, because it can be applicable to the medicine of oral grade.
As explanation of the present invention, for the preparation of filtration and the drying process of isoxazolyl penicillin derivative, can be fully understood by following schema.Fig. 1 is the schema that shows filtration step, and Fig. 2 shows according to the schema of dry technology of the present invention.
The isoxazolyl penicillin derivative of being obtained by aforesaid method also shows that the solvent impurity with low concentration residues in final product.
The method for the preparation of isoxazolyl penicillin as described in each specific embodiment of the present invention is to prepare intermediate with original position, that is thering is the acyl chlorides of 3-phenyl-5-methyl-Isoxazole derivative of formula (II), it is reached height purity and can in separated, purifying and crystallisation process, not lose this intermediate.Therefore,, with respect to the available preparation method of prior art, the efficiency of the inventive method has sizable improvement.Meanwhile, the industrial applicability of methods described herein obviously promotes, and can be arranged to simply technical scale and need not use complicated purification process or equipment, thereby increase efficiency and reduce in fact industrial production cost because of it.
Although the present invention is with its particular specific embodiment explanation, some of the compounds of this invention manufacture method revised, and comprises the equipment of used particular design, is contained in all wittingly category of the present invention.
With regard to the viewpoint of business and manufacture, above-mentioned technology is found significant effective rate and has effect, and the isoxazolyl penicillin derivative of the formula (I) of good quality is provided.By applying by different way announcement of the present invention or revising, can obtain many other useful results in disclosed category.
But several variants of program disclosed herein and method self ground teaching is given those skilled in the art.Yet, should be understood that, announcement of the present invention is relevant preferred embodiment of the present invention, its object only can not be read as limitation category of the present invention for explanation.
Embodiment
Embodiment 1
The preparation of gram husky XiLin sodium (Cloxacillin sodium)
At room temperature, o-chlorobenzaldehyde (850g) is dissolved in to methyl alcohol (2.5-2.6L).Hydroxyl amine salt (516g) added and reaction mixture is heated to 38-40 ℃ and last 1 hour, subsequently sodium carbonate (460-470g) being added.PH value is maintained to approximately 9.5 and also this reaction mixture is cooled to room temperature.Triethylamine (4g) is added and maintain and under 0-5 ℃, pass into chlorine (510-520g) 24 hours in temperature.With nitrogen wash 4-5 hour.Complete after chlorination reaction, methyl alcohol (575L) is added, subsequently sodium carbonate (750-780g) is added so that pH value reaches about 7-7.5.Methyl acetoacetate (686g) and SODA ASH LIGHT 99.2 (50-100g) are added to this reaction mixture until complete thermopositive reaction.The solution of gained is by adding caustic soda (460g) to be hydrolyzed.Sulfuric acid is added and pH value is adjusted to about 8.6-8.8.With solvent extraction organic impurity, acid is separated, be dried and add (approximately 3.5) in toluene.Phosphorus pentachloride (about 540g) is added and continue and stir.After reaction finishes, with clear water washing organic layer, and in the lower toluene that reclaims of decompression.The 3-(2-chloro-phenyl-that ethyl acetate is added to gained)-5-methyl-4-isoxzzole-carbonyl chloride solution.6-amidopenicillanic acid (300g) is dissolved in to ammonium hydroxide (260-270mL) and pH value is adjusted to 7.0-9.0.Subsequently this solution being added to the chloro-phenyl-containing 3-(2-) reaction soln (377g) and the pH value of-5-methyl-4-isoxzzole-carbonyl chloride maintain about 2.0-2.3.Salt (100g) is added and continue and stir, make its layering.Organic layer is the separated and extract that merges is immediately with strong brine washing, subsequently 2 ethyl hexanoic acid sodium (590-630g) added and pH value maintains 7.8-8.1.This solution filters subsequently, and in decompression and nitrogen environment under with organic solvent washing.Moistening throw out carries out vacuum-drying immediately, to produce 6-[[3-(2-chloro-phenyl-)-5-methyl isophthalic acid, 2-oxazole-4-carbonyl] amido]-3, the change sodium salt (gram husky XiLin sodium) of nitrogen dicyclo [3.2.0] heptane-2-carboxylic acid of 3-dimethyl-7-side oxygen base-4-thiophene-1-.
