CN111606870A - Linezolid-related substance and preparation method and application thereof - Google Patents
Linezolid-related substance and preparation method and application thereof Download PDFInfo
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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Abstract
The invention belongs to the technical field of drug synthesis, and discloses a linezolid related substance as well as a preparation method and application thereof. The related substance is compound I with chemical formula C17H24FN3O4The preparation method comprises the following steps: s1, synthesis of a compound C: adding the compound A, the compound B, ethanol and water into a reaction bottle, and stirring for reaction to obtain a compound C; s2, synthesis of a compound D: adding the compound C and an organic solvent into a reaction bottle, and adding hydrazine hydrate for reaction under stirring to obtain a compound D; s3, synthesis of a compound I: and dissolving the compound D in an organic solvent, adding acetic anhydride, and stirring for reaction to obtain a compound I. The preparation method provided by the invention has the advantages of short reaction route, mild condition, high yield and high purity. The compound I disclosed by the invention can be used as a standard reference substance for controlling and researching the quality of linezolid in the preparation process.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a linezolid related substance as well as a preparation method and application thereof.
Background
Linezolid (Linezolid) is an oxazolidinone antibiotic developed by Pharmacia under feverent, chemical name: (S) -N- [ [3- [ 3-fluoro-4- (4-morpholinyl) phenyl ] -2-oxo-5-oxazolidinyl ] methyl ] acetamide, having the trade name Sporo (Zyvox) and having the structural formula shown below. Linezolid is a bacterial protein synthesis inhibitor, and is mainly used for treating infections caused by gram-positive (G +) cocci, including suspected or confirmed nosocomial pneumonia (HAP), community-acquired pneumonia (CAP), complex skin or Skin Soft Tissue Infections (SSTI), and vancomycin-resistant enterococci (VRE) infections caused by methicillin-resistant staphylococcus aureus (MRSA). The chemical formula of linezolid is as follows.
Various impurities are generated in the preparation process of the medicine, and the type and the content of the impurities can have important influence on the quality of the medicine. With the continuous research on the preparation process of linezolid, more and more impurities were found, as shown by L1-L6. The discovery and research of the impurities play an important role in the quality control and improvement of linezolid.
The literature (fine and specialty chemicals, 2016, 24 (08): 36-38) reports a synthetic method for linezolid, the route of which is shown below:
when the applicant carries out the synthesis of linezolid according to the above route, the target product is found to contain a new related substance I. The applicant analyzed the source of this impurity: in the above document, intermediate 5 is acylated with acetyl chloride to prepare intermediate 6, and both amine groups in intermediate 5 can react with acetyl chloride due to its high acylation activity, thereby producing related substance I. The content of the novel related substance in the linezolid medicament is determined by the inventor through a series of means, and the content of the related substance in a plurality of batches exceeds the identification limit of 0.15%. Therefore, the confirmation of the chemical structure and the preparation method of the related substances has important significance for subsequent safety evaluation and quality control research in the preparation process of linezolid.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a linezolid related substance and a preparation method and application thereof.
In order to solve the problems, the technical scheme of the invention is as follows: the invention provides a linezolid related substance, which is a compound I and has a structural formula as follows:
the chemical formula is as follows: c17H24FN3O4Molecular weight: 353.17.
the invention also provides a preparation method of the linezolid related substance, which adopts the following synthetic route:
preferably, the preparation method comprises the following steps:
s1, synthesis of a compound C: adding the compound A, the compound B, ethanol and water into a reaction bottle, stirring for reaction, detecting until the compound A disappears, standing, leaching when solid is separated out, washing a filter cake, and drying to obtain a compound C;
s2, synthesis of a compound D: adding the compound C and an organic solvent into a reaction bottle, adding hydrazine hydrate under stirring for reaction, detecting until the compound C disappears, cooling the system temperature to room temperature, performing suction filtration, washing a filter cake, and removing a filtrate to obtain a compound D;
s3, synthesis of a compound I: dissolving the compound D in an organic solvent, adding acetic anhydride, stirring for reaction, detecting until the compound D disappears, removing the organic solvent, and purifying by column chromatography to obtain the compound I.
