CN103588842A - Synthetic method of betamethasone or prednisolone intermediate - Google Patents
Synthetic method of betamethasone or prednisolone intermediate Download PDFInfo
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- CN103588842A CN103588842A CN201210286894.6A CN201210286894A CN103588842A CN 103588842 A CN103588842 A CN 103588842A CN 201210286894 A CN201210286894 A CN 201210286894A CN 103588842 A CN103588842 A CN 103588842A
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Abstract
The invention discloses a synthetic method of 11 beta,17 alpha-dihydroxy-1,4-diene pregne-3,20-diketone-21-acetate. The invention employs 11 alpha-hydroxy-1,4-diene-16,17-epoxy progesterone (ii) as a starting material, which together with methyl p-toluenesulfonate is subjected to a Mitunobu reaction for inversion under the catalysis of diethyl azodiformate and triphenyl phosphine to obtain 11 beta-p-toluenesulfonyl-16,17 epoxy-1,4-diene progesterone (iii), namely a 11 beta-hydroxy protector; the (iii) is subjected to protective group removal in the presence of HBr, and 16,17-epoxy addition to obtain 11 beta, 17 alpha-dihydroxy-16 beta-bromo-1,4-allyl progesterone (iv); the (iv) is subjected to 3 steps to synthesize 11 beta,17 alpha-dihydroxy-1,4-diene pregne-3,20-diketone (v), which is added with iodine to obtain 11 beta,17 alpha-dihydroxy-1,4-diene pregne-3,20- diketone-21-iodine (vi); and the (vi) is subjected to replacement with potassium acetate to obtain the 11 beta,17 alpha-dihydroxy-1,4-diene pregne-3,20-diketone-21-acetate (i). The method provided by the invention can avoid complex strain breeding, has the advantages of simple operation, high yield, little environmental pollution, and has good industrial application prospect.
Description
Technical field
The invention belongs to pharmaceutical chemistry field, be specifically related to the synthetic method of a kind of Betamethasone Valerate or prednisolone intermediate.
Background technology
11 β, 17 Alpha-hydroxy-1, pregnant steroid-3 of 4-alkene, 20-diketone-21-acetic ester (i) belongs to medicine intermediate, can be used for preparing prednisolone, Betamethasone Valerate and derivative thereof, its synthetic starting raw material is 11 Alpha-hydroxy-1,4-diene-16,17-epoxy Progesterone (ii), is called again mould dehydrogen substance, suitability for industrialized production is many, and raw material sources are wide.The method of producing at present 11 beta-hydroxies has 3 kinds: (1) biological fermentation process, utilizes energy direct oxidation to generate the bacterial classification One-step production of 11 beta-hydroxies.This method is comparatively advanced at present, and yield is high, and shortcoming is strain improvement trouble, is difficult to obtain.(2) with 11-carbonyl reduction, be 11 beta-hydroxies, there is relatively morning in this method, but need to first protect 3,20-dicarbapentaborane, is reduced to after 11 beta-hydroxies, then sloughs protecting group, and yield is not high.(3) with 9(11) the bromine hydroxyl addition of-alkene, restore and slough 9 α-bromine and obtain 11 beta-hydroxies, this method yield is also higher, but in reaction, needs to use compound or other metals of chromium, and environmental pollution is serious.
Summary of the invention
The object of the present invention is to provide a kind of 11 β, pregnant steroid-3 of 17 Alpha-hydroxies-Isosorbide-5-Nitrae-diene, the synthetic method of 20-diketone-21-acetic ester.
