CN112194696A - Method for preparing 9 beta, 10 alpha-5, 7-diene steroid compound - Google Patents
Method for preparing 9 beta, 10 alpha-5, 7-diene steroid compound Download PDFInfo
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- CN112194696A CN112194696A CN202011159322.2A CN202011159322A CN112194696A CN 112194696 A CN112194696 A CN 112194696A CN 202011159322 A CN202011159322 A CN 202011159322A CN 112194696 A CN112194696 A CN 112194696A
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- mercury lamp
- doped mercury
- diene
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
- C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention relates to a method for preparing 9 beta, 10 alpha-5, 7 diene steroids, which is characterized in that 9 beta, 10 alpha-5, 7 diene steroids are prepared by irradiating 9 alpha, 10 beta-5, 7 diene steroids by using an iron-doped mercury lamp, a calcium-doped mercury lamp or a combination thereof, the preparation method is simple, the cost is low, the process stability is high, the yield of the 9 beta, 10 alpha-5, 7 diene steroids is greatly improved, and the method is suitable for batch production of the 9 beta, 10 alpha-5, 7 diene steroids.
Description
Technical Field
The invention belongs to the field of chemistry, and particularly relates to a method for preparing 9 beta, 10 alpha-5, 7-diene steroid compounds.
Background
Dydrogesterone (Dydrogesterone), also known as Dydrogesterone, is a synthetic progestational drug with oral activity, can be used for treating progesterone deficiency, endometriosis, preventing threatened abortion, improving neonatal weight, treating climacteric syndrome and other pharmacological actions, has generally better pharmacological activity than other progestational drugs, and has higher safety. Therefore, it is widely used in clinical practice.
The 9 beta, 10 alpha-5, 7-diene steroid is an important intermediate compound for synthesizing dehydroprogesterone, and Dauben (J.Am.Chem.Soc.1982,104, pp355) uses laser to irradiate the 9 alpha, 10 beta-5, 7-diene steroid to prepare the 9 beta, 10 alpha-5, 7-diene steroid, but a laser generator is very expensive, and the preparation method greatly increases the synthesis cost of the 9 beta, 10 alpha-5, 7-diene steroid. US patent US5304291 describes a process for preparing 9 β,10 α -5,7 diene steroid intermediates by irradiating 9 α,10 β -5,7 diene steroids with an indium-doped mercury lamp, but indium-doped mercury lamps are not only expensive, but also unstable in operation, resulting in failure to obtain a stable yield.
The invention aims to provide a preparation method for reducing the synthesis cost of 9 beta, 10 alpha-5, 7-diene steroids.
Disclosure of Invention
The invention aims to provide a low-cost 9 beta, 10 alpha-5, 7-diene steroid synthesis method, and particularly provides a method for preparing 9 beta, 10 alpha-5, 7-diene steroids, which is characterized in that 9 alpha, 10 beta-5, 7-diene steroids are irradiated by a doped mercury lamp, and the doped mercury lamp is not an indium doped mercury lamp.
Preferably, the doped mercury lamp is an iron-doped mercury lamp, a calcium-doped mercury lamp, or a combination thereof;
more preferably, the doped mercury lamp is a combination of an iron-doped mercury lamp and a calcium-doped mercury lamp;
preferably, the synthesis method is to use an iron-doped mercury lamp and a calcium-doped mercury lamp for co-irradiation or sequential irradiation of 9 alpha, 10 beta-5, 7-diene steroids.
Preferably, the synthesis method comprises the steps of irradiating the 9 alpha, 10 beta-5, 7-diene steroid by using an iron-doped mercury lamp and a calcium-doped mercury lamp together;
preferably, the synthesis method comprises the steps of irradiating 9 alpha, 10 beta-5, 7-diene steroids by using an iron-doped mercury lamp, and then irradiating by using a calcium-doped mercury lamp;
more preferably, the synthesis method comprises the steps of irradiating the 9 alpha, 10 beta-5, 7-diene steroid by using a calcium-doped mercury lamp, and then irradiating by using an iron-doped mercury lamp.
Most preferably, the synthesis method comprises the steps of irradiating the 9 alpha, 10 beta-5, 7-diene steroid by using an iron-doped mercury lamp, then irradiating the 9 alpha, 10 beta-5, 7-diene steroid by using an iron-doped mercury lamp and a calcium-doped mercury lamp together or irradiating the 9 alpha, 10 beta-5, 7-diene steroid by using a calcium-doped mercury lamp, and then irradiating the 9 alpha, 10 beta-5, 7-diene steroid by using an iron-doped mercury lamp and a calcium-doped mercury lamp together.
Preferably, the synthesis method further optionally comprises group protection and deprotection steps.
The invention has the advantages of
The invention utilizes the iron-doped mercury lamp, the calcium-doped mercury lamp or the combination thereof to irradiate the 9 alpha, 10 beta-5, 7 diene steroid to prepare the 9 beta, 10 alpha-5, 7 diene steroid, greatly reduces the synthesis cost of the 9 beta, 10 alpha-5, 7 diene steroid, has high process stability, greatly improves the yield of the 9 beta, 10 alpha-5, 7 diene steroid by optimizing the irradiation sequence and the irradiation time of the iron-doped mercury lamp and the calcium-doped mercury lamp, and is very suitable for the batch production of the 9 beta, 10 alpha-5, 7 diene steroid.