More preferably, in step S1, the stirring reaction temperature is controlled at 80 ℃, the temperature of the system is reduced to 0 ℃ after the compound a disappears, and then the system is left to stand.
Most preferably, the following steps of step S1 are specifically: standing overnight, separating out solid, filtering, washing filter cake with small amount of cold ethanol, and vacuum drying the filter cake.
More preferably, in the step S1, the molar ratio of the compound a to the compound B is 1:1.1, and the volume ratio of ethanol to water is 9: 1; for every 1g of Compound A, 9mL of ethanol were added.
More preferably, in step S2, the organic solvent is one or more of methanol, ethanol, isopropanol, tetrahydrofuran, 1, 4-dioxane and chloroform; 10-20 mL of organic solvent is added to 1g of compound C.
More preferably, in the step S2, 80% by weight of hydrazine hydrate is selected, the molar ratio of the compound C to the hydrazine hydrate is 1: 3-8, and the reaction temperature is controlled to be 40-100 ℃.
Most preferably, in step S2, the organic solvent is ethanol.
Most preferably, in the step S2, 15 to 20mL of organic solvent is added per 1g of the compound C. In the step S2, the molar ratio of the compound C to the hydrazine hydrate is 1: 5-6, and the reaction temperature is controlled to be 80-85 ℃.
Most preferably, the following steps of step S2 are specifically: the filter cake was washed with dichloromethane and the filtrate was evaporated off under reduced pressure.
More preferably, in step S3, the organic solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, 1, 4-dioxane, diethyl ether and methyl tert-butyl ether; adding 8-15 mL of organic solvent into 1g of compound D.
More preferably, in the step S3, the molar ratio of the compound D to the acetic anhydride is 1:2 to 3, and the reaction temperature is controlled at 0 ℃.
Most preferably, in step S3, the organic solvent is tetrahydrofuran.
Most preferably, in the step S3, 10 to 12mL of organic solvent is added per 1g of the compound D. In the step S3, the molar ratio of the compound D to the acetic anhydride is 1: 2-2.2. Removing the organic solvent by reduced pressure evaporation.
The invention also protects the application of the linezolid related substance in the quality control of medicines as a reference substance and in the research and development of medicines.
The invention has the beneficial effects that: firstly, the invention discovers that the prior linezolid can generate a new related substance compound I in the synthesis process for the first time, and provides a foundation for further improving the quality control of the prior linezolid preparation process; secondly, the structure of the substance is confirmed, and the related substance I can be used as a standard substance, so that the quality standard of linezolid is expected to be further improved; finally, the invention also provides a preparation method of the related substance compound I, which has the advantages of short route, high yield and high purity and provides an important material basis for subsequent safety evaluation of the compound I and quality control in the preparation process of linezolid.
Detailed Description
The principles and features of this invention are described below in conjunction with examples which are set forth to illustrate, but are not to be construed to limit the scope of the invention.
The linezolid related substance is a compound I, and the structural formula is as follows:
the chemical formula is as follows: c17H24FN3O4Molecular weight: 353.17.
the linezolid-related substance is generated when linezolid is synthesized based on a method reported in the literature (fine and specialty chemicals, 2016, 24 (08): 36-38). The inventor selects different parameters according to the synthesis method of the document, performs more than 20 times of synthesis experiments, and measures the impurity content of the synthesized linezolid, wherein the content of the related substances in the linezolid exceeds the impurity limit of 0.15%.
