CN111205305A - The preparation technology of cloxacillin sodium - Google Patents

The preparation technology of cloxacillin sodium Download PDF

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CN111205305A
CN111205305A CN202010082794.6A CN202010082794A CN111205305A CN 111205305 A CN111205305 A CN 111205305A CN 202010082794 A CN202010082794 A CN 202010082794A CN 111205305 A CN111205305 A CN 111205305A
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sodium
cloxacillin
preparation process
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organic solvent
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CN111205305B (en
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沈灏
李京喜
吴永锋
唐鹤鸣
华军杰
张昕
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Shandong Erye Pharmaceutical Co ltd
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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
    • 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
    • C07D499/18—Separation; Purification
    • C07D499/20—Separation; Purification via salts with organic bases
    • 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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Abstract

本公开提供了一种氯唑西林钠的制备工艺，包括以下步骤：将6‑氨基青霉烷酸与10％的氢氧化钠反应生成6‑氨基青霉烷酸钠；使6‑氨基青霉烷酸钠与邻氯酰氯发生缩合反应；然后加入稀硫酸酸化；并加入成盐剂异辛酸钠生成氯唑西林钠；过滤结晶得到产物氯唑西林钠。

Figure 202010082794

The present disclosure provides a preparation process of cloxacillin sodium, comprising the following steps: reacting 6-aminopenicillic acid with 10% sodium hydroxide to generate sodium 6-aminopenicillin; making 6-aminopenicillin Sodium alkanoate and o-chloroacyl chloride undergo condensation reaction; then add dilute sulfuric acid for acidification; and add salt-forming agent sodium isooctanoate to generate cloxacillin sodium; filter and crystallize to obtain product cloxacillin sodium.

Figure 202010082794

Description

Preparation process of cloxacillin sodium
Technical Field
The disclosure relates to a medicine in the field of medicine, in particular to a preparation process of cloxacillin sodium.
Background
Cloxacillin Sodium (Cloxacillin Sodium), also called Cloxacillin Sodium, has the chemical name: (2S,5R,6R) -3, 3-dimethyl-6- [ 5-methyl-3- (2-chlorophenyl) -4-isoxazolecarboxamido) -7-oxo-4-thia-1-azabicyclo [3.2.0]Heptane-2-carboxylic acid sodium salt; the molecular formula is as follows: c19H17ClN3NaO5S; molecular weight: 457.87, respectively; the structural formula is shown as formula I:
Figure BDA0002380907980000011
cloxacillin sodium white powder or crystalline powder; slightly smelly, bitter in taste and hygroscopic in nature. Is very soluble in water, is easy to dissolve in ethanol and is hardly soluble in ethyl acetate.
The cloxacillin sodium is acid-resistant and enzyme-resistant isoxazole antibiotic, has strong antibacterial activity, can inhibit the synthesis of cell walls, and has high oral absorption rate and high protein binding rate up to 98%. The product is semi-synthetic penicillin, has acid resistance and penicillinase resistance, has antibacterial activity against gram-positive coccus and neisseria, has stronger antibacterial activity against staphylococcus (including staphylococcus aureus and coagulase-negative staphylococcus) enzyme-producing strains than oxacillin, has weaker antibacterial action against penicillin-sensitive staphylococcus and various streptococcus than penicillin, and has no effect on methicillin-resistant staphylococcus.
The compound is clinically applicable to the penicillin-producing staphylococcus infection, including septicemia, endocarditis, pneumonia, skin and soft tissue infection and the like. Can also be used for treating mixed infection caused by Streptococcus pyogenes or Streptococcus pneumoniae and penicillin-resistant staphylococcus.
