CN103588853A - Method for preparing 9,11beta-epoxy steroid compound - Google Patents
Method for preparing 9,11beta-epoxy steroid compound Download PDFInfo
- Publication number
- CN103588853A CN103588853A CN201310618900.8A CN201310618900A CN103588853A CN 103588853 A CN103588853 A CN 103588853A CN 201310618900 A CN201310618900 A CN 201310618900A CN 103588853 A CN103588853 A CN 103588853A
- Authority
- CN
- China
- Prior art keywords
- reaction
- solvent
- formula
- beta
- ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- HJUTWXOYPNKLSA-QLLDWXIKSA-N CCC[C@@H](C)C(C[C@H](C)[C@](COC(C)=O)(N)O[O](C)=C)C(CCC[C@@H]1C=C)CC/C1=C/C=O Chemical compound CCC[C@@H](C)C(C[C@H](C)[C@](COC(C)=O)(N)O[O](C)=C)C(CCC[C@@H]1C=C)CC/C1=C/C=O HJUTWXOYPNKLSA-QLLDWXIKSA-N 0.000 description 1
- GRKPBVAUFVYLHO-MQHDJVRRSA-N C[C@@H](C1)C(COC)[C@@](C)(CC2)C1[C@H](CC1)C2[C@@](C)(C=C2)C1=CC2=O Chemical compound C[C@@H](C1)C(COC)[C@@](C)(CC2)C1[C@H](CC1)C2[C@@](C)(C=C2)C1=CC2=O GRKPBVAUFVYLHO-MQHDJVRRSA-N 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Abstract
The present invention provides a method for preparing a 9,11beta-epoxy steroid compound represented by a formula 1. According to the method, a 9,11-double bond-21-ester steroid compound is adopted as a raw material, and reacts with a halogenating agent in a suitable organic solvent containing 70% perchloric acid to produce a 9alpha-halo-11beta-ester-21-ester steroid compound, and the 9alpha-halo-11beta-ester-21-ester steroid compound reacts with a strong base in an organic solvent to obtain the 9,11beta-epoxy steroid compound. The 9,11beta-epoxy steroid compound can be used for preparation of dexamethasone, betamethasone and series other drugs. According to the present invention, the 9,11beta-epoxy steroid compound can be prepared from the almost equimolar amount of the 9,11-double bond-21-ester steroid compound, such that the method is the synthesis method with characteristics of economy, efficiency and environmental protection.
Description
Technical field
The present invention relates to pharmaceutical chemistry, be specifically related to the preparation method of pharmaceutical intermediate, relate in particular to the preparation method for the preparation of key intermediate 9,11 beta epoxide steroids of dexamethasone and Betamethasone Valerate medicine series.
Background technology
9,11 beta epoxide steroids are key intermediates of dexamethasone series and Betamethasone Valerate medicine series, and its structural formula (formula 1) is as follows:
9,11 beta epoxide steroids can make dexamethasone or Betamethasone Valerate very easily by 9 fluoro, by a series of modifications of 3,6,16,21, can make medicine series.
In Chinese patent CN101397319, provide a kind of then carry out epoxidation with alkali and re-use highly basic hydrolysis and make 9 by generating halogenide in fatty alcohol, halohydrocarbon, ketone or ether solvent, the method of 11 beta epoxide steroids, in US Patent No. 3725392, also provide a kind of similar method to make 9,11 beta epoxide steroids.But aforesaid method can generate the organic impurity of 2-5% in epoxy and hydrolytic process, affected quality and the yield of product, therefore, require further improvement.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, and a kind of raw material of research and design is easy to get, easy and simple to handle, improves the quality of products and yield, is suitable for the preparation method of 9,11 beta epoxide steroids of suitability for industrialized production.
The invention provides the method for preparation 9,11 beta epoxide steroids.
Formula 19,11 beta epoxide steroids
The inventive method is with 9, two key-21-ester the steroides of 11-are that raw material is reacting containing in the suitable organic solvent of 70% perchloric acid with halogenating agent, produce 9 alpha-halogen-11 β-ester-21-ester steroides, then 9 alpha-halogen-11 β-ester-21-ester steroides are reacted in organic solvent with highly basic at low temperatures, obtain 9,11 beta epoxide steroids.
The inventive method comprises the following steps:
(1) in solvent, under perchloric acid exists, 9 of formula 2, the two key-21-ester steroides of 11-react with halogenating agent; Reaction finishes, and adds water, produces precipitation, filters, and being precipitated thing is 9 alpha-halogen-11 β-ester-21-ester steroides of formula 3; Or before elutriation, add C
1-C
6fatty alcohol stop oxidizing reaction, preferred fat alcohol is methyl alcohol, ethanol or Virahol, most preferably is methyl alcohol;
(2) in solvent, 9 alpha-halogen-11 β-ester-21-ester steroides of formula 3 react with highly basic, by determining, do not exist after raw material and intermediate, use organic acid for adjusting pH to 3-6 termination reaction; After reaction finishes, add elutriation to go out the precipitation of formula 1 compound, filter 9,11 beta epoxide steroids of sediment separate out formula 1; Or by distillation, remove after most of reaction solvent again 9,11 beta epoxide steroids that row elutriation obtains formula 1 before elutriation;
(3) purifying:
9 of formula 1,11 beta epoxide steroids are heated in 45 ℃ of methylene dichloride and methanol mixed solution that are dissolved in 20-30 times of weight ratio, then by filtering, air distillation to 65 ℃, be cooled to 5 ℃ following, filter, 60 ℃ of constant pressure and dries, obtain 9,11 beta epoxide steroids of purifying.
Step described in the inventive method (1) halogenating agent is selected from 1,3-bis-bromo-5,5-T10 (DBH), N-bromo-succinimide (NBS), N-chloro imide or two chlordantoins, preferred DBH, the consumption of halogenating agent is 0.5 to 3 mol ratio of formula 2 compounds, be preferably 0.65-0.8 mol ratio, more preferably 0.75-0.9 times of mol ratio, most preferably is 0.7 mol ratio.
Reaction solvent is selected from dimethyl formamide (DMF) or N,N-DIMETHYLACETAMIDE (DMAC), and quantity of solvent is the compound 0.5-10 times weight ratio of formula 2, is preferably 1-5 times of weight ratio, most preferably is 3.5 times of weight ratios.
Reaction finishes, and adds 70% high chloro acid solution, produces precipitation, and 70% high chloro acid solution's consumption is the compound 0.5-3 times mol ratio of formula 2, is preferably 0.8-1.2 doubly, most preferably is 1.0 times of mol ratios.