The invention provides a preparation method of linezolid related substances, which adopts the following synthetic route:
the preparation method of the invention specifically comprises the following steps:
s1, synthesis of a compound C: adding the compound A, the compound B, ethanol and water into a reaction bottle, stirring for reaction, detecting by TLC until the compound A disappears, standing, leaching when solid is separated out, washing a filter cake, and drying to obtain a compound C;
s2, synthesis of a compound D: adding the compound C and an organic solvent into a reaction bottle, adding hydrazine hydrate under stirring for reaction, detecting by TLC until the compound C disappears, cooling the system temperature to room temperature, performing suction filtration, washing a filter cake, and removing a filtrate to obtain a compound D;
s3, synthesis of a compound I: dissolving the compound D in an organic solvent, adding acetic anhydride, stirring for reaction, detecting by TLC until the compound D disappears, removing the organic solvent, and purifying by column chromatography to obtain the compound I.
In some preferred embodiments, the step S1 specifically includes the following operations: the stirring reaction temperature is controlled at 80 ℃, the temperature of the system is reduced to 0 ℃ after the compound A disappears, and then the system is kept stand.
More preferably, the specific steps of the subsequent processing in step S1 are: standing overnight, separating out solid, filtering, washing filter cake with small amount of cold ethanol, and vacuum drying the filter cake.
After the research of the inventor, the reaction temperature is controlled to be 80 ℃, and the reaction efficiency is highest. And the subsequent cooling can be more favorable for the precipitation of the solid, and the lower the temperature is, the larger the precipitation amount of the solid is. When the precipitation amount of the solid reaches the maximum value at 0 ℃, the temperature is continuously reduced, and impurities are precipitated together. And cold ethanol is adopted to clean the filter cake, so that residual mother liquor on the surface of the sample can be removed, and the filter cake can be prevented from being dissolved in the cleaning process to cause loss.
After the detailed research on the reaction conditions by the inventor, the reaction temperature of 70-85 ℃ is reduced to 0-8 ℃ subsequently, the reaction efficiency and the impurity content of the final product can be controlled in a relatively proper range, the reaction time can be controlled within 20 hours, the purity of the final product can be controlled to be more than 85%, and the requirement of subsequent synthesis can be well met.
In some preferred embodiments, in step S1, the molar ratio of compound a to compound B is 1:1.1, and the volume ratio of ethanol to water is 9: 1; for every 1g of Compound A, 9mL of ethanol were added.
The above reaction parameters are the optimum reaction parameters in step S1. Can ensure the lowest feeding loss, the highest yield and the lowest impurity amount.
In some preferred embodiments, in the step S2, the organic solvent is one or more of methanol, ethanol, isopropanol, tetrahydrofuran, 1, 4-dioxane and chloroform; 10-20 mL of organic solvent is added to 1g of compound C.
More preferably, in step S2, the organic solvent is ethanol. Adding 15-20 mL of organic solvent into 1g of compound C.
The selection of the organic solvent and the control of the addition amount can ensure that the content of reaction impurities is in a lower level and the organic solvent is not wasted on the premise of ensuring that the compound C is effectively dissolved. In addition, the inventor also finds that when the adding ratio of 15-20 mL of organic solvent is added to every 1g of compound C, the subsequent filtration and cleaning processes are more convenient, and the yield of the final reaction product can be improved. The inventors have studied and considered that the use of an excessive amount of the organic solvent may cause a part of the final reaction product to be dissolved in the system, or the excess amount of the organic solvent may cause a change in the equilibrium of the reaction system, may generate a part of impurities, and may cause a decrease in yield.
More preferably, in the step S2, 80% by weight of hydrazine hydrate is selected, the molar ratio of the compound C to the hydrazine hydrate is 1: 3-8, and the reaction temperature is controlled to be 40-100 ℃.
In the step S2, the molar ratio of the compound C to the hydrazine hydrate is 1: 5-6, and the reaction temperature is controlled to be 80-85 ℃.
The inventors have studied the synthesis conditions of this scheme and found that the reaction temperature and the ratio of reactants have a large influence on the results of the synthesis.
Under other conditions with better parameters, the final yield can reach more than 70 percent under the condition that the molar ratio of the compound C to the hydrazine hydrate is 1: 3-8. With the change of the mixture ratio, when the molar ratio of the compound C to the hydrazine hydrate is changed from 1:3 to 1:5, the yield of the final compound D is in an increasing trend, and the yield is higher and higher. When the molar ratio of the compound C to the hydrazine hydrate is controlled to be 1: 5-6, the yield of the final compound D can reach more than 92%. When the molar ratio of compound C to hydrazine hydrate is varied from 1:6 to 1:8, the yield of the final compound D tends to decrease.