The present invention adopts 11 Alpha-hydroxy-1, 4-diene-16, 17-epoxy Progesterone is (ii) as starting raw material, with methyl tosylate, under diethyl azodiformate and triphenylphosphine catalysis, through Mitunobu reaction (light prolongs reaction) reversion, obtain 11 β-p-toluenesulfonyl-16, 17-epoxy-1, 4-diene Progesterone (iii), 11 beta-hydroxies are protected things, under existing, HBr sloughs protecting group again, while 16, the addition of 17-epoxy obtains 11 β, 17 Alpha-hydroxy-16 β-bromo-1, 4-diene Progesterone (iv), through synthetic 11 β of 3 steps, 17 Alpha-hydroxy-1, pregnant steroid-3 of 4-diene, 20-diketone (v), upper iodine obtains 11 β, 17 alpha-dihydroxy--1, pregnant steroid-3 of 4-diene, 20-diketone-21-iodine (vi), then obtain 11 β with potassium acetate displacement, 17 alpha-dihydroxy--1, pregnant steroid-3 of 4-diene, 20-diketone-21-acetic ester (i).Reaction equation as shown in Figure 1.The invention provides a kind of synthetic 11 beta-hydroxies of method that utilize chemical transposition, to overcome existing defect in prior art.
11 β of the present invention, pregnant steroid-3 of 17 Alpha-hydroxies-Isosorbide-5-Nitrae-diene, the synthetic method of 20-diketone-21-acetic ester comprises the steps:
(a), 11 Alpha-hydroxies-Isosorbide-5-Nitrae-diene-16, under the condition that 17-epoxy Progesterone and methyl tosylate exist at organic solvent and catalyzer, through Mitunobu reaction reversion, obtain 11 β-p-toluenesulfonyl-16,17-epoxy-Isosorbide-5-Nitrae-alkene Progesterone;
(b), described 11 β-p-toluenesulfonyl-16, under the condition that 17-epoxy-Isosorbide-5-Nitrae-diene Progesterone exists at hydrogen bromide and acetic acid, reaction generates 11 β, 17 alpha-dihydroxy--16 β-bromo-Isosorbide-5-Nitrae-diene Progesterone;
(c), described 11 β, under the condition that 17 alpha-dihydroxy--16 β-bromo-Isosorbide-5-Nitrae-diene Progesterone exists at catalyzer and reductive agent, reaction generates 11 β, pregnant steroid-3 of 17 alpha-dihydroxy-s-Isosorbide-5-Nitrae-alkene, 20-diketone;
(d), described 11 β, pregnant steroid-3 of 17 alpha-dihydroxy-s-Isosorbide-5-Nitrae-diene, 20-diketone obtains 11 β with Iod R in organic solvent, pregnant steroid-3 of 17 alpha-dihydroxy-s-Isosorbide-5-Nitrae-diene, 20-diketone-21-iodine;
(e), described 11 β, pregnant steroid-3 of 17 alpha-dihydroxy-s-Isosorbide-5-Nitrae-diene, 20-diketone-21-iodine reacts with Potassium ethanoate and obtains 11 β in organic solvent, pregnant steroid-3 of 17 Alpha-hydroxies-Isosorbide-5-Nitrae-diene, 20-diketone-21-acetic ester.
According to the present invention, described in described step (a), organic solvent is selected from: tetrahydrofuran (THF) or toluene.
According to the present invention, described in described step (a), catalyzer is selected from: diethyl azodiformate and triphenylphosphine or azoformic acid dipropyl and triphenylphosphine.
According to the present invention, described in described step (b), Hydrogen bromide is 48%(w/w) hydrobromic acid aqueous solution.
According to the present invention, the temperature of reaction of described step (b) is 20-25 ℃.
According to the present invention, described in described step (c), catalyzer is nickel.
According to the present invention, described in described step (c), reductive agent is hydrogen.
According to the present invention, described in described step (d), organic solvent is methyl alcohol.
According to the present invention, described in described step (d), the temperature of reaction of reaction is 15-20 ℃.
According to the present invention, described in described step (e), organic solvent is acetone.
According to the present invention, described in described step (e), the temperature of reaction of reaction is 55-60 ℃.
The present invention has following beneficial effect:
1, can avoid repetition, loaded down with trivial details strain improvement work;
2, do not need first to protect 3,20-dicarbapentaborane, simple to operate, yield reaches 75%;
3, do not need the compound containing chromium or other heavy metals, environmental pollution is little.