℃-50 ℃, temperature of reaction-20, preferably-5-10 ℃, most preferably is-2-2 ℃; Reaction times 1-4 hour, carrys out detection reaction by HPLC or TLC, determines raw material reaction time completely.
Reaction finishes, and reactant is incorporated as in the water of 10-100 times of weight of compound of formula 2; Or before elutriation, add alcohol, and be preferably methyl alcohol, ethanol or Virahol, most preferably be methyl alcohol termination reaction, the consumption of alcohol is 1-5 times of weight ratio of formula 2 compounds, is preferably 3 times of weight ratios.
Step described in the inventive method (2) temperature of reaction is-20 ℃ to 20 ℃, preferably-10 ℃-0 ℃, most preferably is-5 ℃.
Highly basic is the compound 2.0-5.0 mol ratio of formula 3, is preferably 3.0-3.5 mol ratio, most preferably is 3.15 mol ratios; Highly basic is organic bases or mineral alkali, is selected from sodium hydroxide, potassium hydroxide, salt of wormwood, sodium methylate, potassium methylate, sodium ethylate or potassium ethylate, is preferably sodium hydroxide.Highly basic can directly add, or is dissolved in solvent and adds, and described solvent is selected from water or lower aliphatic alcohols, and described lower aliphatic alcohols is methyl alcohol, ethanol or Virahol, is preferably water.Dissolve the water of alkali or the compound 0.5-3 times weight ratio that lower aliphatic alcohols consumption is formula 3, be preferably 0.8-1.2 doubly, most preferably be 1.0 times of weight ratios.
Reaction solvent is selected from one or more mixed solvents of tetrahydrofuran (THF), methylene dichloride, lower aliphatic alcohols or acetonitrile, and described lower aliphatic alcohols is methyl alcohol, ethanol or Virahol; Be preferably methylene dichloride and methanol mixed solvent or single methyl alcohol, most preferably be methylene dichloride and methanol mixed solvent, methylene dichloride and methanol mixed solvent ratios are 1:5 to 10:1, are preferably 3:1 to 7:1, most preferably are 5:1; The two total amount is 8 to 20 times of weight ratios of the compound of formula 3, is preferably 9～12 times of weight ratios, most preferably is 12 times of weight ratios.
Use organic acid for adjusting pH to 3～6 termination reaction, organic acid is selected from formic acid, acetic acid, tartrate or toluene sulfonic acide, is preferably acetic acid.
After reaction finishes, add elutriation to go out the precipitation of formula 1 compound, described amount of water is 10～30 times of weight ratios of formula 3 compounds.Or before elutriation, by distillation, to remove after most of reaction solvent amount of water described in row elutriation be 10～30 times of weight ratios of formula 3 compounds again.
Preparation 9 of the present invention, the method of 11 beta epoxide steroids, can also pass through with 9, two key-21-ester the steroides of 11-are that raw material is reacting containing in the organic solvent of 70% perchloric acid with halogenating agent, produce 9 alpha-halogen-11 β-ester-21-ester steroides, then 9 alpha-halogen-11 β-ester-21-ester steroides are reacted in organic solvent with highly basic, generate 9,11 beta epoxides-21-ester steroide, again 9,11 beta epoxides-21-ester steroide is reacted in organic solvent with highly basic at low temperatures, obtain 9,11 beta epoxide steroids
Shown in following reaction formula:
R wherein
1for hydrogen or C
1-C
6low alkyl group; Preferred R
1for low alkyl group, be most preferably-CH3; R
2for hydrogen or C
1-C
4low alkyl group, R most preferably
2for-CH
3; R
3for-COH or-COCH
3, be preferably-COH;
(a) in solvent, 9 alpha-halogen-11 β-ester-21-ester steroides of formula 3 react with highly basic, reaction finish that halogen is removed in rear filtration or with organic acid for adjusting pH to 3-6, wash, 9,11 beta epoxides-21-ester-steroide pressed powder that solvent obtains formula 4 is removed in distillation;
(b) in solvent, 9,11 beta epoxides of formula 4-21-ester steroide reacts with highly basic, and reaction finishes the organic acid for adjusting pH of rear use and carrys out termination reaction to 3-6; Before elutriation, by distillation, removing most of reaction solvent makes reaction system become after viscous pastes 9,11 beta epoxide steroids that row elutriation obtains formula 1 again.
Step of the present invention (a) temperature of reaction be 0 ℃ to 60 ℃, be preferably 30-60 ℃, most preferably 50 ℃.
Highly basic is the compound 1.0-10 mol ratio of formula 4, is preferably 5.0 mol ratios; Highly basic is organic bases or mineral alkali, is selected from sodium hydroxide, potassium hydroxide, salt of wormwood, sodium methylate, potassium methylate, sodium ethylate or potassium ethylate, is preferably potassium hydroxide; Highly basic directly adds solid or is dissolved in solvent and adds, and described solvent is selected from water or lower aliphatic alcohols, more preferably water, and the concentration of alkali aqueous solution is 10% to 50%, is preferably 40%.
Reaction solvent is selected from one or more mixed solvents of methylene dichloride, lower aliphatic alcohols, toluene, hexanaphthene, acetone, tetrahydrofuran (THF), acetonitrile or ethyl acetate, described lower aliphatic alcohols is methyl alcohol, ethanol or Virahol, be preferably methylene dichloride or toluene, most preferably be toluene; Solvent load is 10-30 times of weight ratio of the compound of formula 3, is preferably 15 times of weight ratios.
Reaction finishes, and after use organic acid or elimination halogen, uses organic acid for adjusting pH to 3～6 termination reaction, and organic acid is selected from formic acid, acetic acid, tartrate or toluene sulfonic acide, is preferably acetic acid.After termination reaction, use the salt in appropriate water washing solvent, the water yield is selected from 10-30 times of weight ratio of compound weight ratio.
The method of the invention step (b) temperature of reaction is-20 ℃ to 20 ℃, is preferably-5 ℃; Highly basic is the 1.0-5.0 mol ratio of formula 3 compounds, is preferably 1.3 mol ratios; Highly basic is selected from sodium hydroxide, potassium hydroxide, salt of wormwood, sodium methylate, potassium methylate, sodium ethylate or potassium ethylate, is preferably sodium hydroxide.Highly basic can directly add or be dissolved in solvent and add, and described solvent is selected from water or lower aliphatic alcohols, is preferably directly and adds.