Detailed Description
The present invention is described in more detail below to facilitate an understanding of the present invention.
Effect example 1: influence of irradiation light source on yield and process stability of 9 beta, 10 alpha-5, 7-diene steroid photochemical conversion method
1.1 preparation method
Weighing 10g of 9 alpha, 10 beta-5, 7 diene steroid, adding the weighed 9 alpha, 10 beta-5, 7 diene steroid into 1L of methyl acetate, stirring and dissolving, putting the mixture into a photochemical reactor, filling nitrogen into the photochemical reactor, maintaining the temperature of the photochemical reactor at-10 ℃ to-5 ℃, and irradiating the mixture by using an irradiation light source to detect the yield of the final product 9 beta, 10 alpha-5, 7 diene steroid, wherein the irradiation light source and the irradiation steps are shown in a table 1, wherein: the yield was determined as actual yield/theoretical yield X100%, the operation was repeated 5 times for each group, and the average, standard deviation and Relative Standard Deviation (RSD) of the yields were calculated for each group, where RSD was determined as standard deviation/average X100%.
Table 1: irradiation light source and irradiation step
1.2 results of the experiment
Table 2 shows that the use of the lower cost Fe-doped mercury lamp, Ca-doped mercury lamp or their combination in the invention instead of the existing expensive indium-doped mercury lamp results in a yield of 9 beta, 10 alpha-5, 7 diene steroids comparable to or even higher than that of the indium-doped mercury lamp, and the irradiation step has a significant effect on the yield of 9 beta, 10 alpha-5, 7 diene steroids, the use of the combination of Fe-doped mercury lamp and Ca-doped mercury lamp
Table 2: effect of the illumination light Source and the illumination step on the throughput
| Group of | Average yield | Standard deviation of yield | Relative Standard Deviation (SD) |
| Control group | 29.06％ | 0.5255 | 18.08％ |
| Example 1 | 28.88％ | 0.1066 | 3.69％ |
| Example 2 | 26.40％ | 0.1936 | 7.34％ |
| Example 3 | 34.54％ | 0.2211 | 6.40％ |
| Example 4 | 31.10％ | 0.1823 | 5.86％ |
| Example 5 | 30.86％ | 0.2669 | 8.65％ |
| Example 6 | 53.04％ | 0.2021 | 3.81％ |
| Example 7 | 43.74％ | 0.2723 | 6.22％ |
The irradiation examples 3-7 had 9 β,10 α -5,7 diene steroid yields significantly higher than those of examples 1-2 and the control using an iron-doped mercury lamp, a calcium-doped mercury lamp or an indium-doped mercury lamp alone, showing that the combined irradiation of an iron-doped mercury lamp and a calcium-doped mercury lamp had significant effects of increasing 9 β,10 α -5,7 diene steroid yields, and the effect of increasing 9 β,10 α -5,7 diene steroid yields by co-irradiation was superior to that by sequential irradiation, while the irradiation sequence of the irradiation light source also had significant effects on 9 β,10 α -5,7 diene steroid yields, and example 4, which was irradiated with an iron-doped mercury lamp first and then with a calcium-doped mercury lamp, had a higher yield than example 5, which was irradiated with a calcium-doped mercury lamp first and then with an iron-doped mercury lamp. The effect of improving the steroid yield of the 9 beta, 10 alpha-5, 7 diene is most obvious in the groups of examples 6-7 adopting single light source irradiation and combined light source co-irradiation, and particularly the effect of the group of example 6 adopting the irradiation of an iron-doped mercury lamp for 1h and then the co-irradiation of the iron-doped mercury lamp and a calcium-doped mercury lamp for 1h is most excellent.
Table 2 experimental results show that the use of the iron-doped mercury lamp, the calcium-doped mercury lamp, or the combination thereof according to the present invention, which is less costly than the use of the existing indium-doped mercury lamp, has significantly improved process stability, in which the relative standard deviation of the steroid yield of diene, 10 α -5,7, is significantly lower than that of the indium-doped mercury lamp of the control group, regardless of whether the iron-doped mercury lamp alone, the calcium-doped mercury lamp, or the combination thereof, in which the irradiation of the iron-doped mercury lamp alone, or the like, of the example 1 group, and the example 6 group, first for 1h, and then the co-irradiation of the iron-doped mercury lamp and the calcium-doped mercury lamp for 1h, are most excellent, and the relative standard deviation thereof is less than 5%, showing very excellent process stability.
The experimental results show that the yield of 9 beta, 10 alpha-5, 7 diene steroids which is equivalent to or even higher than that of indium-doped mercury lamps can be obtained by adopting iron-doped mercury lamps or calcium-doped mercury lamps with lower cost, so that the preparation cost of the 9 beta, 10 alpha-5, 7 diene steroids can be greatly reduced.
The foregoing describes preferred embodiments of the present invention, but is not intended to limit the invention thereto. Modifications and variations of the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.
