CN102374987A - Method for testing content of 4-acetoxyazetidion intermediate body - Google Patents
Method for testing content of 4-acetoxyazetidion intermediate body Download PDFInfo
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- CN102374987A CN102374987A CN2010102554564A CN201010255456A CN102374987A CN 102374987 A CN102374987 A CN 102374987A CN 2010102554564 A CN2010102554564 A CN 2010102554564A CN 201010255456 A CN201010255456 A CN 201010255456A CN 102374987 A CN102374987 A CN 102374987A
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Abstract
The invention discloses a method for testing content of a 4-acetoxyazetidion intermediate body, which comprises the steps that: (1) a specimen is accurately measured and is dissolved in dimethylformamide to be arranged in a conical bottle, two to three drops of saturated solution indicating agent of azo violet are added into the bottle, the solution is titrated by 0.1mol/L sodium methoxide solution until the titration end point is developed in pure blue or a jump point during the electrictitration is adopted as a titration end point; (2) the reagent dimethylformamide for testing the specimen is fetched to have blank test under the same condition, 0.1 mol/L methoxide solution is used for titration to the identical titration end point, and a reading is used for correcting the titration reading result of the specimen; and (3) the calculation is done according to a formula. The method has technical advantages that: 1 content of epoxy butyric acid in the 4-acetoxyazetidion intermediate body can be quickly, accurately and conveniently tested. 2 The test is free from being interfered by L-threonine.
Description
Technical field
The present invention relates to a kind of content assaying method of 4-acetoxyazetidinone intermedium, belong to the chemical detection method, promptly utilize anhydrous titration method to measure the method for the intermedium epoxy butyric acid content of 4-acetoxyazetidinone.
Background technology
4-acetoxy-3-[1-(tertiary butyl dimethyl Si base) ethyl] aza cyclo-butanone (being called for short 4-AA or 4-acetoxyazetidinone) is the key intermediate of synthetic penem and carbapenem antibiotic, under the structural formula:
Because this compound is in synthetic entirely and the structure 3 asymmetric carbon atoms to be arranged, so synthesis step is more.In recent years, method with fastest developing speed is to utilize the chirality of natural L-threonine to synthesize 4-AA, and stereoselectivity is high, and total recovery can reach 30%.With the L-threonine is that initiation material has two kinds of routes, and wherein elder generation introduces carboxylic acid, ethyl esters at 4, under the lead orthoplumbate effect, is substituted by acetoxyl group after being hydrolyzed into carboxylic acid.Another route; Generate the chiral epoxy butyric acid by the L-threonine; With the condensation of N-methoxyphenyl-N-(acetyl) methyl amine, under the titanium tetrachloride effect, generate aza cyclo-butanone, introduce hydroxyl protecting group then; Make acetyl group change acetoxyl group into through oxidation again, slough amido protection base at last and generate target compound 4-AA.
The structural formula of chiral epoxy butyric acid is following:
The chiral epoxy butyric acid is the synthetic key intermediate of 4-AA.In the process of synthetic 4-AA, the content of control loop oxy butyrate is very important.The epoxy butyric acid is the very weak carboxylic acid of an acidity, can't do assay with common acid base titration, needs to select other method.Simultaneously, in the epoxy butyric acid, also contain not L-threonine and other impurity of complete reaction, be prone to the detection of epoxy butyric acid is produced interference.
And the present detection method that report chiral epoxy butyric acid is not arranged as yet.Therefore, the invention provides a kind of detection method of content of epoxy butyric acid.
Summary of the invention
The invention provides the content assaying method of a kind of 4-acetoxyazetidinone intermedium-epoxy butyric acid; Can measure the content of epoxy butyric acid in the 4-acetoxyazetidinone intermedium fast, accurately, easily; Do not receive the interference of L-threonine, be applicable to the intermedium fast detecting in the synthesis technique.
The present invention adopts following technical proposal to solve the problems of the technologies described above:
A kind of content assaying method of 4-acetoxyazetidinone intermedium may further comprise the steps:
(1) accurately takes by weighing an amount of test sample; With an amount of dimethyl formamide dissolving, be positioned in the fine taper bottle, add the saturated benzole soln indicator of 2～3 azoviolets; Show pure blue to terminal with the titration of 0.1mol/L sodium methoxide solution, or the hop point during with potentiometric titration is a titration end-point;
Used reagent dimethyl formamide when (two) getting test sample and measure is being done blank test with under the condition, and with 0.1mol/L sodium methoxide solution titration identical terminal point extremely, its reading is used to proofread and correct the reading result of test sample titration;
(3) calculate according to formula, in epoxy butyric acid content %=E (V1-V2)/m% formula:
E-is the weight (mg/ml) of the suitable measured matter of every 1ml sodium methoxide vs;
V1-is the reading (ml) that test sample consumes vs;
V2-is the reading (ml) that blank test consumes vs;
M-is for getting test sample amount (mg).