Reaction solvent is selected from one or more mixed solvents of tetrahydrofuran (THF), methylene dichloride, lower aliphatic alcohols or acetonitrile, and described lower aliphatic alcohols is methyl alcohol, ethanol or Virahol, is preferably the mixed solvent of methylene dichloride and methyl alcohol, most preferably is methyl alcohol; Quantity of solvent is 8 to 20 times of weight ratios of the compound of formula 4, is preferably 9～15 times of weight ratios, most preferably is 10 times of weight ratios.
Reaction finishes, and uses organic acid for adjusting pH to 3～6 termination reaction, and organic acid is selected from formic acid, acetic acid, tartrate or toluene sulfonic acide, is preferably acetic acid.After termination reaction, add elutriation to go out the precipitation of formula 1 compound, described amount of water is 10～30 times of weight ratios of formula 4 compounds.Or before elutriation, by distillation, removing most of reaction solvent, to make reaction system become after viscous pastes amount of water described in row elutriation be 10～30 times of weight ratios of formula 4 compounds again.
Except as otherwise noted, following term used herein has described implication:
Alkyl: the straight or branched hydrocarbon group that contains 1～20 carbon atom
Low alkyl group: the straight or branched alkyl that contains 1～6 carbon atom, comprises the alkyl such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl
DBH:1,3-bis-is bromo-5,5-T10
DMF: dimethyl formamide
DMAC: N,N-DIMETHYLACETAMIDE
DCM: methylene dichloride
NBS:N-bromo-succinimide
Those skilled in the art are known, key
represent α or beta comfiguration, for example:
Represent respectively
9,11 beta epoxide steroids of the formula 1 that the present invention makes can be used for preparing the medicines such as dexamethasone and Betamethasone Valerate series.With existing method contrast, the present invention is by generating 9 alpha-halogen-11 β-ester-21-ester steroides as synthetic 9, the key intermediate of 11 beta epoxide steroids, reduced the generation of organic impurity in reaction, can be close to equimolar amount from 9, two key-21-ester the steroides of 11-make 9,11 beta epoxide steroids, are the synthetic methods of a kind of economy, efficient, environmental protection.Especially the method for epoxy, hydrolysis one-step synthesis, compared with epoxy, hydrolysis method of fractional steps reactions steps still less, more efficient, and more environmental protection is more economical, has good industrial prospect.
Embodiment
The following examples are intended to illustrate and unrestricted, and for a person skilled in the art, by considering specification sheets, other embodiments are apparent.By reference to the embodiment that elaborates the preparation and application of the present composition once, further describe the present invention.It will be apparent for a person skilled in the art that and do not departing from the scope of the invention, all practicable a lot of modifications aspect materials and methods two.
Embodiment 1:16 Beta-methyl-9 are alpha-brominated-11 β-methanoyl-Isosorbide-5-Nitrae-diene-pregnant steroid-11 β, and 17 α, 21-trihydroxy--3, the preparation of 20-diketone-21-acetic ester
16 Beta-methyls-the Isosorbide-5-Nitrae of throw-in type 2.1 under nitrogen protection, 9-triolefin-pregnant steroid-17 α; 21-dihydroxyl-3,20-diketone-21-acetic ester 10.0g, DMF35.0g, be cooled to 0 ℃; keep temperature to be no more than 5 ℃ and drip 3.6g70% high chloro acid solutions, finish and minute add altogether DBH5.0g 3 times.React 2 hours, HPLC detects without raw material point, adds 30g methyl alcohol, stirs half an hour.Reaction soln pours in 300g mixture of ice and water, temperature control 0-5 ℃ is stirred 1 hour, suction filtration, 40 ℃ of oven dry of filter cake vacuum obtain 13.0g16 Beta-methyl-9 alpha-brominated-11 β-methanoyl-1,4-diene-pregnant steroid-11 β, 17 α, 21-trihydroxy--3,20-diketone-21-acetic ester (formula 3.1), HPLC99.5%.
Embodiment 2:16 Beta-methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3, the preparation of 20-diketone
Under nitrogen protection 16 Beta-methyl-9 of throw-in type 3.1 alpha-brominated-11 β-methanoyl-Isosorbide-5-Nitrae-diene-pregnant steroid-11 β, 17 α, 21-trihydroxy--3,20-diketone-21-acetic ester 10.0g, DCM100g, methyl alcohol 20g, be cooled to-5 ℃.Drip 40% aqueous sodium hydroxide solution containing sodium hydroxide 3.0g, temperature control-5～0 ℃ insulation reaction 2 hours, HPLC detects without dripping 8g glacial acetic acid after raw material.40 ℃ of concentrating under reduced pressure, dense to remaining 25g, reaction soln pours in 200g mixture of ice and water, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, crude product 7.0g must wet.Drop into wet crude product, DCM170g, methyl alcohol 25g, stir and be warming up to backflow, reflux half an hour, heat filter.Filtrate normal pressure is concentrated into 60 ℃ of interior temperature, cooling, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, 60 ℃ of oven dry of filter cake.Obtain 16 Beta-methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone (formula 1.1) 6.6g, [M+Na]
+395, [2M+Na]
+767, DSC262 ℃, confirming after testing product is 16 Beta-methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone, HPLC99.3%.
Embodiment 3:16 Beta-methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3, the preparation of 20-diketone
Under nitrogen protection 16 Beta-methyl-9 of throw-in type 3.1 alpha-brominated-11 β-methanoyl-Isosorbide-5-Nitrae-diene-pregnant steroid-11 β, 17 α, 21-trihydroxy--3,20-diketone-21-acetic ester 10.0g, methyl alcohol 200g, be cooled to 0 ℃.Drip 25% methanol solution containing sodium hydroxide 2.5g, temperature control 0-5 ℃ insulation reaction 2 hours, HPLC detects without dripping 8g glacial acetic acid after raw material.40 ℃ of concentrating under reduced pressure, it is dense that to remaining about 25g, reaction soln pours in 200g mixture of ice and water, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, crude product 7.0g must wet.Drop into wet crude product, DCM170g, methyl alcohol 25g, stir and be warming up to backflow, reflux half an hour, heat filter.Filtrate normal pressure is concentrated into 60 ℃ of interior temperature, cooling, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, 60 ℃ of oven dry of filter cake.Obtain 16 Beta-methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone (formula 1.1) 6.6g, confirming after testing product is 16 Beta-methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone, [M+Na]
+395, [2M+Na]
+767, DSC262 ℃, HPLC99.2%.