Embodiment 2
The preparation of Stampen (Dicloxacillin sodium)
At room temperature, 2,6-dichlorobenzaldehyde (850g) is dissolved in to methyl alcohol (2.5-2.6L).Hydroxyl amine salt (400-425g) added and reaction mixture is heated to 38-40 ℃ and last 1 hour, subsequently sodium carbonate (350-460g) being added.PH value is maintained to approximately 9.5 and also this reaction mixture is cooled to room temperature.Triethylamine (4g) is added and maintain and under 0-5 ℃, pass into chlorine (about 400g) 24 hours in temperature.With nitrogen wash 4-5 hour.Complete after chlorination reaction, methyl alcohol (about 1000ml) is added, subsequently sodium carbonate (about 700gm) is added so that pH value reaches about 7-7.5.Methyl acetoacetate (about 550g) and SODA ASH LIGHT 99.2 (25-50g) are added to this reaction mixture until complete thermopositive reaction.The solution of gained is by adding caustic soda (340-375g) to carry out saponification.Sulfuric acid is added and pH value is adjusted to about 8.6-8.8.With solvent extraction organic impurity, acid is separated, be dried and add (about 3.5mL) in toluene.Phosphorus pentachloride (about 540gm) is added and continue and stir.After reaction finishes, with clear water washing organic layer, and in the lower toluene that reclaims of decompression.The 3-(2 that ethyl acetate is added to gained, 6-dichlorophenyl)-5-methyl-4-isoxzzole-carbonyl chloride solution.6-amidopenicillanic acid (300g) is dissolved in to ammonium hydroxide (260-270mL) and pH value is adjusted to 7.0-8.0.Subsequently this solution being added containing 3-(2 to 6-dichlorophenyl) reaction soln (411g) and the pH value of-5-methyl-4-isoxzzole-carbonyl chloride maintain about 2.0-3.0.Salt (about 100g) is added and continue and stir, make its layering.Organic layer is the separated and extract that merges is immediately with strong brine washing, subsequently 2 ethyl hexanoic acid sodium (590-630g) added and pH value maintains 7.0-9.0.Subsequently by agitation and be cooled to 0-5 ℃.The throw out of gained is filtered, and under decompression and nitrogen environment with organic solvent washing.Moistening throw out carries out vacuum-drying immediately to produce 6-[[3-(2,6-chloro-phenyl-)-5-methyl isophthalic acid, 2-oxazole-4-carbonyl] amido]-3, the change sodium salt (Stampen) of nitrogen dicyclo [3.2.0] heptane-2-carboxylic acid of 3-dimethyl-7-side oxygen base-4-thiophene-1-.
Embodiment 3
The preparation of Sodium flucloxacillin (Flucloxacillin sodium)
At room temperature, the chloro-6-fluorobenzaldehyde of 2-(850g) is dissolved in to methyl alcohol (2.5-2.6L).Hydroxyl amine salt (475-500g) added and reaction mixture is heated to 38-40 ℃ and last 1 hour, subsequently sodium carbonate (460-500g) being added.PH value is maintained to approximately 9.5 and also this reaction mixture is cooled to room temperature.Triethylamine (4g) is added and maintain under 0-5 ℃ and pass into chlorine (400-500g) approximately 24 hours in temperature.With nitrogen wash 4-5 hour.Complete after chlorination reaction, methyl alcohol (about 1000L) is added, subsequently sodium carbonate (about 600g) is added so that pH value reaches about 7-7.5.Methyl acetoacetate (500-550g) and SODA ASH LIGHT 99.2 (25-50g) are added to this reaction mixture until complete thermopositive reaction.The solution of gained is by adding caustic soda (about 460g) to carry out saponification.Sulfuric acid is added and pH value is adjusted to about 8.6-8.8.With solvent extraction organic impurity, acid is separated, be dried and add (approximately 3.5) in toluene.Subsequently phosphorus pentachloride (about 540g) is added and continue and stir.After reaction finishes, with clear water washing organic layer, and in the lower toluene that reclaims of decompression.The chloro-6-fluorophenyl of 3-(2-that ethyl acetate is added to gained)-5-methyl-4-isoxzzole-carbonyl chloride solution.6-amidopenicillanic acid (300g) is dissolved in to ammonium hydroxide (260-270mL) and pH value is adjusted to 7.0-9.0.Subsequently this solution being added containing 3-(2-to chloro-6-fluorophenyl) reaction soln (399g) and the pH value of-5-methyl-4-isoxzzole-carbonyl chloride maintain about 2.0-2.3.Salt (100g) is added and continue and stir, make its layering.Organic layer is the separated and extract that merges is immediately with strong brine washing, subsequently 2 ethyl hexanoic acid sodium (590-630g) added and pH value maintains 7.8-8.1.Subsequently by agitation and be cooled to 0-5 ℃.Under decompression and nitrogen environment, the throw out of gained is filtered.Moistening throw out carries out vacuum-drying immediately to produce the chloro-6-fluorophenyl of 6-[[3-(2-)-5-methyl isophthalic acid, 2-oxazole-4-carbonyl] amido]-3, the change sodium salt (Sodium flucloxacillin) of nitrogen dicyclo [3.2.0] heptane-2-carboxylic acid of 3-dimethyl-7-side oxygen base-4-thiophene-1-.