No matter technical scheme disclosed in this invention is technically or from environment protection, all has good prospects for commercial application.
Accompanying drawing explanation
Fig. 1 is reaction equation of the present invention.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.Should be understood that following examples are only for the present invention is described but not for limiting scope of the present invention.
Embodiment 1:
(a), in 500ml there-necked flask, add successively 10g(0.029mol) 11 Alpha-hydroxy-1,4-diene-16,17-epoxy Progesterone (ii), about 140ml tetrahydrofuran (THF), 10.1g(0.059mol) diethyl azodiformate and 29.9g(0.116mol) triphenylphosphine, stir 30 minutes, be cooled to-10～-5 ℃, at-10 ℃, start to drip 11.3g(0.061mol) methyl tosylate, within approximately 1 hour, drip off, then be warmed up to 20 ℃, insulation reaction 2 hours, TLC follows the tracks of reaction and finishes.Reclaim tetrahydrofuran (THF) from reaction solution after, obtain solid, add 20ml methyl alcohol, stir 30 minutes, be cooled to 0-5 ℃, filter, obtain 11 β-p-toluenesulfonyl-16,17-epoxy-Isosorbide-5-Nitrae-diene Progesterone (iii).
(b), described 11 β-p-toluenesulfonyl-16,17-epoxy-Isosorbide-5-Nitrae-diene Progesterone does not (iii) need to be dried; directly drop in another clean 500ml there-necked flask; add 20ml glacial acetic acid and 48%HBr 10ml, 20 ℃ are stirred 3 hours, and TLC tracks to and reacts completely; add frozen water 400ml; solid filtering is separated out in stirring, and 80 ℃ dry, obtains 8g 11 β; 17 Alpha-hydroxy-16 β-bromo-Isosorbide-5-Nitrae-diene Progesterone (iv).
(c), by described 11 β, 17 Alpha-hydroxy-16 β-bromo-Isosorbide-5-Nitrae-diene Progesterone (iv) drops in another clean 500ml there-necked flask, adds ethanol 300ml, nickel catalyzator 5g, ammonium acetate 1g, under stirring, pass into hydrogen 3 hours, TLC follows the tracks of reaction and finishes, and concentrating under reduced pressure ethanol obtains solid, 80 ℃ of dry white solid 11 β that obtain, 17 alpha-dihydroxy--1, pregnant steroid-3 of 4-diene, 20-diketone (v), yield 75%.
(d), by described 11 β, 17 alpha-dihydroxy--1, pregnant steroid-3 of 4-diene, 20-diketone (v) drops in another clean 500ml there-necked flask, add methyl alcohol 50ml, cool to 15 ℃, add 3g calcium oxide, within 1-2 hour, drip iodine liquid (iodine liquid preparation way: 9g iodine drops in 200ml single port bottle, add 2g Calcium Chloride Powder Anhydrous, 30ml methyl alcohol, stir dissolving in 2 hours) complete, add frozen water 400ml, stir and separate out solid, filter and obtain 11 β, pregnant steroid-3 of 17 alpha-dihydroxy-s-Isosorbide-5-Nitrae-diene, 20-ketone-21-iodine (vi).
(e), described 11 β, 17 alpha-dihydroxy--1, pregnant steroid-3 of 4-diene, 20-diketone-21-iodine does not (vi) need to be dried, directly drop in another clean 500ml there-necked flask, add 200ml acetone, 20ml glacial acetic acid, 10g Potassium ethanoate, be heated to 55 ℃ of reactions 3 hours, concentrating under reduced pressure acetone, add frozen water 400ml to stir precipitate, filtration obtains solid, 80 ℃ of dry white solid 11 β that obtain, 17 alpha-dihydroxy--1, pregnant steroid-3 of 4-diene, 20-diketone-21-acetic ester (i), yield 75%, with the consistent (HPLC of prednisolone acetic ester standard control, fusing point), can determine it is same product.