Embodiment 4:16 Alpha-Methyl-9 are alpha-brominated-11 β-methanoyl-Isosorbide-5-Nitrae-diene-pregnant steroid-11 β, and 17 α, 21-trihydroxy--3, the preparation of 20-diketone-21-acetic ester
16 Alpha-Methyls-the Isosorbide-5-Nitrae of throw-in type 2.2 under nitrogen protection, 9-triolefin-pregnant steroid-17 α; 21-dihydroxyl-3,20-diketone-21-acetic ester 10.0g, DMF35.0g, be cooled to 0 ℃; keep temperature to be no more than 5 ℃ and drip 3.6g70% high chloro acid solutions, finish and minute add altogether NBS6.0g 3 times.React 2 hours, HPLC detects without raw material point, adds 30g methyl alcohol, stirs half an hour.Reaction soln pours in 300g mixture of ice and water, temperature control 0-5 ℃ is stirred 1 hour, suction filtration, 40 ℃ of vacuum dryings of filter cake obtain 13.0g16 Alpha-Methyl-9 alpha-brominated-11 β-methanoyl-1,4-diene-pregnant steroid-11 β, 17 α, 21-trihydroxy--3,20-diketone-21-acetic ester (formula 3.2), HPLC99.5%.
Embodiment 5:16 Alpha-Methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3, the preparation of 20-diketone
Under nitrogen protection 16 Alpha-Methyl-9 of throw-in type 3.2 alpha-brominated-11 β-methanoyl-Isosorbide-5-Nitrae-diene-pregnant steroid-11 β, 17 α, 21-trihydroxy--3,20-diketone-21-acetic ester 10.0g, methyl alcohol 100g, be cooled to 0 ℃.Drip 25% methanol solution containing sodium hydroxide 2.5g, temperature control 0-5 ℃ insulation reaction 2 hours, HPLC detects without dripping 8g glacial acetic acid after raw material.40 ℃ of concentrating under reduced pressure, dense to remaining 25g, reaction soln pours in 200g mixture of ice and water, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, crude product 7.0g must wet.Drop into wet crude product, DCM150g, methyl alcohol 75g, stir and be warming up to backflow, reflux half an hour, heat filter.Filtrate normal pressure is concentrated into 60 ℃ of interior temperature, cooling, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, 60 ℃ of oven dry of filter cake.Obtain 16 Alpha-Methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone (formula 1.2) 6.6g, confirming after testing product is 16 Alpha-Methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone, [M+Na]
+395, [2M+Na]
+767, DSC265 ℃, HPLC99.3%.
Embodiment 6:16 Beta-methyl-9 are alpha-brominated-11 β-acetoxyl group-Isosorbide-5-Nitrae-diene-pregnant steroid-11 β, and 17 α, 21-trihydroxy--3, the preparation of 20-diketone-21-acetic ester
16 Beta-methyls-the Isosorbide-5-Nitrae of throw-in type 2.1 under nitrogen protection, 9-triolefin-pregnant steroid-17 α; 21-dihydroxyl-3,20-diketone-21-acetic ester 10.0g, DMAC40.0g, be cooled to 0 ℃; keep temperature to be no more than 5 ℃ and drip 5.0g70% high chloro acid solutions, finish and minute add altogether DBH5.5g 3 times.React 2 hours, HPLC detects without raw material point, adds 30g methyl alcohol, stirs half an hour.Reaction soln pours in 300g mixture of ice and water, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, 40 ℃ of vacuum dryings of filter cake obtain 13.3g16 Beta-methyl-9 alpha-brominated-11 β-acetoxyl group-Isosorbide-5-Nitrae-diene-pregnant steroid-11 β, 17 α, 21-trihydroxy--3,20-diketone-21-acetic ester, HPLC95.0%.
Embodiment 7:16 Beta-methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3, the preparation of 20-diketone
Under nitrogen protection 16 Beta-methyl-9 of throw-in type 3.2 alpha-brominated-11 β-acetoxyl group-Isosorbide-5-Nitrae-diene-pregnant steroid-11 β, 17 α, 21-trihydroxy--3,20-diketone-21-acetic ester 10.0g, methyl alcohol 200g, be cooled to 0 ℃.Drip 25% methanol solution containing sodium hydroxide 2.5g, temperature control 0-5 ℃ insulation reaction 2 hours, HPLC drips 8g glacial acetic acid after without raw material.40 ℃ of concentrating under reduced pressure, it is dense that to remaining about 25g, reaction soln pours in 200g mixture of ice and water, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, the about 7.0g of crude product must wet.Drop into wet crude product, DCM170g, methyl alcohol 25g, stir and be warming up to 52～55 ℃, reflux half an hour, heat filter.Filtrate normal pressure is concentrated into 60 ℃ of interior temperature, cooling, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, 60 ℃ of oven dry of filter cake.Obtain 16 Beta-methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone (formula 1.1) 6.2g, confirming after testing product is 16 Beta-methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone, [M+Na]
+395, [2M+Na]
+767, DSC262 ℃, HPLC96.3%.
Embodiment 8:16 Alpha-Methyl-9 are alpha-brominated-11 β-acetoxyl group-Isosorbide-5-Nitrae-diene-pregnant steroid-11 β, and 17 α, 21-trihydroxy--3, the preparation of 20-diketone-21-acetic ester
16 Alpha-Methyls-the Isosorbide-5-Nitrae of throw-in type 2.2 under nitrogen protection, 9-triolefin-pregnant steroid-17 α; 21-dihydroxyl-3,20-diketone-21-acetic ester 10.0g, DMAC35.0g, be cooled to 0 ℃; keep temperature to be no more than 5 ℃ and drip 3.6g70% high chloro acid solutions, finish and minute add altogether NBS6.0g 3 times.React 2 hours, HPLC detects without raw material point, adds 30g methyl alcohol, stirs half an hour.Reaction soln pours in 300g mixture of ice and water, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, 40 ℃ of vacuum dryings of filter cake obtain 13.3g16 Alpha-Methyl-9 alpha-brominated-11 β-acetoxyl group-Isosorbide-5-Nitrae-diene-pregnant steroid-11 β, 17 α, 21-trihydroxy--3,20-diketone-21-acetic ester, HPLC95.0%.
