CN1872844A - Method for synthesizing 2 (alpha - phenyl - alpha - methoxycarbonyl - methyl) thiazolidine - 4 - carboxylic acid and mensurating limitation - Google Patents
Method for synthesizing 2 (alpha - phenyl - alpha - methoxycarbonyl - methyl) thiazolidine - 4 - carboxylic acid and mensurating limitation Download PDFInfo
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- CN1872844A CN1872844A CN 200610039224 CN200610039224A CN1872844A CN 1872844 A CN1872844 A CN 1872844A CN 200610039224 CN200610039224 CN 200610039224 CN 200610039224 A CN200610039224 A CN 200610039224A CN 1872844 A CN1872844 A CN 1872844A
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Abstract
This invention discloses a method for synthesizing 2-(alpha-phenyl-alpha-methoxycarbonyl-methyl) thiazolidin-4-carboxylic acid as the active component for a leukogenic drug. The method uses methyl format, ethyl ether, cysteine hydrochloride and ethanol as the raw materials. For chromatographic detection, octadecylsilyl silica gel is used as the filler, and water-acetonitrile-glacial acetic acid or water-acetonitrile as the mobile phase at the column temperature of 30 deg.C and detection wavelength of 210 nm. This invention overcomes the shortcomings in the present methods that 2-(alpha-phenyl-alpha-methoxycarbonyl-methyl) thiazolidin-4-carboxylic acid cannot be detected, thus ensuring the safety and curative effects of the drug.
Description
Invention field;
The present invention relates to pharmaceutical field, disclose the synthetic and limit measuring method of 2-(α-phenyl-2-α-methoxycarbonyl-methyl) thiazolidine-4-carboxylic acid.
Background technology:
2-(α-phenyl-α-ethoxycarbonyl-methyl) thiazolidine-4-carboxylic acid, for the leucocyte increasing agent leucogen (former name: a related substance the leucogen), structural formula is as follows:
Molecular formula: C
13H
15O
4NS
Leucogen is used to white corpuscle, the thrombocytopenia of preventing and treating a variety of causes to cause, clinically is mainly used in the white corpuscle that tumor chemoradiotherapy, endocrine disturbance medicine etc. cause, the treatment of thrombocytopenia.What use clinically at present is leucogen sheet (10mg/ sheet, two kinds of specifications of 20mg/ sheet), but because of containing 2-(α-phenyl-α-ethoxycarbonyl-methyl) thiazolidine-4-carboxylic acid that quantity does not wait in the leucogen, thereby the part influence the result of treatment of medicine, the popularization of clinical use is restricted.
The invention provides a kind of overcome contain 2-(α-phenyl-α-ethoxycarbonyl-methyl) thiazolidine-4-carboxylic acid in the existing leucogen and unmeasured defective, utilize synthetic 2-(α-phenyl-α-ethoxycarbonyl-methyl) thiazolidine-4-carboxylic acid to carry out limit and measure, further guarantee curative effect.
Goal of the invention
Purpose of the present invention at first is to provide the synthesis technique of 2-(α-phenyl-α-ethoxycarbonyl-methyl) thiazolidine-4-carboxylic acid, secondly, another object of the present invention is the mensuration of carrying out 2-in the leucogen (α-phenyl-α-ethoxycarbonyl-methyl) thiazolidine-4-carboxylic acid limit, further guarantees curative effect.
Summary of the invention
The synthesis technique and the limit thereof that the invention provides 2-(α-phenyl-α-ethoxycarbonyl-methyl) thiazolidine-4-carboxylic acid are measured:
1, synthetic by following technology realization:
(1) condensation, acidifying
Ratio of components: methyl phenylacetate: methyl-formiate: ether: sodium Metal 99.5
0.6~1.3∶0.45~1.1∶1.2~2.8∶0.1~0.3
Ether is added in three mouthfuls of reaction flasks, be cooled to 10-15 ℃, add the sodium Metal 99.5 of handling well, drip methyl phenylacetate and methyl-formiate mixed solution, temperature of reaction is controlled at 20-30 ℃ in the process, and top temperature can not be above 31 ℃.After dripping, continue to stir standing over night 10 hours.Add hydrochloric acid and stir water transfer layer pH to 1.After leaving standstill, divide and get oil reservoir, carry out underpressure distillation, collect 110-120 ℃/30-20mm cut, get α-formyl radical methyl phenylacetate.
