CN101560238A - Intermediates of betamethasone products-3, 20-double ethylene glycol production process - Google Patents
Intermediates of betamethasone products-3, 20-double ethylene glycol production process Download PDFInfo
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- CN101560238A CN101560238A CNA2009100650901A CN200910065090A CN101560238A CN 101560238 A CN101560238 A CN 101560238A CN A2009100650901 A CNA2009100650901 A CN A2009100650901A CN 200910065090 A CN200910065090 A CN 200910065090A CN 101560238 A CN101560238 A CN 101560238A
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Abstract
The invention discloses a process method for producing an intermediate 3,20-diethylene glycol of betamethasone serial products, which belongs to the field of chemical medicaments. The method comprises the following steps: using a cortisone acetate intermediate prowazekii oxide (1) and glycol as raw materials, boron trifluoride and triethyl orthoformate as catalysts, and chloralkane as a menstruum to perform reaction; and concentrating, crystallizing, filtering, washing and drying the reactants to obtain a reaction product. The method can increase the batch charging concentration, shorten the reaction time, and greatly improve the yield and the quality of a condensation compound. Besides, the method reduces the equipment loss, avoids the use of benzene solvents which are more harmful, and greatly reduces the harm to health and the pollution to the environment.
Description
One. technical field:
The present invention relates to the production technique of Betamethasone Valerate series product, the producing and manufacturing technique of 3,20 pairs of condensed ethandiols of particularly a kind of Betamethasone Valerate series product belongs to chemical field of medicaments.
Two. background technology:
Traditional preparation process Betamethasone Valerate series product 3, the production method of 20 pairs of condensed ethandiol intermediates is: with cortisone acetate intermediate Pu Shi oxide compound be raw material with benzene, ethylene glycol stir, after component distillation dewaters, add tosic acid, 80 ℃ of back flow reaction 10 hours, cooling is reclaimed benzene and ethylene glycol through underpressure distillation, separates out crystallization, obtain 3,20 pairs of condensed ethandiol intermediates.Need to use and human body to be poisoned big, the serious benzene of environmental pollution make solvent, long-time back flow reaction preparation is quite serious to equipment loss and energy consumption under high temperature, high rotating speed working condition.And product yield is lower, and the quality situation of condenses is also undesirable.
Three. summary of the invention:
The present invention is directed to a kind of producing and manufacturing technique that does not use high Betamethasone Valerate series product intermediate-3, the 20 pair condensed ethandiol of benzene kind solvent yield is provided.
Betamethasone Valerate series product intermediate-3 provided by the present invention, the producing and manufacturing technique of 20 pairs of condensed ethandiols, comprise that with cortisone acetate intermediate Pu Shi oxide compound (I) and ethylene glycol be raw material, boron trifluoride, triethyl orthoformate are as catalyzer, and chloroparaffin reacts as solvent.Reaction formula is:
Reaction product is concentrated crystallization, filter, washing, drying obtains reaction product.Temperature of reaction is 10 ℃ to 40 ℃, and temperature of reaction is 20 ℃ to 25 ℃, and reaction was carried out 5-10 hour, and reaction product is carried out concentrating under reduced pressure earlier, is cooled to 20 ℃ again.The input part by weight of each raw material is: cortisone acetate intermediate Pu Shi oxide compound: boron trifluoride-ether: triethyl orthoformate: haloalkane: ethylene glycol=1: 0.017-0.04: 0.6-1.5: 2.0: 2.8.
Present method can increase the concentration that feeds intake, and shortens the reaction times, increases substantially the yield and the quality of condenses.Reduced equipment loss, avoided using poisoning a bigger kind solvent benzene, significantly reduced the harm of HUMAN HEALTH and the pollution of environment.
Four. embodiment:
With cortisone acetate intermediate Pu Shi oxide compound and ethylene glycol is raw material, with boron trifluoride-ether, triethyl orthoformate as catalyzer, a kind of alkyl chloride is as solvent, condensation reaction ratio of components: Pu Shi oxide compound: boron trifluoride-ether: triethyl orthoformate: alkyl chloride: ethylene glycol=1: 0.017-0.04: 0.6-1.5: 2.0: 2.8.Carry out condensation reaction 5 hours at 20-25 ℃, reaction finishes, and carries out concentrating under reduced pressure, and cooling is filtered, and drying obtains condenses
Embodiment 1: comparative example, traditional preparation technology
Use existing preparation Betamethasone Valerate series product condenses production technique, cortisone acetate intermediate Pu Shi oxide compound 70g, ethylene glycol 383g, benzene 1218g are added in the reaction flask, divided water 1 hour in 75-80 ℃ of stirring and refluxing, add tosic acid 0.7g and continue to stir 80 ℃ of back flow reaction 10 hours, reaction finishes.Be evaporated to crystallization and separate out, be cooled to 10 ℃ of filtrations, drying obtains condenses 68.5g, HPLC content 86%.