Claims (10)
1. A process for the preparation of a 9 β,10 α -5, 7-diene steroid compound, characterised in that a 9 α,10 β -5, 7-diene steroid is irradiated using a doped mercury lamp, said doped mercury lamp not being an indium doped mercury lamp.
2. The process for the preparation of 9 β,10 α -5, 7-diene steroids according to claim 1, wherein the doped mercury lamp is an iron doped mercury lamp, a calcium doped mercury lamp or a combination thereof.
3. The process for the preparation of 9 β,10 α -5, 7-diene steroids according to claim 2, wherein the doped mercury lamp is an iron doped mercury lamp.
4. The process for the preparation of 9 β,10 α -5, 7-diene steroids according to claim 2, wherein the doped mercury lamp is a calcium doped mercury lamp.
5. The process for the preparation of 9 β,10 α -5, 7-diene steroids according to claim 1, wherein the doped mercury lamp is a combination of an iron doped mercury lamp and a calcium doped mercury lamp.
6. The process for preparing 9 β,10 α -5, 7-diene steroids according to claim 5, wherein the 9 α,10 β -5, 7-diene steroid is co-irradiated or sequentially irradiated with an iron-doped mercury lamp and a calcium-doped mercury lamp.
7. The process for the preparation of 9 β,10 α -5, 7-diene steroids according to claim 6, wherein the 9 α,10 β -5, 7-diene steroid is co-irradiated with a calcium-doped mercury lamp and an iron-doped mercury lamp.
8. The process for preparing 9 β,10 α -5, 7-diene steroids according to claim 7, wherein the 9 α,10 β -5, 7-diene steroid is irradiated using an iron-doped mercury lamp and then irradiated using a calcium-doped mercury lamp.
9. The method for preparing 9 β,10 α -5, 7-diene steroids according to claim 7, wherein the 9 α,10 β -5, 7-diene steroids are irradiated using a calcium-doped mercury lamp and then irradiated using an iron-doped mercury lamp.
10. The method for preparing 9 β,10 α -5, 7-diene steroids according to claim 6, wherein the 9 α,10 β -5, 7-diene steroids are irradiated using an iron-doped mercury lamp, and then irradiated using an iron-doped mercury lamp and a calcium-doped mercury lamp together or irradiated using a calcium-doped mercury lamp, and then irradiated using an iron-doped mercury lamp and a calcium-doped mercury lamp together.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3198792A (en) * | 1962-06-12 | 1965-08-03 | Philips Corp | 10alpha methyl, 9beta hormonal steroids |
| US3219565A (en) * | 1960-05-30 | 1965-11-23 | Philips Corp | Method of producing 10alpha-methyl steroids |
| US4601855A (en) * | 1984-02-15 | 1986-07-22 | Duphar International Research B.V. | Method of preparing 9β, 10α-5,7-diene steroids |
| US5304291A (en) * | 1992-02-27 | 1994-04-19 | Duphar International Research B.V. | Method of preparing 9beta, 10alpha-5,7-diene steroids |
| CN1111987A (en) * | 1995-04-10 | 1995-11-22 | 浙江省医学科学院 | Transcutaneous huperzing sticker |
| WO2009108388A2 (en) * | 2008-02-28 | 2009-09-03 | University Of Tennessee Research Foundation | Enzymatic production or chemical synthesis and uses for 5,7-dienes and uvb conversion products thereof |
| CN111171101A (en) * | 2020-01-03 | 2020-05-19 | 宁波东隆光电科技有限公司 | Preparation method of dydrogesterone intermediate |
-
2020
- 2020-10-26 CN CN202011159322.2A patent/CN112194696B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3219565A (en) * | 1960-05-30 | 1965-11-23 | Philips Corp | Method of producing 10alpha-methyl steroids |
| US3198792A (en) * | 1962-06-12 | 1965-08-03 | Philips Corp | 10alpha methyl, 9beta hormonal steroids |
| US4601855A (en) * | 1984-02-15 | 1986-07-22 | Duphar International Research B.V. | Method of preparing 9β, 10α-5,7-diene steroids |
| US5304291A (en) * | 1992-02-27 | 1994-04-19 | Duphar International Research B.V. | Method of preparing 9beta, 10alpha-5,7-diene steroids |
| CN1111987A (en) * | 1995-04-10 | 1995-11-22 | 浙江省医学科学院 | Transcutaneous huperzing sticker |
| WO2009108388A2 (en) * | 2008-02-28 | 2009-09-03 | University Of Tennessee Research Foundation | Enzymatic production or chemical synthesis and uses for 5,7-dienes and uvb conversion products thereof |
| CN111171101A (en) * | 2020-01-03 | 2020-05-19 | 宁波东隆光电科技有限公司 | Preparation method of dydrogesterone intermediate |
Non-Patent Citations (2)
| Title |
|---|
| Z.L.GRIGORYAN，ET AL.: "Photochemical Transformations of 7-Dehydrocholesterol", 《RUSSIAN JOURNAL OF APPLIED CHEMISTRY》 * |
| 江杉化学: "https://zhuanlan.zhihu.com/p/188638432", 《知乎》 * |
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