Embodiment 2:
(a), in 500ml there-necked flask, add successively 10g(0.029mol) 11 Alpha-hydroxy-1,4-diene-16,17-epoxy Progesterone (ii), about 140ml tetrahydrofuran (THF), 10.1g(0.059mol) azoformic acid dipropyl and 29.9g(0.116mol) triphenylphosphine, stir 30 minutes, be cooled to-10～-5 ℃, at-10 ℃, start to drip 11.3g(0.061mol) methyl tosylate, within approximately 1 hour, drip off, then be warmed up to 22 ℃, insulation reaction 2.5 hours, TLC follows the tracks of reaction and finishes.Reclaim tetrahydrofuran (THF) from reaction solution after, obtain solid, add 20ml methyl alcohol, stir 30 minutes, be cooled to 0-5 ℃, filter, obtain 11 β-p-toluenesulfonyl-16,17-epoxy-Isosorbide-5-Nitrae-diene Progesterone (iii).
(b), described 11 β-p-toluenesulfonyl-16,17-epoxy-Isosorbide-5-Nitrae-diene Progesterone does not (iii) need to be dried; directly drop in another clean 500ml there-necked flask; add 20ml glacial acetic acid and 48%HBr 10ml, 22 ℃ are stirred 3 hours, and TLC tracks to and reacts completely; add frozen water 400ml; solid filtering is separated out in stirring, and 80 ℃ dry, obtains 8g 11 β; 17 Alpha-hydroxy-16 β-bromo-Isosorbide-5-Nitrae-diene Progesterone (iv).
(c), by described 11 β, 17 Alpha-hydroxy-16 β-bromo-Isosorbide-5-Nitrae-diene Progesterone (iv) drops in another clean 500ml there-necked flask, adds ethanol 300ml, nickel catalyzator 5g, ammonium acetate 1g, under stirring, pass into hydrogen 3 hours, TLC follows the tracks of reaction and finishes, and concentrating under reduced pressure ethanol obtains solid, 80 ℃ of dry white solid 11 β that obtain, 17 alpha-dihydroxy--1, pregnant steroid-3 of 4-diene, 20-diketone (v), yield 74.2%.
(d), by described 11 β, 17 alpha-dihydroxy--1, pregnant steroid-3 of 4-diene, 20-diketone (v) drops in another clean 500ml there-necked flask, add methyl alcohol 50ml, cool to 17 ℃, add 3g calcium oxide, within 1-2 hour, drip iodine liquid (iodine liquid preparation way: 9g iodine drops in 200ml single port bottle, add 2g Calcium Chloride Powder Anhydrous, 30ml methyl alcohol, stir dissolving in 2 hours) complete, add frozen water 400ml, stir and separate out solid, filter and obtain 11 β, pregnant steroid-3 of 17 alpha-dihydroxy-s-Isosorbide-5-Nitrae-diene, 20-ketone-21-iodine (vi).
(e), described 11 β, 17 alpha-dihydroxy--1, pregnant steroid-3 of 4-diene, 20-diketone-21-iodine does not (vi) need to be dried, directly drop in another clean 500ml there-necked flask, add 200ml acetone, 20ml glacial acetic acid, 10g Potassium ethanoate, be heated to 58 ℃ of reactions 3 hours, concentrating under reduced pressure acetone, add frozen water 400ml to stir precipitate, filtration obtains solid, 80 ℃ of dry white solid 11 β that obtain, 17 alpha-dihydroxy--1, pregnant steroid-3 of 4-diene, 20-diketone-21-acetic ester (i), yield 74.5%, with the consistent (HPLC of prednisolone acetic ester standard control, fusing point), can determine it is same product.
Embodiment 3:
(a), in 500ml there-necked flask, add successively 10g(0.029mol) 11 Alpha-hydroxy-1,4-diene-16,17-epoxy Progesterone (ii), about 140ml toluene, 10.1g(0.059mol) diethyl azodiformate and 29.9g(0.116mol) triphenylphosphine, stir 30 minutes, be cooled to-10～-5 ℃, at-10 ℃, start to drip 11.3g(0.061mol) methyl tosylate, within approximately 1 hour, drip off, then be warmed up to 25 ℃, insulation reaction 3 hours, TLC follows the tracks of reaction and finishes.Reclaim toluene from reaction solution after, obtain solid, add 20ml methyl alcohol, stir 30 minutes, be cooled to 0-5 ℃, filter, obtain 11 β-p-toluenesulfonyl-16,17-epoxy-Isosorbide-5-Nitrae-diene Progesterone (iii).