And when other conditions are in better parameters, the yield of the final compound D can reach more than 72 percent when the reaction temperature is controlled within the range of 40-100 ℃. When the reaction temperature is varied from 40 ℃ to 80 ℃, the yield of the final compound D tends to increase and the reaction time tends to decrease. When the reaction temperature is controlled within the range of 80-85 ℃, the yield of the final compound D can reach more than 93 percent. When the reaction temperature was changed from 85 ℃ to 100 ℃, the yield of the final compound D tended to decrease.
After the detailed research on the reaction conditions by the inventor, the reaction temperature of 70-90 ℃, the reaction efficiency and the yield can be controlled in a relatively proper range, the reaction time can be controlled within 8 hours, the yield can be controlled to be more than 80%, and the requirements of subsequent synthesis can be well met.
Most preferably, the following steps of step S2 are specifically: the filter cake was washed with dichloromethane and the filtrate was evaporated off under reduced pressure.
In some preferred embodiments, in the step S3, the organic solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, 1, 4-dioxane, diethyl ether and methyl tert-butyl ether; adding 8-15 mL of organic solvent into 1g of compound D.
More preferably, in step S3, the organic solvent is tetrahydrofuran. In the step S3, 10 to 12mL of an organic solvent is added to 1g of the compound D.
The mechanism of selecting the parameters and controlling the amount of the organic solvent to be added is the same as that described in step 2.
In some preferred embodiments, in step S3, the molar ratio of compound D to acetic anhydride is 1:2 to 3, and the reaction temperature is controlled at 0 ℃.
More preferably, in the step S3, the molar ratio of the compound D to the acetic anhydride is 1:2 to 2.2.
The inventors have studied the synthesis conditions of this scheme and found that the reaction temperature and the ratio of reactants have a large influence on the results of the synthesis.
After the research on the reaction temperature, the inventor finds that the purity of the product is higher when the acetic anhydride is added below 0 ℃, and the purity of the product is obviously reduced when the temperature of the added acetic anhydride is higher than 5 ℃. After the acetic anhydride is added, the reaction at room temperature can ensure that the reaction progress time is relatively short, the purity is high, and when the temperature is higher than 35 ℃, the reaction time is shortened, but reaction impurities are more, and the yield is reduced.
And the inventor finds that when other reaction conditions are in the optimal parameters and the molar ratio of the compound D to the acetic anhydride is more than 1:2, the reaction can be completely carried out, otherwise, the compound D remains after the reaction. When the molar ratio of the compound D to the acetic anhydride is in the range of 1:2 to 1:2.2, the yield of the final compound I can reach more than 93 percent. When the molar ratio of the compound D to the acetic anhydride is increased from 1:2.2 to 1:3, the yield of the compound I is gradually reduced, and when the molar ratio is increased to 1:3, the yield is reduced to about 85%. When the molar ratio of the compound D to acetic anhydride exceeds 1:3, the yield of the final compound I tends to decrease in a stepwise manner. It is mainly the excess of acetic anhydride that may react with the bare hydroxyl groups in the structure, resulting in a drastic increase in the impurity content in the final product.
In some preferred embodiments, in step S3, the organic solvent may be removed by evaporation under reduced pressure.
The inventor researches the whole synthesis process and finds that the yield of the final product compound I can stably reach more than 80% when the reaction temperature of 70-85 ℃ is adopted in the step S1, the temperature is subsequently reduced to 0-8 ℃ to precipitate solid, the reaction temperature of 70-90 ℃ is adopted in the step S2, and the acetic anhydride is added at 0-5 ℃ in the step S3. The inventor can confirm that three-step accurate temperature control is a more central technical point of the synthesis method through experimental data analysis. Although the yield of the step and the purity of the intermediate product can be ensured by the accurate temperature control of the single step, the yield and the purity of the final product of the whole process are higher, and the accurate temperature control of three steps is required to be ensured.