Described potentiometric titration does, uses glass electrode to be indicator electrode, and saturated calomel electrode is a contrast electrode, wherein, the saturated absolute methanol solution of potassium chloride is housed in the glass bushing of saturated calomel electrode.
Employed potentiometric titrimeter is a full-automatic titrator during potentiometric titration.
Technological merit of the present invention is: 1, this method can be measured 4-acetoxyazetidinone intermedium-epoxy butyric acid content fast, accurately, easily.2, testing result does not receive the interference of L-threonine.
Embodiment
Embodiment 1
The preparation of material:
(1) preparation of 0.1mol/L sodium methoxide titrant:
Accurately take by weighing the 1.25g sodium metal, when taking by weighing, earlier that it is surperficial oxide excision is clean, places the kerosene of known weight to weigh, and the 100ml absolute methanol is put in chopping back gradation, with filter paper its surperficial kerosene is blotted as far as possible before putting into.During preparation, place ice bath to cool off absolute methanol, gradation adds sodium metal.After treating that sodium metal dissolves fully, it is an amount of to add the methanol solution that contains 30% benzene, makes into 500mL, shakes up.
(2) demarcation of 0.1mol/L sodium methoxide titrant:
Be taken at the about 0.4g of benchmark benzoic acid of drying under reduced pressure to constant weight in the phosphorus pentoxide desiccator, the accurate title, decide, and adds absolute methanol 15mL and make dissolving; Add anhydrous benzene 5mL; 1 of the absolute methanol solution of 1% bromothymol blue, and is proofreaied and correct the result of titration to blue with the vs titration with blank assay.The sodium methoxide vs of every 1mL is equivalent to the benzoic acid of 12.21mg, according to the consumption and the benzoic use amount of vs, calculates the concentration of vs.
The demarcation of vs must not be less than 3 parts.
(3) a kind of content assaying method of 4-acetoxyazetidinone intermedium may further comprise the steps:
(1) precision takes by weighing epoxy butyric acid 91.41mg; With dissolving of 30mL dimethyl formamide and constant volume; Be positioned in the 100mL fine taper bottle; The saturated benzole soln indicator that adds 2 azoviolets is packed in the 10mL buret and is demarcated the apparent to terminal blueness of good 0.110mol/L sodium methoxide solution titration, and the amount that test sample consumes vs is V
1=6.91ml;
(2) get the 30mL dimethyl formamide, doing blank test with under the condition, with 0.110mol/L sodium methoxide solution titration to identical terminal point, the amount of the vs that blank test consumes is V
2=0.07ml;
Epoxy butyric acid content %=E (V1-V2)/m%
In the formula:
E-is the weight (mg/ml) of the suitable measured matter of every 1ml sodium methoxide vs;
V1-is the reading (ml) that test sample consumes vs (0.1mol/L);
V2-is the reading (ml) of the vs (0.1mol/L) of blank test consumption;
M-is for getting test sample amount (mg).
Through calculating, epoxy butyric acid content is 83.96%.
Embodiment 2
A kind of content assaying method of 4-acetoxyazetidinone intermedium may further comprise the steps:
(1) precision takes by weighing with batch epoxy butyric acid 103.24mg, with dissolving of 30mL dimethyl formamide and constant volume, is positioned in the 100mL fine taper bottle; The saturated benzole soln indicator that adds 2 azoviolets; Adopt potentiometric titration, use glass electrode to be indicator electrode, saturated calomel electrode is a contrast electrode; The saturated absolute methanol solution of potassium chloride wherein, is housed in the glass bushing of saturated calomel electrode; 0.092mol/L sodium methoxide solution titration to the potential change of packing in the 10mL buret produces hop point, V1=9.14ml.
Get the 30mL dimethyl formamide, doing blank test, produce identical hop point, record reading V2=0.12ml with 0.092mol/L sodium methoxide solution titration to potential change with under the condition.
Epoxy butyric acid content %=E (V1-V2)/m%
In the formula:
E-is the weight (mg/ml) of the suitable measured matter of every 1ml sodium methoxide vs;
V1-is the reading (ml) that test sample consumes vs (0.1mol/L);
V2-is the reading (ml) of the vs (0.1mol/L) of blank test consumption;
M-is for getting test sample amount (mg).
Through calculating, epoxy butyric acid content is 81.99%.
Other are with embodiment 1.
Embodiment 3
A kind of content assaying method of 4-acetoxyazetidinone intermedium may further comprise the steps:
Precision takes by weighing with batch epoxy butyric acid 132.07mg; With dissolving of 30mL dimethyl formamide and constant volume; Be positioned in the 100mL fine taper bottle, add the saturated benzole soln indicator of 2 azoviolets, adopt full-automatic titrator; 0.132mol/L sodium methoxide solution titration to the potential change of packing in the full-antomatic buret produces hop point, V1=8.39ml.