(2) ring and
Ratio of components: α-formyl radical methyl phenylacetate: cysteine hydrochloride: ethanol: water
0.6~1.3∶0.50~1.12∶4.0~8.2∶5.0~10.0
Water and cysteine hydrochloride are added in three mouthfuls of reaction flasks, stir, temperature control adds sodium bicarbonate in below 40 ℃, transfers about reaction solution pH to 7; Drip α-formyl radical methyl phenylacetate and alcohol mixeding liquid simultaneously, finish, reflux 1 hour, the reaction solution crystallisation by cooling, suction filtration, crystallization is washed with a small amount of ether with distilled water, ethanol elder generation after scouring several times again.Drain, dry, promptly get 2-of the present invention (α-phenyl-α-ethoxycarbonyl-methyl) thiazolidine-4-carboxylic acid, total recovery is about 48%.
2, limit is measured
Strong to close silica gel be weighting agent to the test of chromatographic condition and system suitability with octadecylsilane; With water-acetonitrile-Glacial acetic acid or water-acetonitrile is moving phase; Column temperature is 30 ℃; The detection wavelength is 210nm.
Assay method is got leucogen 10mg, and accurate the title decides, to the 100ml measuring bottle, it is an amount of to add phosphate buffered saline buffer (pH6.8)-acetonitrile (1: 1), and supersound process makes dissolving, with above-mentioned solvent cut to scale, shake up, filter, get subsequent filtrate as need testing solution (100 μ g/ml), precision is measured need testing solution 1ml, place the 100ml measuring bottle, be diluted to scale in right amount with phosphate buffered saline buffer (pH6.8)-acetonitrile (1: 1), shake up, promptly get contrast solution (1 μ g/ml).Get contrast solution 20 μ l and inject liquid chromatograph, regulate detector sensitivity, make the peak height of principal constituent chromatographic peak be about 10%～15% of full range, precision is measured need testing solution and each 20l of reference substance solution respectively again, inject liquid chromatograph, the record appearance time is to main peak retention time duple chromatographic peak, and as showing impurity peaks, its peak area sum must not be greater than the main peak area in the contrast solution color atlas (the related substance limit be less than 1.0%) in the trial-product color atlas.
Embodiments of the invention are as follows:
1. condensation, acidifying
Ratio of components: methyl phenylacetate: methyl-formiate: ether: sodium Metal 99.5
0.9∶0.6∶2.5∶0.16
The 250ml ether is added in the 500ml reaction flask, and water-bath is cooled to 10-15 ℃, adds the sodium Metal 99.5 of handling well, drips 90g methyl phenylacetate and 60g methyl-formiate mixed solution, and temperature of reaction is controlled at 20-30 ℃ in the process, and top temperature can not be above 31 ℃.Mixed solution finishes, and continues to stir 12 hours, leaves standstill 12 hours.Add hydrochloric acid and stir water transfer layer pH to 1.Leave standstill, divide and get oil reservoir, 110-120 ℃/30-20mm fraction is collected in underpressure distillation, gets α-formyl radical methyl phenylacetate.
The ring and
Ratio of components: α-formyl radical methyl phenylacetate: cysteine hydrochloride: ethanol: water
1∶0.85∶6.0∶6.0
300ml water and 42.5g cysteine hydrochloride are added in the 1000ml reaction flask, stir, temperature control adds sodium bicarbonate in below 40 ℃, transfers about reaction solution pH to 7; While Dropwise 5 0g α-formyl radical Phenylacetic acid ethylester and 300ml alcohol mixeding liquid.Finish, reflux 1 hour, the reaction solution crystallisation by cooling, suction filtration, crystallization is washed with a small amount of ether with distilled water, ethanol elder generation after scouring several times again.Drain, 60 ℃ of oven dry, that is, total recovery is about 48%.
3. limit is measured
Strong to close silica gel be weighting agent to the test of chromatographic condition and system suitability with octadecylsilane; With water-acetonitrile-Glacial acetic acid or water-acetonitrile is moving phase; Column temperature is 30 ℃; The detection wavelength is 210nm.