The progress of the above reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), and is generally at the end of the reaction when the starting materials have disappeared.
The following are specific embodiments of the invention
Example 1:
embodiment 1 of the present invention provides a preparation method of an intermediate C, and the synthetic route thereof is as follows:
the preparation method specifically comprises the following steps:
compound A (9.0g, 45.9mmol), compound B (10.3g, 50.5mmol), ethanol (81mL) and water (9mL) were added to a reaction flask, the reaction was stirred at 80 ℃ for 14h and the disappearance of starting material A was detected by TLC. The temperature of the system is reduced to 0 ℃, and the system is kept stand overnight, so that solid is separated out. And (5) carrying out suction filtration, washing a filter cake by using cold ethanol (5mL), and carrying out vacuum drying on the filter cake to obtain a compound C.
The preparation method is adopted to obtain 17.3g of white solid with the yield of 94.4%.
The identification of intermediate C prepared in this example gave the following results:
ESI-MS(m/z):400.2；
1H NMR(300MHz,DMSO-d6)7.81-7.89(m,4H),6.83(t,J＝9.0Hz,1H),6.40(dd,J＝23.3,11.9Hz,2H),5.54(t,J＝5.6Hz,1H),5.15(d,J＝4.5Hz,1H),3.92-4.02(m,1H),3.69(s,4H),3.61-3.64(m,2H),3.07-3.16(m,1H),2.92-3.00(m,1H),2.82(s,4H)。
example 2:
embodiment 2 of the present invention provides a preparation method of an intermediate D, which comprises the following synthetic route:
the preparation method specifically comprises the following steps:
compound C (8.0g, 20.0mmol) and ethanol (120mL) were added to a reaction flask, and 80% by mass of hydrazine hydrate (7.5g, 120.2mmol) was added with stirring, followed by reaction at 80 ℃ for 2h with stirring, and disappearance of compound C was detected by TLC. And (3) cooling the system to room temperature, carrying out suction filtration, washing a filter cake by using dichloromethane (15mL), and carrying out reduced pressure evaporation to remove a filtrate to obtain a compound D.
The yield of the white solid obtained by the method is 5.3g and 98.3 percent.
The identification of intermediate D prepared in this example gave the following results:
ESI-MS(m/z):270.3；
1H NMR(300MHz,DMSO-d6)6.82(m,1H),6.38(ddd,J＝11.8,11.0,2.4Hz,2H),5.46(s,1H),3.69(m,4H),3.50(dd,J＝10.9,5.7Hz,1H),3.19(s,4H),2.82(m,6H),2.61(dd,J＝12.8,4.7Hz,1H)。
example 3:
embodiment 3 of the present invention provides a preparation method of intermediate D:
compound C (7.0g, 17.5mmol) and tetrahydrofuran (110mL) were added to a reaction flask, 80% by mass of hydrazine hydrate (6.6g, 105.2mmol) was added with stirring, followed by reaction at 70 ℃ for 4h with stirring, and disappearance of compound C was detected by TLC. And (3) cooling the system to room temperature, carrying out suction filtration, washing a filter cake by using dichloromethane (15mL), and carrying out reduced pressure evaporation to remove a filtrate to obtain a compound D.
4.1g of white solid is obtained by the method, and the yield is 86.9%.
Example 4:
embodiment 4 of the present invention provides a preparation method of intermediate D:
compound C (7.2g, 18.0mmol) and dichloromethane (80mL) were added to a reaction flask, 80% by mass hydrazine hydrate (6.8g, 108.2mmol) was added with stirring, followed by reaction at 40 ℃ for 8h with stirring, and disappearance of compound C was detected by TLC. And (3) cooling the system to room temperature, carrying out suction filtration, washing a filter cake by using dichloromethane (15mL), and carrying out reduced pressure evaporation to remove a filtrate to obtain a compound D.
