CN110256372A - A kind of Linezolid impurity and preparation method - Google Patents
A kind of Linezolid impurity and preparation method Download PDFInfo
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- CN110256372A CN110256372A CN201910639379.3A CN201910639379A CN110256372A CN 110256372 A CN110256372 A CN 110256372A CN 201910639379 A CN201910639379 A CN 201910639379A CN 110256372 A CN110256372 A CN 110256372A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
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Abstract
The present invention relates to relative substances in a kind of Linezolid production technology and its preparation method and application, belong to bulk pharmaceutical chemicals preparation technical field.The technical scheme is that a kind of 1 compound of formula and preparation method.The preparation method is step 1: 5 compound of formula self-condensation in the presence of tert-butyl alcohol lithium obtains 4 compound of formula.Step 2: 3 compound of formula and 4 compound of the formula compound shown in cyclization production 2 under the effect of tert-butyl alcohol lithium.Step 3: 2 compound of formula hydrolyzes 1 compound of the formula that obtains in strong alkali environment.Technical solution of the present invention has found more large content of process impurity present in Linezolid bulk pharmaceutical chemicals, and provides the preparation method of the impurity reference substance.
Description
Technical field
The present invention relates to relative substances in a kind of Linezolid production technology and its preparation method and application, belong to bulk pharmaceutical chemicals
Preparation technical field.
Background technique
Linezolid is a kind of artificial synthesized (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides antibiotic, is approved by the FDA in the United States within 2000 and is mainly used for controlling
Treat infection, trade name Zyvox caused by gram-positive cocci.
Test discovery, preparing (reaction equation is as follows) Linezolid by prior art has certain the maximum amount of unknown impuritie to occur,
But it has no that American-European pharmacopeia is included in Linezolid standard using 1 compound of formula as impurity, is generally made in actual operation
It is treated for unknown impuritie, there is huge clinical use risks.
。
Therefore, it is analyzed to identify the impurity compound, and provides it according to product, to Linezolid production of raw medicine enterprise and its
The quality control of preparation has far-reaching significance.In addition, needing the impurity of high-purity in carrying out drug quality detection process
Reference substance as corresponding impurity, the quality testing for bulk pharmaceutical chemicals or preparation.
Summary of the invention
The present invention is directed to the requirement of drug quality control, determines the unknown impuritie in Linezolid, and provide its preparation side
Method provides reference substance for the quality control of Linezolid.
The technical scheme is that
Unknown impuritie is collected by LC-MS (HPLC-MS), and carries out structural analysis with nuclear magnetic resonance spectroscopy, is confirmed unknown miscellaneous
Matter is compound of the structural formula as described in formula 1, chemical name are as follows: N-(3- acetylaminohydroxyphenylarsonic acid 2- hydroxypropyl)-N-(((S) -3-(3- is fluoro-
4- morpholinyl phenyl) -2- oxazolone -5- base) methyl) acetamide (hereinafter referred to as: 1 compound of formula) is that the technique of Linezolid is miscellaneous
Matter.
。
Analyze its Producing reason, it may be possible to which at reaction conditions, there is following side reactions:
。
The preparation method of 1 compound of formula of the present invention, includes the following steps:
Step 1: 5 compound of formula self-condensation in the presence of tert-butyl alcohol lithium obtains 4 compound of formula.
Reaction dissolvent is selected from toluene, and the feed ratio of 5 compound of formula and toluene is 1:8~12(mass ratio), preferably 1:10；
The feed ratio of compound shown in formula 5 and tert-butyl alcohol lithium is 1:1.6~2.4(molar ratio), preferably 1:2.0；Reaction temperature is 80
~100 DEG C, preferably 90 DEG C；20~the 28h of reaction time, preferably for 24 hours.Reaction equation is as follows:
Step 2: 3 compound of formula and 4 compound of formula 2 compound of cyclization production under the effect of tert-butyl alcohol lithium.