Assay method is got leucogen 10mg, and accurate the title decides, to the 100ml measuring bottle, it is an amount of to add phosphate buffered saline buffer (pH6.8)-acetonitrile (1: 1), and supersound process makes dissolving, with above-mentioned solvent cut to scale, shake up, filter, get subsequent filtrate as need testing solution (100 μ g/ml), precision is measured need testing solution 1ml, place the 100ml measuring bottle, be diluted to scale in right amount with phosphate buffered saline buffer (pH6.8)-acetonitrile (1: 1), shake up, promptly get contrast solution (1 μ g/ml).Get contrast solution 20 μ l and inject liquid chromatograph, regulate detector sensitivity, make the peak height of principal constituent chromatographic peak be about 10%～15% of full range, precision is measured need testing solution and each 20 μ l of reference substance solution respectively again, inject liquid chromatograph, the record appearance time is to main peak retention time duple chromatographic peak, and as showing impurity peaks, its peak area sum must not be greater than the main peak area in the contrast solution color atlas (the related substance limit be less than 1.0%) in the trial-product color atlas.
Sample determination of related substances result
| Lot number | 1 | 2 | 3 |
| Related substance (≤1.0%) | 0.420％ | 0.310％ | 0.33％ |
Claims (2)
1, the invention provides the synthesis technique and the limit measuring method thereof of 2-(α-phenyl-α-ethoxycarbonyl-methyl) thiazolidine-4-carboxylic acid.It is characterized in that:
The synthesis technique and the limit thereof that the invention provides 2-(α-phenyl-α-ethoxycarbonyl-methyl) thiazolidine-4-carboxylic acid are measured:
(1) synthetic by following technology realization:
A, contract and, acidifying
Ratio of components: methyl phenylacetate: methyl-formiate: ether: sodium Metal 99.5
0.6~1.3∶0.45~1.1∶1.2~2.8∶0.1~0.3
Ether is added in three mouthfuls of reaction flasks, be cooled to 10-15 ℃, add the sodium Metal 99.5 of handling well, drip methyl phenylacetate and methyl-formiate mixed solution, temperature of reaction is controlled at 20-30 ℃ in the process, and top temperature can not be above 31 ℃.After dripping, continue to stir standing over night 10 hours.Add hydrochloric acid and stir water transfer layer pH to 1.After leaving standstill, divide and get oil reservoir, carry out underpressure distillation, collect 110-120 ℃/30-20mm fraction, get α-formyl radical methyl phenylacetate.
B, ring and
Ratio of components: α-formyl radical methyl phenylacetate: cysteine hydrochloride: ethanol: water
0.6~1.3∶0.50~1.12∶4.0~8.2∶5.0~10.0
Water and cysteine hydrochloride are added in three mouthfuls of reaction flasks, stir, temperature control adds sodium bicarbonate in below 40 ℃, transfers about reaction solution pH to 7; Drip α-formyl radical methyl phenylacetate and alcohol mixeding liquid simultaneously, finish, reflux 1 hour, the reaction solution crystallisation by cooling, suction filtration, crystallization is washed with a small amount of ether with distilled water, ethanol elder generation after scouring several times again.Drain, dry, promptly get 2-of the present invention (α-phenyl-α-ethoxycarbonyl-methyl) thiazolidine-4-carboxylic acid, total recovery is about 48%.
(2) limit is measured
Strong to close silica gel be weighting agent to the test of chromatographic condition and system suitability with octadecylsilane; With water-acetonitrile-Glacial acetic acid or water-acetonitrile is moving phase; Column temperature is 30 ℃; The detection wavelength is 210nm.
Assay method is got leucogen 10mg, and accurate the title decides, to the 100ml measuring bottle, it is an amount of to add phosphate buffered saline buffer (pH6.8)-acetonitrile (1: 1), and supersound process makes dissolving, with above-mentioned solvent cut to scale, shake up, filter, get subsequent filtrate as need testing solution (100 μ g/ml), precision is measured need testing solution 1ml, place the 100ml measuring bottle, be diluted to scale in right amount with phosphate buffered saline buffer (pH6.8)-acetonitrile (1: 1), shake up, promptly get contrast solution (1 μ g/ml).Get contrast solution 20 μ l and inject liquid chromatograph, regulate detector sensitivity, make the peak height of principal constituent chromatographic peak be about 10%～15% of full range, precision is measured need testing solution and each 20 μ l of contrast solution respectively again, inject liquid chromatograph, the record appearance time is to main peak retention time duple chromatographic peak, and as showing impurity peaks, its peak area sum must not be greater than the main peak area in the contrast solution color atlas (the related substance limit be less than 1.0%) in the trial-product color atlas.