Embodiment 4
The preparation of oxacillin sodium (Oxacillin sodium)
At room temperature, phenyl aldehyde (850g) is dissolved in to methyl alcohol (4-5L).Hydroxyl amine salt (516-550g) is added and reaction mixture is heated to 38-40 ℃ and last 1 hour, subsequently sodium carbonate (about 450-500g) is added.PH value is maintained to approximately 9.5 and also this reaction mixture is cooled to room temperature.Triethylamine (4g) is added and maintain and under 0-5 ℃, pass into chlorine (510-520g) 24 hours in temperature.With nitrogen wash 4-5 hour.Complete after chlorination reaction, methyl alcohol (about 1000mL) is added, subsequently sodium carbonate (425-450g) is added so that pH value reaches about 7-7.5.Methyl acetoacetate (about 686g) and SODA ASH LIGHT 99.2 (25-50g) are added to this reaction mixture until complete thermopositive reaction.The solution of gained is by adding caustic soda (about 460g) to carry out saponification.Sulfuric acid is added and pH value is adjusted to about 8.6-8.8.With solvent extraction organic impurity, acid is separated, be dried and add (about 3.5lts) in toluene.Phosphorus pentachloride (about 540g) is added and continue and stir.After reaction finishes, with clear water washing organic layer, and in the lower toluene that reclaims of decompression.3-phenyl-5-methyl-4-isoxzzole-carbonyl chloride the solution that ethyl acetate is added to gained.6-amidopenicillanic acid (300g) is dissolved in to ammonium hydroxide (260-270mL) and pH value is adjusted to 7.0-9.0.Subsequently this solution being added to the chloro-phenyl-containing 3-(2-) reaction soln (336g) and the pH value of-5-methyl-4-isoxzzole-carbonyl chloride maintain about 2.0-2.3.Salt (100g) is added and continue and stir, make its layering.Organic layer is the separated and extract that merges is immediately with strong brine washing, subsequently 2 ethyl hexanoic acid sodium (590-630g) added and pH value maintains 7.8-8.1.Subsequently by agitation and be cooled to 0-5 ℃.In the lower throw out that filters gained of decompression, and under nitrogen environment with organic solvent washing.Moistening throw out carries out vacuum-drying immediately to produce 6-[[3-phenyl-5-methyl isophthalic acid, 2-oxazole-4-carbonyl] amido]-3, the change sodium salt (oxacillin sodium) of nitrogen dicyclo [3.2.0] heptane-2-carboxylic acid of 3-dimethyl-7-side oxygen base-4-thiophene-1-.
Claims (12)
1. for the preparation of being selected from the compound of the group being formed by the isoxazolyl penicillin with formula (I) and a method for pharmaceutical acceptable salt class thereof,
X wherein
1with X
2be independently selected from hydrogen and halogen, wherein the method comprises:
A) original position preparation formula (III) intermediate, is dissolved in ester class subsequently,
B) basic solution of the solution of acid chloride of step (a) and 6-amidopenicillanic acid is carried out to condensation reaction, adds subsequently saturated saline solution,
C) with the sodium salt crystal of thylhexoic acid,
D) under decompression and inert gas environment, filter,
E) dry at the pressure of mechanical stress and reduction and temperature.
2. the method for claim 1, wherein reaction mixture is separated for this intermediate of step (a) gained.
3. the method for claim 1, wherein this ester class of step (a) is to be selected from the group being comprised of methyl acetate, ethyl acetate, propyl acetate, isobutyl acetate, n-butyl acetate, acetic acid tri-n-butyl, methyl-formiate, ethyl formate, propyl formate or its mixture.
4. the method for claim 1, wherein this inert gas environment in the process of the filtration of step (d) is to produce with nitrogen or rare gas element family member.