Reaction dissolvent is selected from n,N-dimethylacetamide, the feed ratio of compound shown in formula 3 and n,N-dimethylacetamide
For 1:2~4(mass ratio), preferably 1:3；The feed ratio of compound shown in formula 3 and tert-butyl alcohol lithium is 1:0.8~1.2(molar ratio),
It is preferred that 1:1.0；The feed ratio of 3 compound of formula and 4 compound of formula is 1:1.6~2.4(molar ratio), preferably 1:2.0；Reaction temperature
10~20 DEG C, preferably 15 DEG C；Reaction time 16~for 24 hours, preferably 20h.Reaction equation is as follows:
Step 3: 2 compound of formula hydrolyzes 1 compound of the formula that obtains in strong alkali environment.
The highly basic is selected from through potassium hydroxide, sodium hydroxide；It is preferred that potassium hydroxide.
Reaction dissolvent preferably is selected from methylene chloride, and the feed ratio of 2 compound of formula and methylene chloride is 1:4~8(mass ratio), it is excellent
Select 1:6；The feed ratio of 2 compound of formula and potassium hydroxide is 1:2~6(molar ratio), preferably 1:4；The reaction temperature 20~30
DEG C, preferably 25 DEG C；18~the 30h of reaction time, preferably for 24 hours.Reaction equation is as follows:
。
The present invention also provides the purposes of 1 compound of formula, i.e., as defects inspecting a kind of in Linezolid production technology
Reference substance application.
The invention has the benefit that
Technical solution of the present invention has found more large content of process impurity present in Linezolid bulk pharmaceutical chemicals, and it is miscellaneous to provide this
The preparation method of matter reference substance, thus improve the analysis of Linezolid finished product detection to the accurate positionin of 1 compound of impurity formula and
It is qualitative, be conducive to reinforce the control to the impurity, to improve the quality of Linezolid finished product.
Detailed description of the invention
The HPLC-UV detection of 1 compound of formula obtained in Fig. 1 embodiment 3.
Relative retention time example of 1 compound of formula in Linezolid finished product obtained in Fig. 2 embodiment 3.
Specific embodiment
The embodiment of the present invention is described below in detail.It will be understood to those of skill in the art that the embodiments described below is
Illustratively, for explaining only the invention, it is not considered as limiting the invention.Be not specified in embodiment particular technique or
Condition, it described technology or conditions or is carried out according to the literature in the art according to product description.Agents useful for same or
Production firm person is not specified in instrument, and being can be with conventional products that are commercially available.
Embodiment 1
The preparation of 4 compound of step 1. formula
Compound shown in formula 5 (19.3g, 0.1mol) is added in 154.4g toluene, add tert-butyl alcohol lithium (12.8g,
0.16mol), 80 DEG C are then heated to, 20h is stirred.After reaction solution is cooled to room temperature, filtering, mother liquor concentrations, column chromatography (PE:EA
=2:1 (V/V)), 18.5g brown oil is obtained, yield: 53%, MS:351.76 [M+1]+.
The preparation of 2 compound of step 2. formula
Compound shown in formula 3 (16.5g, 0.05mol) is added in 33.0g n,N-dimethylacetamide, ice-water bath is cooling,
It is added tert-butyl alcohol lithium (3.2g, 0.04mol), compound shown in formula 4 (28.0g, 0.08mol) finishes, 10 DEG C of reaction 16h of temperature control.
Reaction is finished, and puts into 175ml drinking water, then extracted 1 time with 175ml methylene chloride, organic phase concentration, column chromatography (PE:EA=1:
1) 11.24g white solid is obtained, yield: 23%, MS:495.52 [M+1]+.
The preparation of 1 compound of step 3. formula
Formula 2(24.8g, 0.05mol) is added in 99.2g methylene chloride, is added potassium hydroxide (5.6g, 0.10mol), control
20 DEG C of reaction 18h of temperature react and finish, and 200g drinking water is added, and liquid separation separates organic phase, and column chromatographs (PE:EA=1:1) and obtains 16.2
G white solid, yield: 72%, HPLC purity: 98.62%, MS:453.26 [M+1]+.
Embodiment 2
The preparation of 4 compound of step 1. formula
Compound shown in formula 5 (19.3g, 0.1mol) is added in 193g toluene, add tert-butyl alcohol lithium (16.0g,
0.2mol), 90 DEG C are then heated to, stirring is for 24 hours.After reaction solution is cooled to room temperature, filtering, mother liquor concentrations, column chromatography (PE:EA
=2:1 (V/V)), 21.63g brown oil is obtained, yield: 62%, MS:351.76 [M+1]+.