Embodiment 9:16 Alpha-Methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3, the preparation of 20-diketone
Under nitrogen protection 16 Alpha-Methyl-9 of throw-in type 3.4 alpha-brominated-11 β-acetoxyl group-Isosorbide-5-Nitrae-diene-pregnant steroid-11 β, 17 α, 21-trihydroxy--3,20-diketone-21-acetic ester 10.0g, methyl alcohol 100g, be cooled to 0 ℃.Drip 25% methanol solution containing sodium hydroxide 2.5g, temperature control 0-5 ℃ insulation reaction 2 hours, HPLC detects without dripping 8g glacial acetic acid after raw material.40 ℃ of concentrating under reduced pressure, it is dense that to remaining about 25g, reaction soln pours in 200g mixture of ice and water, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, crude product 7.0g must wet.Drop into wet crude product, DCM150g, methyl alcohol 75g, stir and be warming up to backflow, reflux half an hour, heat filter.Filtrate normal pressure is concentrated into 60 ℃ of interior temperature, cooling, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, 60 ℃ of oven dry of filter cake.Obtain 16 Alpha-Methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone 6.2g, confirming after testing product is 16 Alpha-Methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone (formula 1.2) [M+Na]
+395, [2M+Na]
+767, DSC265 ℃, HPLC96.7%.
Embodiment 10:16 Beta-methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3, the preparation of 20-diketone
Under nitrogen protection 16 Beta-methyl-9 of throw-in type 3.1 alpha-brominated-11 β-methanoyl-Isosorbide-5-Nitrae-diene-pregnant steroid-11 β, 17 α, 21-trihydroxy--3,20-diketone-21-acetic ester 10.0g, tetrahydrofuran (THF) 150g, be cooled to 0 ℃.Drip 25% methanol solution containing sodium hydroxide 2.5g, temperature control 0-5 ℃ insulation reaction 2 hours, HPLC detects without dripping 8g glacial acetic acid after raw material.40 ℃ of concentrating under reduced pressure, dense to remaining 25g, reaction soln pours in 200g mixture of ice and water, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, crude product 7.0g must wet.Drop into wet crude product, DCM170g, methyl alcohol 25g, stir and be warming up to backflow, reflux half an hour, heat filter.Filtrate normal pressure is concentrated into 60 ℃ of interior temperature, cooling, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, 60 ℃ of oven dry of filter cake.Obtain 16 Beta-methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone (formula 1.1) 6.3g, confirming after testing product is 16 Beta-methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone [M+Na]
+395, [2M+Na]
+767, DSC262 ℃, HPLC99.2%.
Embodiment 11:16 Alpha-Methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3, the preparation of 20-diketone
Under nitrogen protection 16 Alpha-Methyl-9 of throw-in type 3.2 alpha-brominated-11 β-methanoyl-Isosorbide-5-Nitrae-diene-pregnant steroid-11 β, 17 α, 21-trihydroxy--3,20-diketone-21-acetic ester 10.0g, acetonitrile 100g, methyl alcohol 50g, be cooled to 0 ℃.Drip 25% methanol solution containing sodium hydroxide 2.5g, temperature control 0-5 ℃ insulation reaction 2 hours, HPLC detects without dripping 8g glacial acetic acid after raw material.40 ℃ of concentrating under reduced pressure, it is dense that to remaining about 25g, reaction soln pours in 200g mixture of ice and water, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, crude product 7.0g must wet.Drop into wet crude product, DCM150g, methyl alcohol 75g, stir and be warming up to backflow, reflux half an hour, heat filter.Filtrate normal pressure is concentrated into 60 ℃ of interior temperature, cooling, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, 60 ℃ of oven dry of filter cake.Obtain 16 Alpha-Methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone (formula 1.2) 5.6g, confirming after testing product is 16 Alpha-Methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone [M+Na]
+395, [2M+Na]
+767, DSC265 ℃, HPLC99.0%.
Embodiment 12:16 Alpha-Methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3, the preparation of 20-diketone
Under nitrogen protection 16 Alpha-Methyl-9 of throw-in type 3.2 alpha-brominated-11 β-methanoyl-Isosorbide-5-Nitrae-diene-pregnant steroid-11 β, 17 α, 21-trihydroxy--3,20-diketone-21-acetic ester 10.0g, DCM100g, methyl alcohol 20g, be cooled to 0 ℃.Drip 25% aqueous solution containing salt of wormwood 5.0g, 25～30 ℃ of insulation reaction of temperature control 12 hours, HPLC detects without dripping 8g glacial acetic acid after raw material.40 ℃ of concentrating under reduced pressure, it is dense that to remaining about 25g, reaction soln pours in 200g mixture of ice and water, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, crude product 6.0g must wet.Drop into wet crude product, DCM150g, methyl alcohol 75g, stir and be warming up to backflow, reflux half an hour, heat filter.Filtrate normal pressure is concentrated into 60 ℃ of interior temperature, cooling, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, 60 ℃ of oven dry of filter cake.Obtain 16 Alpha-Methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone 4.3g(formula 1.2), confirming after testing product is 16 Alpha-Methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone [M+Na]
+395, [2M+Na]
+767, DSC265 ℃, HPLC99.0%.
Embodiment 13:16 Beta-methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3, the preparation of 20-diketone-21-acetic ester
Under nitrogen protection 16 Beta-methyl-9 of throw-in type 3.1 alpha-brominated-11 β-methanoyl-Isosorbide-5-Nitrae-diene-pregnant steroid-11 β, 17 α, 21-trihydroxy--3,20-diketone-21-acetic ester 10.0g, toluene 150g, be cooled to 0 ℃.Drip 40% aqueous solution containing potassium hydroxide 5.3g, be warming up to 50 ℃, insulation reaction 4 hours.HPLC detects without raw material and is cooled to suction filtration after room temperature, and filtrate drips 8g glacial acetic acid, adds 150g water, stirs layering.50 ℃ of decompressions of organic layer are dense dry, obtain 16 Beta-methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone-21-acetic ester 7.5g, HPLC98.8%.
Embodiment 14:16 Beta-methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3, the preparation of 20-diketone
16 Beta-methyl-9 of throw-in type 4.1 under nitrogen protection, 11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone-21-acetic ester 10.0g, methyl alcohol 100g, be cooled to 0 ℃.Add 1.25g sodium hydroxide, 0 ℃ of insulation reaction of temperature control 2 hours, HPLC detects without dripping 3g glacial acetic acid after raw material.40 ℃ of concentrating under reduced pressure, dense to remaining 25g, reaction soln pours in 200g mixture of ice and water, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, crude product 9.0g must wet.Drop into wet crude product, DCM170g, methyl alcohol 25g, stir and be warming up to backflow, reflux half an hour, heat filter.Filtrate normal pressure is concentrated into 60 ℃ of interior temperature, cooling, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, 60 ℃ of oven dry of filter cake.Obtain 16 Beta-methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone (formula 1.1) 8.5g, confirming after testing product is 16 Beta-methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone [M+Na]
+395, [2M+Na]
+767, DSC262 ℃, HPLC99.3%.