Embodiment 2: processing method of the present invention
Cortisone acetate intermediate Pu Shi oxide compound 70g, ethylene glycol 196g, triethyl orthoformate 80g, trichloromethane 140g, boron trifluoride-ether 1.5g is added in the reaction flask, and in 20-25 ℃ of stirring reaction 5 hours, reaction finished.Be evaporated to crystallization and separate out, be cooled to 10 ℃ of filtrations, drying obtains condenses 75g, HPLC content 90%.
Embodiment 3: processing method of the present invention
Cortisone acetate intermediate Pu Shi oxide compound 70g, ethylene glycol 196g, triethyl orthoformate 80g, methylene dichloride 140g, boron trifluoride-ether 1.5g is added in the reaction flask, and in 20-25 ℃ of stirring reaction 5 hours, reaction finished.Be evaporated to crystallization and separate out, be cooled to 10 ℃ of filtrations, drying obtains condenses 75.3g, HPLC content 91%.
Embodiment 4: processing method of the present invention
Cortisone acetate intermediate Pu Shi oxide compound 70g, ethylene glycol 196g, triethyl orthoformate 80g, ethylene dichloride 140g, boron trifluoride-ether 1.4g is added in the reaction flask, and in 20-25 ℃ of stirring reaction 5 hours, reaction finished.Be evaporated to crystallization and separate out, be cooled to 10 ℃ of filtrations, drying obtains condenses 74.8g, HPLC content 90.4%.
Embodiment 5: processing method of the present invention
Cortisone acetate intermediate Pu Shi oxide compound 70g, ethylene glycol 196g, triethyl orthoformate 105g, methylene dichloride 140g, boron trifluoride-ether 2.8g is added in the reaction flask, and in 20-25 ℃ of stirring reaction 5 hours, reaction finished.Be evaporated to crystallization and separate out, be cooled to 10 ℃ of filtrations, drying obtains condenses 75.3g, HPLC content 91%.
Embodiment 6: processing method of the present invention
Cortisone acetate intermediate Pu Shi oxide compound 70g, ethylene glycol 196g, triethyl orthoformate 42g, methylene dichloride 140g, boron trifluoride-ether 1.2g is added in the reaction flask, and in 20-25 ℃ of stirring reaction 5 hours, reaction finished.Be evaporated to crystallization and separate out, be cooled to 10 ℃ of filtrations, drying obtains condenses 75.3g, HPLC content 91%.
The detected result of embodiment 1-6 sees Table 1 (form is attached)
The explanation of table 1 partial content:
Yield %=condenses output ÷ Pu Shi oxide compound charging capacity * 100%
Improve yield %=(condenses output-contrast condenses output) ÷ contrast condenses output * 100%
HPLC content: the content that high performance liquid chromatography detects
Improve content %=(condenses content-contrast reduzate content) ÷ contrast condenses content * 100%
Above condenses sample detects through high performance liquid chromatography, and the content of new invention technology sample is apparently higher than the content of prior art sample as can be seen.
As can be seen from the above table, the present invention can make the yield and the quality of Betamethasone Valerate series product condenses intermediate obviously improve.In addition, this technology can also increase the concentration that feeds intake, and shortens the reaction times, increases substantially the yield and the quality of condenses.Reduce equipment loss, avoided using poisoning a bigger kind solvent benzene, significantly reduced the harm to HUMAN HEALTH, the pollution of environment.