5. for the preparation of being selected from the compound of the group being formed by the isoxazolyl penicillin with formula (I) and a method for pharmaceutical acceptable salt class thereof,
X wherein
1with X
2be independently selected from hydrogen and halogen, wherein the method comprises:
A) prepare intermediate, wherein this intermediate is original position preparation, and is characterised in that and comprises the following step:
I. with corresponding benzaldehyde derivative and oxyamine reactant salt, under existing, triethylamine adds chlorine subsequently,
Ii. under existing, sodium methoxide adds ester class, subsequently with phosphorus pentachloride or any chlorination reaction;
B) this intermediate is directly dissolved in ester class, and separated this intermediate in need not reaction mixture,
F) react with the basic solution of 6-amidopenicillanic acid, add subsequently saturated saline solution,
G) with the sodium salt crystal of thylhexoic acid,
H) under decompression and inert gas environment, filter,
I) dry at the pressure of mechanical stress and reduction and temperature.
6. method as claimed in claim 5, wherein this ester class is to be selected from the group being comprised of methyl acetate, ethyl acetate, propyl acetate, isobutyl acetate, n-butyl acetate, acetic acid tri-n-butyl, methyl-formiate, ethyl formate, propyl formate or its mixture.
7. method as claimed in claim 5, wherein this chlorizating agent is to be selected from the group being comprised of thionyl chloride, phosphoryl chloride or oxalyl chloride etc.
8. method as claimed in claim 5, wherein this inert gas environment in the process of the filtration of step (h) is to produce with nitrogen or rare gas element family member.
9. for the preparation of a method for gram husky XiLin (cloxacillin) and pharmaceutical acceptable salt class thereof, wherein the method comprises:
A) preparation formula (III) intermediate, wherein X
1for hydrogen and X
2for chlorine,
Wherein this intermediate is original position preparation, and is characterised in that and comprises the following step:
I. in pH value 9 to 10 scopes by o-chlorobenzaldehyde and oxyamine reactant salt,
Ii. in approximately-10 ℃ to 10 ℃, preferably, in the temperature range of 0 ℃ to 5 ℃, under the inert gas environment existing in triethylamine, pass into chlorine,
Iii. under existing, sodium methoxide adds methyl acetoacetate,
Iv. under vacuum, add phosphorus pentachloride and thionyl chloride;
B) this intermediate is directly dissolved in to ester class, and separated this intermediate in need not reaction mixture,
C) react with the basic solution of 6-amidopenicillanic acid, add subsequently saturated saline solution,
D) with the sodium salt crystal of thylhexoic acid,
E) under decompression and inert gas environment, filter,
F) dry at the pressure of mechanical stress and reduction and temperature.
10. method as claimed in claim 8, wherein this ester class is to be selected from the group being comprised of methyl acetate, ethyl acetate, propyl acetate, isobutyl acetate, n-butyl acetate, acetic acid tri-n-butyl, methyl-formiate, ethyl formate, propyl formate or its mixture.
11. methods as claimed in claim 8, wherein step o-chlorobenzaldehyde is (i) in approximately 30 ℃ to 50 ℃ with reacting of hydroxyl amine salt, preferably in the temperature range of 35 ℃ to 45 ℃, carries out.
12. methods as claimed in claim 8, wherein this inert gas environment is to produce with nitrogen or rare gas element family member.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1533/DEL/2011 | 2011-05-27 | ||
| IN1533DE2011 | 2011-05-27 | ||
| PCT/IB2011/053131 WO2012164355A1 (en) | 2011-05-27 | 2011-07-13 | Improved process for preparing penicillins and intermediate compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103687862A true CN103687862A (en) | 2014-03-26 |
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| CN201180072474.1A Pending CN103687862A (en) | 2011-05-27 | 2011-07-13 | Improved process for preparing penicillins and intermediate compounds |
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| WO (1) | WO2012164355A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108659007A (en) * | 2018-07-23 | 2018-10-16 | 华北制药集团先泰药业有限公司 | A kind of preparation method of dicloxacillin sodium pillar-shaped crystal |
| CN111205305A (en) * | 2020-02-07 | 2020-05-29 | 山东二叶制药有限公司 | Preparation process of cloxacillin sodium |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85102130A (en) * | 1985-04-01 | 1987-01-31 | 生化企业 | The novel method of preparation penicillin and cephalosporins derivatives |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108659007A (en) * | 2018-07-23 | 2018-10-16 | 华北制药集团先泰药业有限公司 | A kind of preparation method of dicloxacillin sodium pillar-shaped crystal |
| CN111205305A (en) * | 2020-02-07 | 2020-05-29 | 山东二叶制药有限公司 | Preparation process of cloxacillin sodium |
| CN111205305B (en) * | 2020-02-07 | 2021-10-22 | 山东二叶制药有限公司 | Preparation process of cloxacillin sodium |
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| WO2012164355A1 (en) | 2012-12-06 |
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