(b), described 11 β-p-toluenesulfonyl-16,17-epoxy-Isosorbide-5-Nitrae-diene Progesterone does not (iii) need to be dried; directly drop in another clean 500ml there-necked flask; add 20ml glacial acetic acid and 48%HBr 10ml, 25 ℃ are stirred 3 hours, and TLC tracks to and reacts completely; add frozen water 400ml; solid filtering is separated out in stirring, and 80 ℃ dry, obtains 11 β; 17 alpha-dihydroxy--16 β-bromo-Isosorbide-5-Nitrae-alkene Progesterone (iv).
(c), by described 11 β, 17 Alpha-hydroxy-16 β-bromo-Isosorbide-5-Nitrae-diene Progesterone (iv) drops in another clean 500ml there-necked flask, adds ethanol 300ml, nickel catalyzator 5g, ammonium acetate 1g, under stirring, pass into hydrogen 3 hours, TLC follows the tracks of reaction and finishes, and concentrating under reduced pressure ethanol obtains solid, 80 ℃ of dry white solid 11 β that obtain, 17 alpha-dihydroxy--1, pregnant steroid-3 of 4-diene, 20-diketone (v), yield 75.3%.
(d), by described 11 β, 17 alpha-dihydroxy--1, pregnant steroid-3 of 4-diene, 20-diketone (v) drops in another clean 500ml there-necked flask, add methyl alcohol 50ml, cool to 20 ℃, add 3g calcium oxide, within 1-2 hour, drip iodine liquid (iodine liquid preparation way: 9g iodine drops in 200ml single port bottle, add 2g Calcium Chloride Powder Anhydrous, 30ml methyl alcohol, stir dissolving in 2 hours) complete, add frozen water 400ml, stir and separate out solid, filter and obtain 11 β, pregnant steroid-3 of 17 alpha-dihydroxy-s-Isosorbide-5-Nitrae-diene, 20-ketone-21-iodine (vi).
(e), described 11 β, 17 alpha-dihydroxy--1, pregnant steroid-3 of 4-diene, 20-diketone-21-iodine does not (vi) need to be dried, directly drop in another clean 500ml there-necked flask, add 200ml acetone, 20ml glacial acetic acid, 10g Potassium ethanoate, be heated to 60 ℃ of reactions 3 hours, concentrating under reduced pressure acetone, add frozen water 400ml to stir precipitate, filtration obtains solid, 80 ℃ of dry white solid 11 β that obtain, 17 alpha-dihydroxy--1, pregnant steroid-3 of 4-diene, 20-diketone-21-acetic ester (i), yield 75.2%, with the consistent (HPLC of prednisolone acetic ester standard control, fusing point), can determine it is same product.