The cloxacillin sodium injection is used for intramuscular injection of 0.5g of cloxacillin, and the blood drug peak concentration (Cmax) is reached within 0.5 hour and is 15 mg/L. 0.75g of cloxacillin is intravenously instilled for 3 hours, and the blood concentration is 15mg/L and 0.6mg/L respectively immediately after the instillation and after 3 hours. The product has a serum protein binding rate of 94%, and can permeate into bone tissue, pus and joint cavity hydrops of patients with acute osteomyelitis, and also has high concentration in pleural effusion. It also penetrates through the placenta and into the fetus, but is difficult to penetrate through the normal blood-cerebrospinal fluid barrier. The blood elimination half-life period (t1/2) of cloxacillin is 0.5-1.1 hours, the cloxacillin is mainly discharged from urine through glomerular filtration and renal tubular secretion, about 62 percent of cloxacillin is discharged from urine and about 6 percent of cloxacillin is discharged from bile after intravenous drip of the cloxacillin, and a small amount of cloxacillin is metabolized in liver.
The invention with the application number of CN201010603242.1 relates to a method for preparing crystals of cloxacillin sodium, which comprises the steps of adding 0.03g/mL-0.2g/mL sodium isooctanoate-alcohol solution into 0.1-0.2g/mL cloxacillin acid solution at the temperature of 5-25 ℃ while stirring, and carrying out reaction crystallization, wherein the pH value at the end point of the reaction process is 5.5-7.5; then adding an ester or ether elution agent with the volume 7-11 times that of the cloxacillin acid solution into the solution for elution crystallization; and after crystallization, carrying out centrifugal separation, solvent washing and drying on the crystal mush to obtain a cloxacillin sodium product.
In the research process, the method of the prepared patent document is repeated to obtain cloxacillin sodium, on one hand, the cost is high, the moisture absorption of the crude product is serious, and great inconvenience is brought to production, packaging and storage; on the one hand, the stability is poor and the impurities are more.
The inventor unexpectedly obtains a cloxacillin sodium compound with high purity and low total impurity content through a large number of tests; the stability is good, and the moisture absorption weight gain is not obvious even under the high humidity condition; the prepared injection has good stability.
Disclosure of Invention
The invention aims to provide a novel preparation process of cloxacillin sodium, so that the product quality and stability of cloxacillin sodium can be effectively improved, the impurity content is reduced, the production cost is reduced, and the production period is shortened.
In order to solve at least one of the above technical problems, the present disclosure provides a process for preparing cloxacillin sodium, comprising the following steps:
(1) dissolving 6-aminopenicillanic acid in purified water, and dropwise adding 10% sodium hydroxide to generate 6-aminopenicillanic acid sodium;
(2) adding o-chloro-chloride into an organic solvent, and stirring until the o-chloro-chloride is completely dissolved;
(3) mixing the components (1) and (2), dropwise adding a dilute sulfuric acid solution to adjust the pH value to be 2.8-3.2, and stirring to perform a condensation reaction;
(4) adding an organic solvent into the mixture obtained in the step (3), dropwise adding a dilute sulfuric acid solution for acidification, adjusting the pH value to 2.0-2.5, and standing for 30 minutes;
(5) adding a salt forming agent sodium isooctanoate into the mixture obtained in the step (4) in the presence of an organic solvent;
(6) and stirring for crystallization, and filtering to obtain cloxacillin sodium crystals.
Further, the mass ratio of the 6-aminopenicillanic acid to the o-chloroacyl chloride is 1: 1.2-1.5.
Further, the mass ratio of the 6-aminopenicillanic acid to the sodium isooctanoate is 1: 1.0-1.5.
Further, the concentration of the dilute sulfuric acid solution is 10% -70%.
Further, the organic solvent is selected from the group consisting of: methyl acetate, ethyl acetate, butyl acetate, propyl acetate, pentane, tetrahydrofuran, dichloromethane, dimethylformamide, acetonitrile and mixtures thereof.
Further, the organic solvent is preferably selected from the group consisting of: methyl acetate, ethyl acetate, butyl acetate, propyl acetate and mixtures thereof.
Further, in the step (1), the reaction temperature is 15 to 17 ℃.
Further, in the step (2), the temperature is controlled to be 36-38 ℃.
Further, in the step (3), the reaction temperature is 24-28 ℃ and the reaction time is 90 +/-10 minutes.