2, according to prescription best in the synthesis technique of the 2-described in the claim 1 (α-phenyl-α-ethoxycarbonyl-methyl) thiazolidine-4-carboxylic acid
Ratio and technology are as follows:
(1) contract and, acidifying
Ratio of components: methyl phenylacetate: methyl-formiate: ether: sodium Metal 99.5
0.9∶0.6∶2.5∶0.16
The 250ml ether is added in the 500ml reaction flask, and water-bath is cooled to 10-15 ℃, adds the sodium Metal 99.5 of handling well, drips 90g methyl phenylacetate and 60g methyl-formiate mixed solution, and temperature of reaction is controlled at 20-30 ℃ in the process, and top temperature can not be above 31 ℃.Mixed solution finishes, and continues to stir 12 hours, leaves standstill 12 hours.Add hydrochloric acid and stir water transfer layer pH to 1.Leave standstill, divide and get oil reservoir, 110-120 ℃/30-20mm fraction is collected in underpressure distillation, gets α-formyl radical methyl phenylacetate.
(2) ring and
Ratio of components: α-formyl radical methyl phenylacetate: cysteine hydrochloride: ethanol: water
1∶0.85∶6.0∶6.0
300ml water and 42.5g cysteine hydrochloride are added in the 1000ml reaction flask, stir, temperature control adds sodium bicarbonate in below 40 ℃, transfers about reaction solution pH to 7.While Dropwise 5 0g α-formyl radical Phenylacetic acid ethylester and 300ml alcohol mixeding liquid.Finish, reflux 1 hour, the reaction solution crystallisation by cooling, suction filtration, crystallization is washed with a small amount of ether with distilled water, ethanol elder generation after scouring several times again.Drain, 60 ℃ of oven dry, that is, total recovery is about 48%.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101354384B (en) * | 2007-07-27 | 2012-07-25 | 中国石油化工股份有限公司 | Method and instrument for quantitatively analyzing trace amount acetylene hydrocarbon in carbon four fractions |
| CN103102324A (en) * | 2011-11-14 | 2013-05-15 | 南京长澳医药科技有限公司 | Preparation method of leucongen |
| CN105467045A (en) * | 2016-01-06 | 2016-04-06 | 福建农林大学 | Method for quickly detecting L-thiazolidine-4-carboxylic acid in lentinula edodes |
| CN115872948A (en) * | 2021-12-30 | 2023-03-31 | 江苏吉贝尔药业股份有限公司 | Crystal form B of leucogen, preparation method and application thereof |
| WO2023124408A1 (en) * | 2021-12-30 | 2023-07-06 | 江苏吉贝尔药业股份有限公司 | Crystalline form of leucogen and method for preparation thereof and use thereof |
| CN116655556A (en) * | 2023-04-17 | 2023-08-29 | 常州亚邦制药有限公司 | Crystal form A of ritodrine and preparation method thereof |
-
2006
- 2006-03-31 CN CN 200610039224 patent/CN1872844A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101354384B (en) * | 2007-07-27 | 2012-07-25 | 中国石油化工股份有限公司 | Method and instrument for quantitatively analyzing trace amount acetylene hydrocarbon in carbon four fractions |
| CN103102324A (en) * | 2011-11-14 | 2013-05-15 | 南京长澳医药科技有限公司 | Preparation method of leucongen |
| CN105467045A (en) * | 2016-01-06 | 2016-04-06 | 福建农林大学 | Method for quickly detecting L-thiazolidine-4-carboxylic acid in lentinula edodes |
| CN115872948A (en) * | 2021-12-30 | 2023-03-31 | 江苏吉贝尔药业股份有限公司 | Crystal form B of leucogen, preparation method and application thereof |
| WO2023124408A1 (en) * | 2021-12-30 | 2023-07-06 | 江苏吉贝尔药业股份有限公司 | Crystalline form of leucogen and method for preparation thereof and use thereof |
| CN115872948B (en) * | 2021-12-30 | 2023-09-26 | 江苏吉贝尔药业股份有限公司 | Crystal form B of ritodrine, and preparation method and application thereof |
| CN116655556A (en) * | 2023-04-17 | 2023-08-29 | 常州亚邦制药有限公司 | Crystal form A of ritodrine and preparation method thereof |
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