Embodiment 15:16 Alpha-Methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3, the preparation of 20-diketone-21-acetic ester
Under nitrogen protection 16 Alpha-Methyl-9 of throw-in type 3.1 alpha-brominated-11 β-methanoyl-Isosorbide-5-Nitrae-diene-pregnant steroid-11 β, 17 α, 21-trihydroxy--3,20-diketone-21-acetic ester 10.0g, toluene 150g, be cooled to 0 ℃.Drip 40% aqueous solution containing potassium hydroxide 5.3g, be warming up to 50 ℃, insulation reaction 6 hours.HPLC detects without raw material and is cooled to suction filtration after room temperature, and filtrate drips 8g glacial acetic acid, adds 150g water, stirs layering.50 ℃ of decompressions of organic layer are dense dry, obtain 16 Alpha-Methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone-21-acetic ester 7.5g, HPLC98.5%.
Embodiment 16:16 Alpha-Methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3, the preparation of 20-diketone
16 Alpha-Methyl-9 of throw-in type 4.1 under nitrogen protection, 11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone-21-acetic ester 10.0g, methyl alcohol 100g, be cooled to 0 ℃.Add 1.25g sodium hydroxide, 0 ℃ of insulation reaction of temperature control 2 hours, HPLC detects without dripping 3g glacial acetic acid after raw material.40 ℃ of concentrating under reduced pressure, it is dense that to remaining about 25g, reaction soln pours in 200g mixture of ice and water, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, crude product 9.0g must wet.Drop into wet crude product, DCM170g, methyl alcohol 25g, stir and be warming up to backflow, reflux half an hour, heat filter.Filtrate normal pressure is concentrated into 60 ℃ of interior temperature, cooling, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, 60 ℃ of oven dry of filter cake.Obtain 16 Alpha-Methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone (formula 1.1) 8.5g, confirming after testing product is 16 Alpha-Methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone, [M+Na]
+395, [2M+Na]
+767, DSC265 ℃, HPLC99.1%.
Embodiment 17:16 Beta-methyl-9 are alpha-brominated-11 β-methanoyl-Isosorbide-5-Nitrae-diene-pregnant steroid-11 β, and 17 α, 21-trihydroxy--3, the preparation of 20-diketone-21-acetic ester
16 Beta-methyls-the Isosorbide-5-Nitrae of throw-in type 2.1 under nitrogen protection, 9-triolefin-pregnant steroid-17 α; 21-dihydroxyl-3,20-diketone-21-acetic ester 10.0g, DMF35.0, be cooled to 0 ℃; keep temperature to be no more than 5 ℃ and drip 1.0g70% high chloro acid solutions, finish and minute add altogether DBH5.6g 3 times.React 4 hours, HPLC detects without raw material point, adds 30g methyl alcohol, stirs half an hour.Reaction soln pours in 300g mixture of ice and water, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, 40 ℃ of oven dry of filter cake vacuum obtain 12.8g16 Beta-methyl-9 alpha-brominated-11 β-methanoyl-Isosorbide-5-Nitrae-diene-pregnant steroid-11 β, 17 α, 21-trihydroxy--3,20-diketone-21-acetic ester, HPLC91.2%.
Embodiment 18:16 Alpha-Methyl-9,11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3, the preparation of 20-diketone
Under nitrogen protection 16 Alpha-Methyl-9 of throw-in type 3.2 alpha-brominated-11 β-methanoyl-Isosorbide-5-Nitrae-diene-pregnant steroid-11 β, 17 α, 21-trihydroxy--3,20-diketone-21-acetic ester 10.0g, methyl alcohol 100g, be cooled to 0 ℃.Add potassium hydroxide 2.8g, temperature control 0-5 ℃ insulation reaction 2 hours, HPLC detects without dripping 8g glacial acetic acid after raw material.40 ℃ of concentrating under reduced pressure, dense to remaining 25g, reaction soln pours in 200g mixture of ice and water, and temperature control 0-5 ℃ is stirred 1 hour, suction filtration, crude product 16 Alpha-Methyl-9 of must wetting, 11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid-17 α, 21-dihydroxyl-3,20-diketone (formula 1.2) 7.0g, HPLC93.6%.
Although invention has been described in conjunction with above-mentioned specific embodiment, multiple replacement, modification and change that it is carried out are predictable to this area researchist, and all these are replaced, modify and change all in essential scope of the present invention.
Claims (10)
1. the method for preparation 9,11 beta epoxide steroids, is characterized in that, the method comprises the following steps:
(1) in solvent, under perchloric acid exists, 9 of formula 2, the two key-21-ester steroides of 11-react with halogenating agent; Reaction finishes, and adds water, produces precipitation, filters, and being precipitated thing is 9 alpha-halogen-11 β-ester-21-ester steroides of formula 3; Or before elutriation, add C
1-C
6fatty alcohol stop oxidizing reaction, preferred fat alcohol is methyl alcohol, ethanol or Virahol, most preferably is methyl alcohol;
(2) in solvent, 9 alpha-halogen-11 β-ester-21-ester steroides react with highly basic, by determining, do not exist after raw material and intermediate, use organic acid for adjusting pH to 3-6 termination reaction; After reaction finishes, add elutriation to go out the precipitation of 9,11 beta epoxide steroids, filter sediment separate out 9,11 beta epoxide steroids; Or before elutriation, by distillation, remove after most of reaction solvent row elutriation again and obtain 9,11 beta epoxide steroids;
(3) purifying:
9,11 beta epoxide steroids are heated in 45 ℃ of methylene dichloride and methanol mixed solution that are dissolved in 20-30 times of weight ratio, then by filtering, air distillation to 65 ℃, be cooled to 5 ℃ following, filter, 60 ℃ of constant pressure and dries, obtain 9,11 beta epoxide steroids of purifying:
With following reaction formula, represent:
R wherein
1for hydrogen or C
1-C
6low alkyl group; Preferred R
1for low alkyl group, be most preferably-CH3; R
2for hydrogen or C
1-C
4low alkyl group, R most preferably
2for-CH
3; R
3for-COH or-COCH
3, be preferably-COH.