Further, in the step (5), the temperature is controlled to be 35 to 40 ℃.
Further, in the step (6), the temperature is controlled to be 0-5 ℃, the mixture is stirred for 2-6 hours, filtered, washed twice by using an organic solvent, and dried in vacuum at 40-60 ℃ to obtain cloxacillin sodium crystals.
Further, the method is characterized by also comprising the steps of crushing the cloxacillin sodium crystals and sieving the crushed cloxacillin sodium crystals by a 40-100-mesh sieve.
Drawings
The accompanying drawings, which are included to provide a further understanding of the disclosure and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the disclosure and together with the description serve to explain the principles of the disclosure.
Figure 1 shows a process flow diagram for the preparation of cloxacillin sodium.
Detailed Description
The present disclosure will be described in further detail with reference to the drawings and embodiments. It is to be understood that the specific embodiments described herein are for purposes of illustration only and are not to be construed as limitations of the present disclosure. It should be further noted that, for the convenience of description, only the portions relevant to the present disclosure are shown in the drawings.
It should be noted that the embodiments and features of the embodiments in the present disclosure may be combined with each other without conflict. The present disclosure will be described in detail below with reference to the accompanying drawings in conjunction with embodiments.
In a preferred embodiment, the present disclosure discloses a process for preparing cloxacillin sodium, comprising the following route:
(1) reacting 6-aminopenicillanic acid with sodium hydroxide to generate 6-aminopenicillanic acid sodium;
Figure BDA0002380907980000041
(2) condensing 6-amino penicillanic acid sodium and o-chloro chloride in the presence of organic solvent to obtain the compound in the formula III;
Figure BDA0002380907980000042
(3) dropwise adding a dilute sulfuric acid solution into the compound of the formula III in the presence of an organic solvent to obtain a compound of a formula IV;
Figure BDA0002380907980000043
(4) adding a salt forming agent sodium isooctanoate into the compound of the formula IV, and obtaining the compound of the formula V in the presence of an organic solvent.
Figure BDA0002380907980000051
Further, the mass ratio of the 6-aminopenicillanic acid to the o-chloroacyl chloride is 1: 1.0-1.5.
Further, the mass ratio of the 6-aminopenicillanic acid to the sodium isooctanoate is 1: 1.0-1.5.
Further, the concentration of the dilute sulfuric acid solution is 10% -70%.
The organic solvent is not particularly limited, and there may be mentioned, for example, methyl acetate, ethyl acetate, butyl acetate, propyl acetate, pentane, tetrahydrofuran, dichloromethane, dimethylformamide, acetonitrile or a mixture thereof; preferably selected from the group consisting of: methyl acetate, ethyl acetate, butyl acetate, propyl acetate or mixtures thereof.
The organic solvent may be 1 kind, or a mixture of 2 or more kinds.
In a preferred embodiment, the compound of formula V obtained in the above scheme (4) is washed twice with an organic solvent and dried under vacuum at 40-60 ℃ to obtain the finished cloxacillin sodium.
In a preferred embodiment, the method also comprises the step of crushing the cloxacillin sodium finished product and sieving the crushed cloxacillin sodium finished product through a 40-100-mesh sieve.
Examples
The following disclosed examples illustrate the present invention in more detail, however, the present invention is not limited to these examples.
Example 1
(1) Adding 900L of purified water into a condensation reaction tank, cooling to 15-17 deg.C, adding 80kg of 6-aminopenicillanic acid (6-APA), stirring, and adding 10% sodium hydroxide solution to completely dissolve 6-aminopenicillanic acid.