The preparation of 2 compound of step 2. formula
Compound shown in formula 3 (16.5g, 0.05mol) is added in 49.5g n,N-dimethylacetamide, ice-water bath is cooling, adds
Enter tert-butyl alcohol lithium (4.0g, 0.05mol), compound shown in formula 4 (35.0g, 0.1mol) finishes, 15 DEG C of reaction 20h of temperature control.Instead
It should finish, put into 175ml drinking water, then extracted 1 time with 175ml methylene chloride, organic phase concentration, column chromatographs (PE:EA=1:1)
12.71g white solid is obtained, yield: 26%, MS:495.52 [M+1]+.
The preparation of 1 compound of step 3. formula
Formula 2(24.8g, 0.05mol) is added in 144.8g methylene chloride, is added potassium hydroxide (11.2g, 0.20mol),
25 DEG C of temperature control reactions for 24 hours, are reacted and are finished, and 200ml drinking water is added, and liquid separation separates organic phase, and column chromatographs (PE:EA=1:1) and obtains
16.9 g white solids, yield: 75%, HPLC purity: 98.96%, MS:453.26 [M+1]+.
Embodiment 3
The preparation of 4 compound of step 1. formula
Compound shown in formula 5 (19.3g, 0.1mol) is added in 231.6g toluene, addition tert-butyl alcohol lithium (19.2g,
0.24mol), 100 DEG C are then heated to, 28h is stirred.After reaction solution is cooled to room temperature, filtering, mother liquor concentrations, column chromatography (PE:
EA=2:1 (V/V)), 19.2g brown oil is obtained, yield: 55%, MS:351.76 [M+1]+.
The preparation of 2 compound of step 2. formula
Compound shown in formula 3 (16.5g, 0.05mol) is added in 66.0g n,N-dimethylacetamide, ice-water bath is cooling, adds
Enter tert-butyl alcohol lithium (4.8g, 0.06mol), compound shown in formula 4 (42.0g, 0.12mol) finishes, and 20 DEG C of temperature control reactions are for 24 hours.Instead
It should finish, put into 175ml drinking water, then extracted 1 time with 175ml methylene chloride, organic phase concentration, column chromatographs (PE:EA=1:1)
10.7g white solid is obtained, yield: 22%, MS:495.52 [M+1]+.
The preparation of 1 compound of step 3. formula
Formula 2(24.8g, 0.05mol) is added in 198.4g methylene chloride, is added potassium hydroxide (16.8g, 0.30mol),
30 DEG C of reaction 30h of temperature control, reaction are finished, addition 200g drinking water, liquid separation, separation organic phase, column chromatography (PE:EA=1:1)
16.7 g white solids, yield: 74%, HPLC purity: 98.52%, MS:453.26 [M+1]+.
Table 1: 1 compound N of formula-(3- acetylaminohydroxyphenylarsonic acid 2- hydroxypropyl)-N-(((S) the fluoro- 4- morpholinyl phenyl of -3-(3-) -2- evil
Oxazolone -5- base) methyl) acetamide hydrogen nuclear magnetic resonance modal data (CDCl3).
Table 2:N-(3- acetylaminohydroxyphenylarsonic acid 2- hydroxypropyl)-N-(((S) the fluoro- 4- morpholinyl phenyl of -3-(3-) -2- oxazolone -5-
Base) methyl) acetamide carbon-13 nmr spectra data (CDCl3).
Claims (10)
1. a kind of Linezolid impurity compound, structural formula as described in formula 1,
。
2. application of the compound described in claim 1 in the control of Linezolid quality as impurity reference substance.