Get the 30mL dimethyl formamide, doing blank test, produce identical hop point, record reading V2=0.08ml with 0.132mol/L sodium methoxide solution titration to potential change with under the condition.
Epoxy butyric acid content %=E (V1-V2)/m%
In the formula:
E-is the weight (mg/ml) of the suitable measured matter of every 1ml sodium methoxide vs;
V1-is the reading (ml) that test sample consumes vs (0.1mol/L);
V2-is the reading (ml) of the vs (0.1mol/L) of blank test consumption;
M-is for getting test sample amount (mg).
Through calculating, epoxy butyric acid content is 84.72%.
Other are with embodiment 1 and embodiment 2.
Claims (3)
1. the content assaying method of a 4-acetoxyazetidinone intermedium may further comprise the steps:
(1) accurately take by weighing test sample, with dimethyl formamide dissolving, be positioned in the conical flask, add the saturated benzole soln indicator of 2～3 azoviolets, with the apparent to terminal pure blue of 0.1mol/L sodium methoxide solution titration, or the hop point during with potentiometric titration is a titration end-point;
Used dimethyl formamide when (two) getting test sample and measure is being done blank test with under the condition, and with 0.1mol/L sodium methoxide solution titration identical terminal point extremely, its reading is used to proofread and correct the reading result of test sample titration;
(3) calculate content %=E (V according to formula
1-V
2In the)/m% formula:
V1-is the reading (ml) that test sample consumes vs;
V2-is the reading (ml) that blank test consumes vs;
M-is for getting test sample amount (mg)
E-is the weight (mg/ml) of the suitable measured matter of every 1ml sodium methoxide vs.
2. the content assaying method of 4-acetoxyazetidinone intermedium according to claim 1; It is characterized in that; Described potentiometric titration does, uses glass electrode to be indicator electrode, and saturated calomel electrode is a contrast electrode; The saturated absolute methanol solution of potassium chloride wherein, is housed in the glass bushing of saturated calomel electrode.
3. the content assaying method of 4-acetoxyazetidinone intermedium according to claim 1 is characterized in that, full-automatic titrator is adopted in said potentiometric titration.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104634778A (en) * | 2015-01-27 | 2015-05-20 | 桂林华信制药有限公司 | Determination method for 2-chloromethyl-3,5 dimethyl-4-methoxyl pyridine hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1264372A (en) * | 1997-07-16 | 2000-08-23 | 三星精密化学株式会社 | Process for the preparation of chiral 3,4-epoxybutyric acid and the salt thereof |
| CN101427486A (en) * | 2006-05-23 | 2009-05-06 | 英特尔公司 | Millimeter-wave communication system with directional antenna and one or more millimeter-wave reflectors |
-
2010
- 2010-08-17 CN CN2010102554564A patent/CN102374987A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1264372A (en) * | 1997-07-16 | 2000-08-23 | 三星精密化学株式会社 | Process for the preparation of chiral 3,4-epoxybutyric acid and the salt thereof |
| CN101427486A (en) * | 2006-05-23 | 2009-05-06 | 英特尔公司 | Millimeter-wave communication system with directional antenna and one or more millimeter-wave reflectors |
Non-Patent Citations (3)
| Title |
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| 于如嘏: "非水溶液中的酸碱滴定", 《南京药学院学报》 * |
| 张理平等: "三聚氰酸纯度化学分析方法", 《化学推进剂与高分子材料》 * |
| 殷岱宗: "有机酸类药物的非水溶液滴定", 《云南医学》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104634778A (en) * | 2015-01-27 | 2015-05-20 | 桂林华信制药有限公司 | Determination method for 2-chloromethyl-3,5 dimethyl-4-methoxyl pyridine hydrochloride |
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Owner name: SHANGHAI XINYA PHARMACEUTICAL INDUSTRY CO. LTD. Free format text: FORMER OWNER: SHANGHAI XINXIANFENG PHARMACEUTICAL CO., LTD. Effective date: 20131213 |
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Effective date of registration: 20131213 Address after: 201209 Chuansha Road, Shanghai, No. 978, No. Applicant after: Shanghai Xinya Pharmaceutical Industry Co., Ltd. Applicant after: Liaoning Medya Pharmaceutical Co., Ltd. Address before: 201203 Pudong New Area Zhangjiang Road, Shanghai, No. 92 Applicant before: Shanghai Xinxianfeng Pharmaceutical Co., Ltd. Applicant before: Liaoning Medya Pharmaceutical Co., Ltd. |
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Application publication date: 20120314 |