4.0g of white solid is obtained by the method, and the yield is 82.4%.
Example 5:
example 5 of the present invention provides a method for preparing compound I, the synthetic route of which is as follows:
the preparation method specifically comprises the following steps:
compound D (5.0g, 18.6mmol) was dissolved in tetrahydrofuran (50mL), acetic anhydride (4.2g, 40.8mmol) was added at 0 deg.C, and after the addition, the reaction was stirred at room temperature for 8h, and disappearance of compound D was detected by TLC. The organic solvent was evaporated under reduced pressure and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate and ═ 1:1, v/v) to give compound I.
6.3g of white solid obtained by the method is obtained, and the yield is 96.0%.
The compound I prepared in this example was identified with the following results:
ESI-MS(m/z):354.3；
1HNMR(400MHz,CDCl3)7.35(d,J＝13.6Hz,1H),7.20(d,J＝8.0Hz,1H),7.08(t,J＝9.1Hz,1H),6.46(s,1H),3.73-3.84(m,6H),3.41(dd,J＝13.4,5.9Hz,1H),3.02-3.05(m,4H),2.89-2.92(m,1H),2.60-2.64(m,1H),2.03(s,3H),1.75(s,3H).
example 6:
example 6 of the present invention provides a method of preparing compound I:
compound D (4.0g, 14.9mmol) was dissolved in 1, 4-dioxane (60mL), acetic anhydride (3.3g, 32.7mmol) was added at 0 deg.C, and after completion of addition, the reaction was stirred at room temperature for 10h, and disappearance of compound D was detected by TLC. The organic solvent was evaporated under reduced pressure and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate and ═ 1:1, v/v) to give compound I.
4.8g of white solid obtained by the method is obtained, and the yield is 91.5%.
Example 7:
example 7 of the present invention provides a process for the preparation of compound I:
compound D (4.5g, 16.7mmol) was dissolved in tetrahydrofuran (45mL), acetic anhydride (4.3g, 41.8mmol) was added at 0 deg.C, and after the addition, the reaction was stirred at room temperature for 8h, and disappearance of compound D was detected by TLC. The organic solvent was evaporated under reduced pressure and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate and ═ 1:1, v/v) to give compound I.
4.9g of white solid was obtained by the method, yield 83.0%.
According to the relevant regulations of national drug administration, strict quality control is required to be performed in the production of medicines, and the research on the relevant safety and the quality control in the production are required for new medicine impurities found in the production regardless of the content ratio. In particular, strict quality control is required for impurities with a content of 0.15% or more. Therefore, the invention also protects the application of the linezolid related substance in the quality control of linezolid.
For the research and development of new drugs, the research on the efficacy of drug impurities is one of the effective research and development approaches for the research and development of new drugs. Therefore, the invention also protects the application of the linezolid related substance in drug development.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. Linezolid related substance is characterized by being a compound I, wherein the structural formula of the compound I is shown in the specification
2. A method for preparing linezolid-related substance according to claim 1, characterized in that the following synthetic route is adopted:
3. the method of claim 2, comprising the steps of:
s1, synthesis of a compound C: adding the compound A, the compound B, ethanol and water into a reaction bottle, stirring for reaction, detecting until the compound A disappears, standing, leaching when solid is separated out, washing a filter cake, and drying to obtain a compound C;
s2, synthesis of a compound D: adding the compound C and an organic solvent into a reaction bottle, adding hydrazine hydrate under stirring for reaction, detecting until the compound C disappears, cooling the system temperature to room temperature, performing suction filtration, washing a filter cake, and removing a filtrate to obtain a compound D;
s3, synthesis of a compound I: dissolving the compound D in an organic solvent, adding acetic anhydride, stirring for reaction, detecting until the compound D disappears, removing the organic solvent, and purifying by column chromatography to obtain the compound I.
4. The method for preparing linezolid-related substance according to claim 3, wherein in step S1, the stirring reaction temperature is controlled at 80 ℃, the temperature of the system is reduced to 0 ℃ after the compound A disappears, and then the system is left to stand.