Table 1: each embodiment result relatively
| Numbering | Criticize charging capacity g | Production method | Output g | Yield % | Improve yield % | HPLC content % | Improve content % |
| 1 | 70 | Prior art | 68.5 | 97.86 | 0 | 86 | 0 |
| 2 | 70 | The technology of the present invention, with trichloromethane as solvent, proportioning raw materials: Pu Shi oxide compound: boron trifluoride diethyl etherate: triethyl orthoformate=1: 0.02: 1.14 | 75 | 107.14 | 9.49 | 90 | 4.65 |
| 3 | 70 | The technology of the present invention, with methylene dichloride as solvent, proportioning raw materials: Pu Shi oxide compound: boron trifluoride diethyl etherate: triethyl orthoformate=1: 0.02: 1.14 | 75.3 | 107.57 | 9.92 | 91 | 5.81 |
| 4 | 70 | The technology of the present invention, with ethylene dichloride as solvent, proportioning raw materials: Pu Shi oxide compound: boron trifluoride diethyl etherate: triethyl orthoformate=1: 0.02: 1.14 | 74.8 | 106.86 | 9.19 | 90.4 | 5.11 |
| 5 | 70 | The technology of the present invention, with methylene dichloride as solvent, proportioning raw materials: Pu Shi oxide compound: boron trifluoride diethyl etherate: triethyl orthoformate=1: 0.04: 1.5 | 75.2 | 107.43 | 9.57 | 90.9 | 4.9 |
| 6 | 70 | The technology of the present invention, with methylene dichloride as solvent, proportioning raw materials: Pu Shi oxide compound: boron trifluoride diethyl etherate: triethyl orthoformate=1: 0.017: 0.6 | 74.9 | 107 | 9.14 | 90.3 | 4.3 |
Claims (6)
1. the producing and manufacturing technique of Betamethasone Valerate series product intermediate-3,20 a pair condensed ethandiol is characterized in that:
1) be raw material with cortisone acetate intermediate Pu Shi oxide compound (I) and ethylene glycol, boron trifluoride, triethyl orthoformate are as catalyzer, and chloroparaffin reacts as solvent.Reaction formula is:
Pu Shi oxide compound condenses
2) reaction product is concentrated crystallization, filter, washing, drying obtains reaction product.
2. the producing and manufacturing technique of Betamethasone Valerate series product intermediate-3,20 pair condensed ethandiol according to claim 1 is characterized in that: temperature of reaction is 10 ℃ to 40 ℃
3. the producing and manufacturing technique of Betamethasone Valerate series product intermediate-3,20 pair condensed ethandiol according to claim 1 is characterized in that: temperature of reaction is 20 ℃ to 25 ℃.
4. the producing and manufacturing technique of Betamethasone Valerate series product intermediate-3,20 pair condensed ethandiol according to claim 1 is characterized in that: reaction was carried out 5-10 hour.
5, the producing and manufacturing technique of Betamethasone Valerate series product intermediate-3,20 pair condensed ethandiol according to claim 1 is characterized in that: reaction product is carried out concentrating under reduced pressure earlier and is cooled to 10 ℃ again.
6. the producing and manufacturing technique of Betamethasone Valerate series product intermediate-3,20 pair condensed ethandiol according to claim 1 is characterized in that: the input weight ratio of each raw material is:
Cortisone acetate intermediate Pu Shi oxide compound: boron trifluoride-ether: triethyl orthoformate: alkyl chloride: ethylene glycol=1: 0.017-0.04: 0.61.5: 2.0: 2.8.
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| CNA2009100650901A CN101560238A (en) | 2009-05-22 | 2009-05-22 | Intermediates of betamethasone products-3, 20-double ethylene glycol production process |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101948503A (en) * | 2010-09-10 | 2011-01-19 | 天津金汇药业集团有限公司 | Method for preparing betamethasone ketal by homogeneous reaction at normal temperature |
| CN102827230A (en) * | 2012-09-25 | 2012-12-19 | 河南利华制药有限公司 | Preparation method of hydrocortisone acetate |
| CN106699830A (en) * | 2016-11-20 | 2017-05-24 | 中国石油大学(华东) | 16-beta methylpregnene steroid hormone intermediate and preparation method of 16-beta methylpregnene steroid hormone intermediate |
-
2009
- 2009-05-22 CN CNA2009100650901A patent/CN101560238A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101948503A (en) * | 2010-09-10 | 2011-01-19 | 天津金汇药业集团有限公司 | Method for preparing betamethasone ketal by homogeneous reaction at normal temperature |
| CN101948503B (en) * | 2010-09-10 | 2013-01-02 | 天津金汇药业集团有限公司 | Method for preparing betamethasone ketal by homogeneous reaction at normal temperature |
| CN102827230A (en) * | 2012-09-25 | 2012-12-19 | 河南利华制药有限公司 | Preparation method of hydrocortisone acetate |
| CN106699830A (en) * | 2016-11-20 | 2017-05-24 | 中国石油大学(华东) | 16-beta methylpregnene steroid hormone intermediate and preparation method of 16-beta methylpregnene steroid hormone intermediate |
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Open date: 20091021 |