The foregoing is only preferred embodiment of the present invention, in order to limit the present invention, within the spirit and principles in the present invention not all, any modification of making, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Claims (11)
1. 11 β, pregnant steroid-3 of 17 alpha-dihydroxy-s-Isosorbide-5-Nitrae-alkene, the synthetic method of 20-diketone-21-acetic ester, is characterized in that, described synthetic method comprises the steps:
(a), 11 Alpha-hydroxies-Isosorbide-5-Nitrae-diene-16, under the condition that 17-epoxy Progesterone and methyl tosylate exist at organic solvent and catalyzer, through Mitunobu reaction reversion, obtain 11 β-p-toluenesulfonyl-16,17-epoxy-Isosorbide-5-Nitrae-diene Progesterone;
(b), described 11 β-p-toluenesulfonyl-16, under the condition that 17-epoxy-Isosorbide-5-Nitrae-diene Progesterone exists at hydrogen bromide and acetic acid, reaction generates 11 β, 17 Alpha-hydroxy-16 β-bromo-Isosorbide-5-Nitrae-alkene Progesterone;
(c), described 11 β, under the condition that 17 Alpha-hydroxy-16 β-bromo-Isosorbide-5-Nitrae-alkene Progesterone exists at catalyzer and reductive agent, reaction generates 11 β, pregnant steroid-3 of 17 alpha-dihydroxy-s-Isosorbide-5-Nitrae-alkene, 20-diketone;
(d), described 11 β, pregnant steroid-3 of 17 Alpha-hydroxies-Isosorbide-5-Nitrae-alkene, 20-diketone obtains 11 β with Iod R in organic solvent, pregnant steroid-3 of 17 Alpha-hydroxies-Isosorbide-5-Nitrae-alkene, 20-ketone-21-iodine;
(e), described 11 β, pregnant steroid-3 of 17 Alpha-hydroxies-Isosorbide-5-Nitrae-diene, 20-diketone-21-iodine reacts with Potassium ethanoate and obtains 11 β in organic solvent, pregnant steroid-3 of 17 alpha-dihydroxy-s-Isosorbide-5-Nitrae-diene, 20-diketone-21-acetic ester.
2. synthetic method as claimed in claim 1, is characterized in that, described in described step (a), organic solvent is selected from: tetrahydrofuran (THF) or toluene.
3. synthetic method as claimed in claim 1, is characterized in that, described in described step (a), catalyzer is selected from: diethyl azodiformate and triphenylphosphine or azoformic acid dipropyl and triphenylphosphine.
4. synthetic method as claimed in claim 1, is characterized in that, described in described step (b), Hydrogen bromide is 48%(w/w) hydrobromic acid aqueous solution.
5. synthetic method as claimed in claim 1, is characterized in that, the temperature of reaction of described step (b) is 20-25 ℃.
6. synthetic method as claimed in claim 1, is characterized in that, described in described step (c), catalyzer is nickel.
7. synthetic method as claimed in claim 1, is characterized in that, described in described step (c), reductive agent is hydrogen.
8. synthetic method as claimed in claim 1, is characterized in that, described in described step (d), organic solvent is methyl alcohol.
9. synthetic method as claimed in claim 1, is characterized in that, described in described step (d), the temperature of reaction of reaction is 15-20 ℃.
10. synthetic method as claimed in claim 1, is characterized in that, described in described step (e), organic solvent is acetone.
11. synthetic methods as claimed in claim 1, is characterized in that, described in described step (e), the temperature of reaction of reaction is 55-60 ℃.
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| CN201210286894.6A CN103588842A (en) | 2012-08-13 | 2012-08-13 | Synthetic method of betamethasone or prednisolone intermediate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104370988A (en) * | 2014-11-07 | 2015-02-25 | 浙江仙琚制药股份有限公司 | Preparation method of prednisone acetate |
| CN105801650A (en) * | 2016-04-13 | 2016-07-27 | 浙江仙琚制药股份有限公司 | Method for preparing prednisolone |
| CN106893752A (en) * | 2015-12-21 | 2017-06-27 | 天津金耀集团有限公司 | A kind of preparation method of the ketone-21- acetic ester compounds of the pregnant double bond of steroid-1,4-11 |
-
2012
- 2012-08-13 CN CN201210286894.6A patent/CN103588842A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104370988A (en) * | 2014-11-07 | 2015-02-25 | 浙江仙琚制药股份有限公司 | Preparation method of prednisone acetate |
| CN106893752A (en) * | 2015-12-21 | 2017-06-27 | 天津金耀集团有限公司 | A kind of preparation method of the ketone-21- acetic ester compounds of the pregnant double bond of steroid-1,4-11 |
| CN105801650A (en) * | 2016-04-13 | 2016-07-27 | 浙江仙琚制药股份有限公司 | Method for preparing prednisolone |
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Application publication date: 20140219 |