(2) Adding 600L of butyl acetate into the primary extraction tank, controlling the temperature to be 36-38 ℃, adding 96kg of o-chlorocarbonyl chloride, and stirring until the o-chlorocarbonyl chloride is completely dissolved;
(3) sucking the feed liquid in the primary extraction tank into a condensation tank, controlling the temperature to be 24-28 ℃, reacting for 90 +/-10 minutes, and dropwise adding a dilute sulfuric acid solution to adjust the pH value to be 2.8-3.2;
(4) stirring was stopped, the mixture was allowed to stand for 15 minutes, and the lower aqueous solution was sucked into a secondary extraction tank. Adding 600L of butyl acetate, dropwise adding dilute sulfuric acid, adjusting the pH value to 2.0-2.5, standing for 30 minutes, and discharging lower-layer wastewater into a sewage treatment station through a wastewater pipe network;
(5) mixing the primary extractive solution with the secondary extractive solution, adding 1.5kg medicinal active carbon, stirring, decolorizing for 10 min, sterilizing, and filtering to obtain filtrate;
(6) adding 500L butyl acetate into a salt forming agent preparation tank, controlling the temperature to be 35-40 ℃, adding 100kg sodium isooctanoate, stirring for dissolving, sterilizing and filtering to a crystallizing tank;
(7) stirring for crystallization, controlling the temperature to be 0-5 ℃, stirring for 4h, filtering, washing twice by 300L ethyl acetate, and drying in vacuum at 40 ℃ to obtain a finished product. Pulverizing, sieving with 40 mesh sieve, and packaging into sterilized aluminum barrel.
Example 2
(1) Adding 900L of purified water into a condensation reaction tank, cooling to 15-17 deg.C, adding 80kg of 6-aminopenicillanic acid (6-APA), stirring, and adding 10% sodium hydroxide solution to completely dissolve 6-aminopenicillanic acid.
(2) Adding 600L of butyl acetate into the primary extraction tank, controlling the temperature to be 36-38 ℃, adding 110kg of o-chlorocarbonyl chloride, and stirring until the o-chlorocarbonyl chloride is completely dissolved;
(3) sucking the feed liquid in the primary extraction tank into a condensation tank, controlling the temperature to be 24-28 ℃, reacting for 90 +/-10 minutes, and dropwise adding a dilute sulfuric acid solution to adjust the pH value to be 2.8-3.2;
(4) stirring was stopped, the mixture was allowed to stand for 15 minutes, and the lower aqueous solution was sucked into a secondary extraction tank. Adding 600L of butyl acetate, dropwise adding dilute sulfuric acid, adjusting the pH value to 2.0-2.5, standing for 30 minutes, and discharging lower-layer wastewater into a sewage treatment station through a wastewater pipe network;
(5) mixing the primary extractive solution with the secondary extractive solution, adding 1.5kg medicinal active carbon, stirring, decolorizing for 10 min, sterilizing, and filtering to obtain filtrate;
(6) adding 500L of butyl acetate into a salt forming agent preparation tank, controlling the temperature to be 35-40 ℃, adding 80kg of sodium isooctanoate, stirring for dissolving, sterilizing and filtering to a crystallization tank;
(7) stirring for crystallization, controlling the temperature to be 0-5 ℃, stirring for 4h, filtering, washing twice by 300L ethyl acetate, and vacuum drying at 50 ℃ to obtain a finished product. Pulverizing, sieving with 70 mesh sieve, and packaging in sterilized aluminum barrel.
Example 3
(1) Adding 900L of purified water into a condensation reaction tank, cooling to 15-17 deg.C, adding 80kg of 6-aminopenicillanic acid (6-APA), stirring, and adding 10% sodium hydroxide solution to completely dissolve 6-aminopenicillanic acid.