5. The method for preparing linezolid-related substance according to claim 3, wherein in step S1, the molar ratio of compound A to compound B is 1:1.1, and the volume ratio of ethanol to water is 9: 1; for every 1g of Compound A, 9mL of ethanol were added.
6. The method according to claim 3, wherein in step S2, the organic solvent is one or more selected from methanol, ethanol, isopropanol, tetrahydrofuran, 1, 4-dioxane and chloroform; 10-20 mL of organic solvent is added to 1g of compound C.
7. The method for preparing linezolid-related substances according to claim 3, wherein in step S2, 80% by weight of hydrazine hydrate is selected, the molar ratio of the compound C to the hydrazine hydrate is 1: 3-8, and the reaction temperature is controlled at 40-100 ℃.
8. The method according to claim 3, wherein in step S3, the organic solvent is one or more selected from dichloromethane, chloroform, tetrahydrofuran, 1, 4-dioxane, diethyl ether and methyl tert-butyl ether; adding 8-15 mL of organic solvent into 1g of compound D.
9. The method for preparing linezolid-related substance according to claim 3, wherein in step S3, the molar ratio of compound D to acetic anhydride is 1: 2-3, and the reaction temperature is controlled at 0 ℃.
10. The linezolid-related substance according to claim 1 for use as a control in the quality control of pharmaceuticals and in the development of pharmaceuticals.
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|---|---|---|---|---|
| CN112110862A (en) * | 2020-09-23 | 2020-12-22 | 重庆华邦制药有限公司 | Preparation method and application of 1,4,5, 6-tetrahydro-5-hydroxypyrimidine compound and hydrochloride thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664813A (en) * | 2013-12-18 | 2014-03-26 | 沈阳中海药业有限公司 | Preparation method of linezolid |
| WO2014170908A1 (en) * | 2013-04-18 | 2014-10-23 | Nosch Labs Private Limited | Process for preparation of oxazolidinone derivatives |
| CN104672217A (en) * | 2013-11-27 | 2015-06-03 | 北京众和民健医药科技有限公司 | New linezolid intermediate, preparation method thereof, and linezolid synthesis method |
| CN105315231A (en) * | 2014-06-11 | 2016-02-10 | 成都自豪药业有限公司 | Preparation method of linezolid related substance |
| CN109232457A (en) * | 2018-03-26 | 2019-01-18 | 华夏生生药业(北京)有限公司 | A kind of preparation method of Linezolid |
-
2020
- 2020-05-31 CN CN202010481399.5A patent/CN111606870A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014170908A1 (en) * | 2013-04-18 | 2014-10-23 | Nosch Labs Private Limited | Process for preparation of oxazolidinone derivatives |
| CN104672217A (en) * | 2013-11-27 | 2015-06-03 | 北京众和民健医药科技有限公司 | New linezolid intermediate, preparation method thereof, and linezolid synthesis method |
| CN103664813A (en) * | 2013-12-18 | 2014-03-26 | 沈阳中海药业有限公司 | Preparation method of linezolid |
| CN105315231A (en) * | 2014-06-11 | 2016-02-10 | 成都自豪药业有限公司 | Preparation method of linezolid related substance |
| CN109232457A (en) * | 2018-03-26 | 2019-01-18 | 华夏生生药业(北京)有限公司 | A kind of preparation method of Linezolid |
Non-Patent Citations (1)
| Title |
|---|
| 杨勇等: "利奈唑胺的合成工艺研究", 《精细与专用化学品》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112110862A (en) * | 2020-09-23 | 2020-12-22 | 重庆华邦制药有限公司 | Preparation method and application of 1,4,5, 6-tetrahydro-5-hydroxypyrimidine compound and hydrochloride thereof |
| CN112110862B (en) * | 2020-09-23 | 2023-10-17 | 重庆华邦制药有限公司 | Preparation method and application of 1,4,5, 6-tetrahydro-5-hydroxypyrimidine compound and hydrochloride thereof |
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