2. prepare according to claim 1 the method for 9,11 beta epoxide steroids, it is characterized in that, described step (1) halogenating agent is selected from 1,3-bis-is bromo-5,5-T10, N-bromo-succinimide, N-chloro imide or two chlordantoins, preferably 1,3-bis-bromo-5,5-T10, the consumption of halogenating agent is 0.5 to 3 mol ratio of formula 2 compounds, is preferably 0.65-0.8 mol ratio, more preferably 0.75-0.9 times of mol ratio, most preferably is 0.7 mol ratio; Reaction solvent is selected from dimethyl formamide or N,N-DIMETHYLACETAMIDE, and the amount of solvent dimethyl formamide or N,N-DIMETHYLACETAMIDE is the compound 0.5-10 times weight ratio of formula 2, is preferably 1-5 times of weight ratio, most preferably is 3.5 times of weight ratios;
℃-50 ℃, temperature of reaction-20, preferably-5-10 ℃, most preferably is-2-2 ℃; Reaction times 1-4 hour.
3. prepare according to claim 19, the method of 11 beta epoxide steroids, it is characterized in that, when described step (1) reaction finishes, add 70% high chloro acid solution, 70% high chloro acid solution's consumption is 0.5-3 times of mol ratio of formula 2 compounds, is preferably 0.8-1.2 doubly, most preferably is 1.0 times of mol ratios; Reaction finishes, and reactant is incorporated as in the water of 10-100 times of weight of compound of formula 2; Or before elutriation, add alcohol, and be preferably methyl alcohol, ethanol or Virahol, most preferably be methyl alcohol termination reaction, the consumption of alcohol is 1-5 times of weight ratio of formula 2 compounds, is preferably 3 times of weight ratios.
4. prepare according to claim 1 the method for 9,11 beta epoxide steroids, it is characterized in that, described step (2) temperature of reaction is-20 ℃ to 20 ℃, preferably-10 ℃-0 ℃, most preferably is-5 ℃; Highly basic is the 2.0-5.0 mol ratio of formula 3 compounds, is preferably 3.0-3.5 mol ratio, most preferably is 3.15 mol ratios; Highly basic is organic bases or mineral alkali, is selected from sodium hydroxide, potassium hydroxide, salt of wormwood, sodium methylate, potassium methylate, sodium ethylate or potassium ethylate, is preferably sodium hydroxide; Or highly basic is dissolved in solvent and adds, described solvent is selected from water or lower aliphatic alcohols, and described lower aliphatic alcohols is methyl alcohol, ethanol or Virahol, is preferably water; Dissolve the water of alkali or the compound 0.5-3 times weight ratio that lower aliphatic alcohols consumption is formula 3, be preferably 0.8-1.2 doubly, most preferably be 1.0 times of weight ratios.
5. prepare according to claim 19, the method of 11 beta epoxide steroids, it is characterized in that, described step (2) reaction solvent is selected from one or more mixed solvents of tetrahydrofuran (THF), methylene dichloride, lower aliphatic alcohols or acetonitrile, and described lower aliphatic alcohols is methyl alcohol, ethanol or Virahol; Be preferably methylene dichloride and methanol mixed solvent or single methyl alcohol, most preferably be methylene dichloride and methanol mixed solvent, methylene dichloride and methanol mixed solvent ratios are 1:5 to 10:1, are preferably 3:1 to 7:1, most preferably are 5:1; Quantity of solvent is 8 to 20 times of weight ratios of the compound of formula 3, is preferably 9～12 times of weight ratios, most preferably is 12 times of weight ratios.
6. prepare according to claim 1 the method for 9,11 beta epoxide steroids, it is characterized in that, described step (2) is used organic acid for adjusting pH to 3～6 termination reaction, and organic acid is selected from formic acid, acetic acid, tartrate or toluene sulfonic acide, is preferably acetic acid; After reaction finishes, add elutriation to go out the precipitation of 9,11 beta epoxide steroids, described amount of water is 10～30 times of weight ratios of formula 3 compounds; Or by distillation, remove after most of reaction solvent row elutriation again before elutriation.
7. the method for preparation 9,11 beta epoxide steroids, is characterized in that, the method comprises the following steps:
(a) in solvent, 9 alpha-halogen-11 β-ester-21-ester steroides of formula 3 react with highly basic, reaction finish that halogen is removed in rear filtration or with organic acid for adjusting pH to 3-6, wash, distillation is removed solvent and is obtained 9,11 beta epoxides-21-ester-steroide pressed powder;
(b) in solvent, 9,11 beta epoxides of formula 4-21-ester steroide reacts with highly basic, and reaction finishes the organic acid for adjusting pH of rear use to 3-6 termination reaction; By distillation, removing most of reaction solvent makes reaction system become after viscous pastes row elutriation again to obtain 9,11 beta epoxide steroids;
Shown in following reaction formula:
R wherein
1for hydrogen or C
1-C
6low alkyl group; Preferred R
1for low alkyl group, be most preferably-CH3; R
2for hydrogen or C
1-C
4low alkyl group, R most preferably
2for-CH
3; R
3for-COH or-COCH
3, be preferably-COH.
8. prepare according to claim 7 the method for 9,11 beta epoxide steroids, it is characterized in that, described step (a) temperature of reaction be 0 ℃ to 60 ℃, be preferably 30-60 ℃, most preferably 50 ℃; Highly basic is the compound 1.0-10 mol ratio of formula 4, is preferably 5.0 mol ratios; Highly basic is organic bases or mineral alkali, is selected from sodium hydroxide, potassium hydroxide, salt of wormwood, sodium methylate, potassium methylate, sodium ethylate or potassium ethylate, is preferably potassium hydroxide; Highly basic directly adds solid or is dissolved in solvent and adds; Described solvent is selected from water or lower aliphatic alcohols, more preferably water, and the concentration of alkali aqueous solution is 10% to 50%, is preferably 40%.
9. prepare according to claim 79, the method of 11 beta epoxide steroids, it is characterized in that, described step (a) reaction solvent is selected from one or more mixed solvents of methylene dichloride, lower aliphatic alcohols, toluene, hexanaphthene, acetone, tetrahydrofuran (THF), acetonitrile or ethyl acetate, described lower aliphatic alcohols is methyl alcohol, ethanol or Virahol, be preferably methylene dichloride or toluene, most preferably be toluene; Solvent load is 10-30 times of weight ratio of the compound of formula 3, is preferably 15 times of weight ratios; Reaction finishes, and after use organic acid or elimination halogen, uses organic acid for adjusting pH to 3～6 termination reaction, and organic acid is selected from formic acid, acetic acid, tartrate or toluene sulfonic acide, is preferably acetic acid; After termination reaction, make to wash with water the salt in solvent, the water yield is 10-30 times of weight ratio of compound weight ratio.