(2) Adding 600L of butyl acetate into the primary extraction tank, controlling the temperature to be 36-38 ℃, adding 120kg of o-chlorocarbonyl chloride, and stirring until the o-chlorocarbonyl chloride is completely dissolved;
(3) sucking the feed liquid in the primary extraction tank into a condensation tank, controlling the temperature to be 24-28 ℃, reacting for 90 +/-10 minutes, and dropwise adding a dilute sulfuric acid solution to adjust the pH value to be 2.8-3.2;
(4) stirring was stopped, the mixture was allowed to stand for 15 minutes, and the lower aqueous solution was sucked into a secondary extraction tank. Adding 600L of butyl acetate, dropwise adding dilute sulfuric acid, adjusting the pH value to 2.0-2.5, standing for 30 minutes, and discharging lower-layer wastewater into a sewage treatment station through a wastewater pipe network;
(5) mixing the primary extractive solution with the secondary extractive solution, adding 1.5kg medicinal active carbon, stirring, decolorizing for 10 min, sterilizing, and filtering to obtain filtrate;
(6) adding 500L of butyl acetate into a salt forming agent preparation tank, controlling the temperature to be 35-40 ℃, adding 120kg of sodium isooctanoate, stirring for dissolving, sterilizing and filtering to a crystallization tank;
(7) stirring for crystallization, controlling the temperature to be 0-5 ℃, stirring for 4h, filtering, washing twice by 300L ethyl acetate, and vacuum drying at 60 ℃ to obtain a finished product. Pulverizing, sieving with 100 mesh sieve, and packaging in sterilized aluminum barrel.
Comparative example 1
Taking 800mL of 0.1g/mL cloxacillin acid butyl acetate-water solution with the water content of 1%, stirring and dropwise adding 0.03g/mL sodium isooctanoate methanol solution at the temperature of 10 ℃, and controlling the end point pH value of the reaction process to be 6.5. Then 7200mL of butyl acetate is dripped into the reacted cloxacillin sodium solution at the temperature of 10 ℃, the dripping speed is 360mL/h, and elution crystallization is carried out. After the crystallization, the crystals were centrifuged, washed with acetone, and dried at 20 ℃ under a vacuum of 0.03MPa for 5 hours. The final crystal product had a content of 99.4% and a pH of 5.7.
Example 4 Long term stability test
Batch production: 100 bottles, specification: 1.25 g/bottle, package: penicillin bottle
Examination conditions were as follows: 25 plus or minus 2 ℃/60 plus or minus 10% RH;
the results are shown in Table 1 below, which shows the results of the long-term stability test.
TABLE 1 Long term stability test results
Figure BDA0002380907980000081
Long-term stability tests show that the cloxacillin sodium compound disclosed by the invention has good stability in the preparation and storage processes, and the curative effect and safety of clinical use are ensured.
Because the vacuum drying technology is adopted, the obtained product of the present disclosure has the advantages of high stability, small side effect, good encapsulation efficiency maintenance and convenient product transportation and storage.
In the description herein, reference to the description of the terms "one embodiment/mode," "some embodiments/modes," "example," "specific example," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment/mode or example is included in at least one embodiment/mode or example of the application. In this specification, the schematic representations of the terms used above are not necessarily intended to be the same embodiment/mode or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments/modes or examples. Furthermore, the various embodiments/aspects or examples and features of the various embodiments/aspects or examples described in this specification can be combined and combined by one skilled in the art without conflicting therewith.
It will be understood by those skilled in the art that the foregoing embodiments are merely for clarity of illustration of the disclosure and are not intended to limit the scope of the disclosure. Other variations or modifications may occur to those skilled in the art, based on the foregoing disclosure, and are still within the scope of the present disclosure.