3. the preparation method of compound described in claim 1, which comprises the steps of:
Step 1: 5 compound of formula self-condensation in the presence of tert-butyl alcohol lithium obtains 4 compound of formula, and reaction dissolvent is selected from toluene, instead
Answering temperature is 80~100 DEG C,
Step 2: 3 compound of formula and 4 compound of formula 2 compound of cyclization production, reaction dissolvent under the effect of tert-butyl alcohol lithium are selected from
N,N-dimethylacetamide, 10~20 DEG C of reaction temperature,
Step 3: 2 compound of formula hydrolyzes 1 compound of the formula that obtains in strong alkali environment, and the highly basic is selected from through potassium hydroxide, hydrogen-oxygen
Change sodium, reaction dissolvent be selected from methylene chloride, 20~30 DEG C of reaction temperature,
。
4. preparation method according to claim 3, which is characterized in that in step 1, the quality that feeds intake of 5 compound of formula and toluene
Than for 1:8~12.
5. preparation method according to claim 3, which is characterized in that in step 1, the quality that feeds intake of 5 compound of formula and toluene
Than for 1:10.
6. preparation method according to claim 3, which is characterized in that in step 1,5 compound of formula feeds intake with tert-butyl alcohol lithium
Molar ratio is 1:1.6~2.4.
7. preparation method according to claim 3, which is characterized in that in step 1,5 compound of formula feeds intake with tert-butyl alcohol lithium
Molar ratio is 1:2.0.
8. preparation method according to claim 3, which is characterized in that in step 2, compound shown in formula 3 and tert-butyl alcohol lithium
Molar ratio is 1:0.8~1.2, and the molar ratio of 3 compound of formula and 4 compound of formula is 1:1.6~2.4.
9. preparation method according to claim 3, which is characterized in that in step 2, compound shown in formula 3 and tert-butyl alcohol lithium
Molar ratio is 1:1.0；The molar ratio of 3 compound of formula and 4 compound of formula is 1:2.0；15 DEG C of reaction temperature.
10. preparation method according to claim 3, which is characterized in that in step 3,2 compound of formula and methylene chloride feed intake
Mass ratio is 1:4~8, and the molar ratio of 2 compound of formula and potassium hydroxide is 1:2~6；25 DEG C of reaction temperature.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910639379.3A CN110256372A (en) | 2019-07-16 | 2019-07-16 | A kind of Linezolid impurity and preparation method |
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| CN201910639379.3A CN110256372A (en) | 2019-07-16 | 2019-07-16 | A kind of Linezolid impurity and preparation method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113979961A (en) * | 2021-11-08 | 2022-01-28 | 湖南增达生物科技有限公司 | Linezolid impurity and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007064818A1 (en) * | 2005-12-01 | 2007-06-07 | Teva Pharmaceutical Industries Ltd. | Isolated desfluoro-linezolid, preparation thereof and its use as a reference marker and standard |
| CN107573297A (en) * | 2017-08-31 | 2018-01-12 | 桂林南药股份有限公司 | A kind of preparation method of the acidic hydrolysis impurity of Linezolid |
-
2019
- 2019-07-16 CN CN201910639379.3A patent/CN110256372A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007064818A1 (en) * | 2005-12-01 | 2007-06-07 | Teva Pharmaceutical Industries Ltd. | Isolated desfluoro-linezolid, preparation thereof and its use as a reference marker and standard |
| CN107573297A (en) * | 2017-08-31 | 2018-01-12 | 桂林南药股份有限公司 | A kind of preparation method of the acidic hydrolysis impurity of Linezolid |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113979961A (en) * | 2021-11-08 | 2022-01-28 | 湖南增达生物科技有限公司 | Linezolid impurity and preparation method thereof |
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| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20210928 Address after: 264205 Wendeng economic and Technological Development Zone, Weihai City, Shandong Province Applicant after: Dijia Pharmaceutical Group Co.,Ltd. Applicant after: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Address before: 266440 No.268, Tianrun Road, Wendeng economic and Technological Development Zone, Weihai City, Shandong Province Applicant before: WEIHAI DISU PHARMACEUTICAL Co.,Ltd. Applicant before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Effective date of registration: 20210928 Address after: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Applicant after: Dijia Pharmaceutical Group Co.,Ltd. Address before: 264205 Wendeng economic and Technological Development Zone, Weihai City, Shandong Province Applicant before: Dijia Pharmaceutical Group Co.,Ltd. Applicant before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. |
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Address after: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Applicant after: Dijia Pharmaceutical Group Co.,Ltd. Address before: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Applicant before: Dijia Pharmaceutical Group Co.,Ltd. |
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Application publication date: 20190920 |