10. prepare according to claim 7 the method for 9,11 beta epoxide steroids, it is characterized in that, described step (b) temperature of reaction is-20 ℃ to 20 ℃, is preferably-5 ℃; Highly basic is the 1.0-5.0 mol ratio of formula 3 compounds, is preferably 1.3 mol ratios; Highly basic is selected from sodium hydroxide, potassium hydroxide, salt of wormwood, sodium methylate, potassium methylate, sodium ethylate or potassium ethylate, is preferably sodium hydroxide, and highly basic can directly add or be dissolved in solvent and add, and described solvent is selected from water or lower aliphatic alcohols, is preferably directly and adds; Reaction solvent is selected from one or more mixed solvents of tetrahydrofuran (THF), methylene dichloride, lower aliphatic alcohols or acetonitrile, and described lower aliphatic alcohols is methyl alcohol, ethanol or Virahol, is preferably the mixed solvent of methylene dichloride and methyl alcohol, most preferably is methyl alcohol; Quantity of solvent is 8 to 20 times of weight ratios of formula 4 compounds, is preferably 9～15 times of weight ratios, most preferably is 10 times of weight ratios; Reaction finishes, and uses organic acid for adjusting pH to 3～6 termination reaction, and organic acid is selected from formic acid, acetic acid, tartrate or toluene sulfonic acide, is preferably acetic acid; After termination reaction, add elutriation to go out the precipitation of formula 1 compound, described amount of water is 10～30 times of weight ratios of formula 4 compounds; Or before elutriation, by distillation, remove most of reaction solvent and make reaction system become after viscous pastes row elutriation again, described amount of water is 10～30 times of weight ratios of formula 4 compounds.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310618900.8A CN103588853A (en) | 2013-11-28 | 2013-11-28 | Method for preparing 9,11beta-epoxy steroid compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310618900.8A CN103588853A (en) | 2013-11-28 | 2013-11-28 | Method for preparing 9,11beta-epoxy steroid compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103588853A true CN103588853A (en) | 2014-02-19 |
Family
ID=50079203
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310618900.8A Pending CN103588853A (en) | 2013-11-28 | 2013-11-28 | Method for preparing 9,11beta-epoxy steroid compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103588853A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108864240A (en) * | 2018-05-29 | 2018-11-23 | 湖南新合新生物医药有限公司 | The method of purification of dexamethasone epoxy hydrolysate |
| CN109851653A (en) * | 2018-11-21 | 2019-06-07 | 奥锐特药业股份有限公司 | The preparation method of 16 alpha-hydroxy prednisonlones |
| CN115466301A (en) * | 2022-08-29 | 2022-12-13 | 扬州奥锐特药业有限公司 | Steroid compound, crystal form A thereof, and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB881501A (en) * | 1958-07-09 | 1961-11-01 | American Cyanamid Co | Substituted pregnenes |
| CN1209138A (en) * | 1995-12-20 | 1999-02-24 | 先灵公司 | Process for prepn. of 9,11 beta epoxide steroids |
| CN102746370A (en) * | 2011-04-22 | 2012-10-24 | 天津金耀集团有限公司 | Novel technology for oxosynthesis of pregnane 11-bit ketonic group |
-
2013
- 2013-11-28 CN CN201310618900.8A patent/CN103588853A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB881501A (en) * | 1958-07-09 | 1961-11-01 | American Cyanamid Co | Substituted pregnenes |
| CN1209138A (en) * | 1995-12-20 | 1999-02-24 | 先灵公司 | Process for prepn. of 9,11 beta epoxide steroids |
| CN102746370A (en) * | 2011-04-22 | 2012-10-24 | 天津金耀集团有限公司 | Novel technology for oxosynthesis of pregnane 11-bit ketonic group |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108864240A (en) * | 2018-05-29 | 2018-11-23 | 湖南新合新生物医药有限公司 | The method of purification of dexamethasone epoxy hydrolysate |
| CN109851653A (en) * | 2018-11-21 | 2019-06-07 | 奥锐特药业股份有限公司 | The preparation method of 16 alpha-hydroxy prednisonlones |
| CN115466301A (en) * | 2022-08-29 | 2022-12-13 | 扬州奥锐特药业有限公司 | Steroid compound, crystal form A thereof, and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102603843B (en) | Preparation method of dexamethasone intermediate | |
| CN103601782A (en) | Preparation method of prednisone acetate or analogues thereof | |
| CN105001293A (en) | Preparation method of estrone | |
| CN103588853A (en) | Method for preparing 9,11beta-epoxy steroid compound | |
| CN112062805A (en) | High-efficiency delta9,11Process for the preparation of (E) -canrenone | |
| US9522934B2 (en) | Acetatic abiraterone trifluoroacetate and preparation method and application of same | |
| CN102875538A (en) | Method for preparing vilazodone or hydrochloride thereof | |
| CN105693802A (en) | Preparation method of 16 beta-methyl steroid | |
| EP2921473B1 (en) | 1-cyan-1-(7-methoxyl-1-naphtyl) methanol ester compound and preparation method and use thereof | |
| CN106279341A (en) | A kind of preparation method of fluticasone furoate | |
| CN102633851B (en) | Method for synthetizing clarithromycin intermediate | |
| CN103641879B (en) | The preparation method of prednisolone intermediate or its analogue | |
| CN114276406B (en) | Preparation method of intermediate of deoxomilpine | |
| CN103641876B (en) | The preparation method of cortisone acetic ester | |
| CN107814824B (en) | Preparation method of tetraene acetate | |
| CA3022444C (en) | Method for preparing azoxystrobin | |
| CN101817796A (en) | Method for preparing cefotiam side chain | |
| CN102712602A (en) | Process for preparing 2-methyl-4-amino-5-cyanopyrimidine | |
| CN105439978A (en) | Preparation method of acotiamide intermediate | |
| CN105237605B (en) | A kind of intermediate and its preparation method and application for synthesizing gestodene | |
| CN103641877B (en) | The preparation method of hydrocortisone intermediate | |
| CN101027287A (en) | Method of manufacturing 2-chloro-4-nitroimidazole | |
| CN108997340B (en) | Synthetic method of 5-bromo-7-azaindole | |
| CN115260276B (en) | Process for preparing steroid 16, 17-epoxy compound | |
| CN110294783B (en) | Preparation method of 16-alkene steroid compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140219 |