Claims (11)

1.一种氯唑西林钠的制备工艺，其特征在于，包括以下步骤：1. a preparation technique of cloxacillin sodium, is characterized in that, comprises the following steps: (1)将6-氨基青霉烷酸溶于纯化水中，滴加10％的氢氧化钠，生成6-氨基青霉烷酸钠；(1) 6-aminopenicillic acid is dissolved in purified water, and 10% sodium hydroxide is added dropwise to generate sodium 6-aminopenicillanoic acid; (2)在有机溶剂中加入邻氯酰氯，搅拌至完全溶解；(2) in organic solvent, add o-chloroacyl chloride, stir to dissolve completely; (3)将(1)与(2)混合在一起，滴加稀硫酸溶液调节pH值2.8-3.2之间，搅拌使其发生缩合反应；(3) mixing (1) and (2) together, adding dilute sulfuric acid solution dropwise to adjust the pH value between 2.8-3.2, stirring to make it condensation reaction; (4)向(3)中加入有机溶剂，并滴加稀硫酸溶液酸化，调节pH值2.0-2.5，静置30分钟；(4) in (3), add organic solvent, and dropwise add dilute sulfuric acid solution to acidify, adjust pH value 2.0-2.5, stand for 30 minutes; (5)在有机溶剂的存在下，向(4)中加入成盐剂异辛酸钠；(5) in the presence of organic solvent, in (4), add salt-forming agent sodium isooctanoic acid; (6)搅拌结晶，过滤得到氯唑西林钠晶体。(6) stirring to crystallize, and filtering to obtain cloxacillin sodium crystals. 2.根据权利要求1所述的制备工艺，其特征在于，6-氨基青霉烷酸和邻氯酰氯的质量比为1:1.0-1.5。2. preparation technology according to claim 1 is characterized in that, the mass ratio of 6-aminopenicillic acid and o-chloroacyl chloride is 1:1.0-1.5. 3.根据权利要求1所述的制备工艺，其特征在于，6-氨基青霉烷酸与异辛酸钠的质量比为1:1.2-1.5。3. preparation technology according to claim 1 is characterized in that, the mass ratio of 6-aminopenicillic acid and sodium isooctanoic acid is 1:1.2-1.5. 4.根据权利要求1所述的制备工艺，其特征在于，所述稀硫酸溶液的浓度为10％-70％。4. The preparation process according to claim 1, wherein the concentration of the dilute sulfuric acid solution is 10%-70%. 5.根据权利要求1所述的制备工艺，其特征在于，所述有机溶剂选自下组：乙酸甲酯、乙酸乙酯、乙酸丁酯、乙酸丙酯、戊烷、四氢呋喃、二氯甲烷、二甲基甲酰胺、乙腈及其混合物；优选地选自下组：乙酸甲酯、乙酸乙酯、乙酸丁酯、乙酸丙酯及其混合物。5. preparation technique according to claim 1 is characterized in that, described organic solvent is selected from following group: methyl acetate, ethyl acetate, butyl acetate, propyl acetate, pentane, tetrahydrofuran, dichloromethane, Dimethylformamide, acetonitrile and mixtures thereof; preferably selected from the group consisting of methyl acetate, ethyl acetate, butyl acetate, propyl acetate and mixtures thereof. 6.根据权利要求1所述的制备工艺，其特征在于，在步骤(1)中，反应温度为15-17℃。6 . The preparation process according to claim 1 , wherein, in step (1), the reaction temperature is 15-17° C. 7 . 7.根据权利要求1所述的制备工艺，其特征在于，在步骤(2)中，控制温度为36-38℃。7 . The preparation process according to claim 1 , wherein, in step (2), the temperature is controlled to be 36-38° C. 8 . 8.根据权利要求1所述的制备工艺，其特征在于，在步骤(3)中，反应温度为24-28℃，反应时间90±10分钟。8 . The preparation process according to claim 1 , wherein, in step (3), the reaction temperature is 24-28° C., and the reaction time is 90±10 minutes. 9 . 9.根据权利要求1所述的制备工艺，其特征在于，在步骤(5)中，控制温度为35-40℃。9 . The preparation process according to claim 1 , wherein, in step (5), the temperature is controlled to be 35-40° C. 10 . 10.根据权利要求1所述的制备工艺，其特征在于，在步骤(6)中，控温0-5℃搅拌2-6h，过滤，用有机溶剂洗涤两次，40-60℃真空干燥得到氯唑西林钠晶体。10. The preparation process according to claim 1, characterized in that, in step (6), the temperature is controlled at 0-5°C and stirred for 2-6h, filtered, washed twice with an organic solvent, and vacuum-dried at 40-60°C to obtain Cloxacillin sodium crystals. 11.根据权利要求10所述的制备工艺，其特征在于，还包括将所述氯唑西林钠晶体粉碎并过40-100目筛。11. The preparation process according to claim 10, further comprising pulverizing the cloxacillin sodium crystals and passing through a 40-100 mesh sieve.
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