CN104710496B - On a kind of preparation method of the pregnant diketone steroid derivative of 16 alkene of steroid 3,20 - Google Patents
On a kind of preparation method of the pregnant diketone steroid derivative of 16 alkene of steroid 3,20 Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
- C07J13/005—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 16 (17)
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Abstract
The present invention relates to a kind of pregnant diketone steroid derivative of 16 alkene of steroid 3,20（II）Preparation method, it is characterized in that preparing the standby side hydroxy steroid derivatives I of acetenyl 17 with reagent A by 17 or the organic solvent containing reagent A reacts and obtained, reaction temperature：25 DEG C~solvent reflux temperature, the reagent A is dissolved in the solution that methanesulfonic acid is formed for 5%~15% phosphorus pentoxide.
Description
Technical field
The invention belongs to steroidal synthesis technical field, be related to 17 α-beta-hydroxy steroid derivative of acetenyl -17 prepare pregnant steroid -
16- alkene -3,20- diketone steroid derivatives.
Background technology
Pregnant steroid -4,16- diene -3,20- diketone and its derivative are the key intermediates of synthesizing steroid compound, for making
Such as dexamethasone, BETAMETHASONE, methylprednisolone, hydrocortisone, metacortandracin steroid drugs are made, with very high economic valency
Value.The conventional method of present pregnant steroid -4,16- diene -3, the 20- diketone of industrial production and its derivative is double with pregnant steroid -5,16-
Alkene -20- ketone -3- hydroxyl -3- acetates (abbreviation diene thing) are prepared for raw material.Diene thing be then by Chinese yam saponin by cracking,
Oxidation, hydrolysis three steps generation, first, this production process needs substantial amounts of sulfuric acid, and a large amount of pollutions are easily produced to environment；Second, with
The continuous improvement of Environmental Protection in China consciousness, in recent years, country increases the environmentally friendly supervision to production of saponin enterprise, eliminates
The medium and small production of saponin enterprise in part, saponin supply is becoming tight, and has caused saponin price continuous rise since 2007, at the beginning of 2007
It is per ton 130,000 yuan go up more than 90 ten thousand yuan per ton to 2013.The raising of saponin price to the cost of cortin manufacturer and
Production and operation bring extreme influence；3rd, the plantation of Chinese yam saponin needs largely prolonged land occupation.Therefore, develop newly
Natural resources, find a kind of raw material of alternative diene thing, can be prepared with lower cost and more environmentally-friendly method pregnant steroid-
4,16- diene -3,20- diketone and its derivative, have great importance for steroidal industry.
Last century the seventies, Marsheck, (Appl.Microbiol.23,72,1972) and Sih, C.J. etc. such as W.J.
(J.Am.Chem.Soc.87,1387,1965) utilizes the leftover bits and pieces after soybean extract oil --- and phytosterol ferments by bioanalysis
With very in high yield obtain can be used for production steroid drugs important intermediate Isosorbide-5-Nitrae-androstane diene -3,17- diketone (abbreviation ADD) and
AD (abbreviation 4AD).Compared with producing widely used diene thing at present, 4AD and ADD raw materials are based on
Industrial waste, source more horn of plenty is consolidated, and price is cheaper, and very little is polluted in production process, is a kind of advantageous original
Material.Meanwhile, it is high with 4AD and ADD purity prepared by biological fermentation process, be conducive to improving the quality of steroid drugs finished product.If can be very
Good solution synthetic route and the method for industrialized production, will occur revolution for the production technology level of many steroid drugs
The change of property and it is greatly improved.
Since last century the seventies obtain 4AD and ADD by microbial fermentation, height has been synthesized using 4AD and ADD
The efficient cortin of value is always external chemist extremely problem interested.There is few quantifier elimination both at home and abroad in this respect again
Report, external Nitta, I et al. has been delivered for 1985 on Bull.Chem.Soc.Jpn (1985,58,978) utilizes 4AD lifes
Into pregnant Gona-4-ene-3, the method for 20- diketone -21- acetates.Issei, N. etc. (Bull.Chem.Soc.Jpn.58,981,
1985) using ADD as raw material, reacted by seven steps, obtain Isosorbide-5-Nitrae-pregnen diethylene -17 α, 21- dihydroxy -3,20- diketone -17 α, 21-
Diacetate.
Cause domestic and international steroid chemical men extensive although preparing steroidal compounds by initiation material of 4AD and ADD
Concern, but its industrialization is but undecided all the time.
It the present invention relates to the use of 4AD or ADD 17 α-beta-hydroxy derivative of acetenyl -17（I）For starting material, prepare pregnant
Steroid -16- alkene -3,20- diketone steroid derivatives（II）.Compound (I) is prepared by starting material of 4AD or ADD, may be referred to text
17 α-beta-hydroxy of acetenyl -17 can be introduced at 17 by offering Bull.Chem.Soc.Jpn.V58, P981,1985 method, or
Bibliography Biol.Pharm.Bull.23 (9) 1059~1065（2000）Method can introduce 6 Alpha-Methyls, or with reference to text
6 α-fluorine or 6 β-fluorine, or bibliography " Steroids, 71 (11- can be introduced by offering United States Patent (USP) US4383947 method
12),979-983;2006 " method introduces Alpha-hydroxy and beta-hydroxy at 11, then using 11 Alpha-hydroxy derivatives as starting
Thing, the method for bibliography " CN102040639 " generates 11- beta-hydroxies, 9 α-bromine or 11- beta-hydroxies, 9 α-fluorine derivative or
Person is using 11 Alpha-hydroxy derivatives as starting material, bibliography " Gazzetta Chimica Italiana, 85,639-45;
1955 " method, carbonyl is introduced at 11.
Compound（II）It is pregnant steroid -4,16- diene -3,20- diketone or derivatives thereof, is the key of synthesizing steroid compound
Intermediate, such as dexamethasone, BETAMETHASONE, methylprednisolone, hydrocortisone, metacortandracin can be manufactured by further reacting
Steroid drugs.
For double bond or singly-bound
R be-H orCH3OrF orF
R2For-H orBr orF
R1For==O orOH orOH
WhenR2ForBr orDuring F,R1ForOH
R1During for==O,R2For-H ... ... ... ... ... ... ...
It is at present that starting material prepares pregnant steroid -16- alkene -3,20- bis- with the 17 α-beta-hydroxy of acetenyl -17 steroidal compounds (I)
Ketone steroid derivative（II）Preparation method mainly have following three kinds：
Method one, the 17 α-beta-hydroxy of acetenyl -17 steroidal compounds (I) prepare 16- alkene -17- acetylene with dehydrating agent reaction
Base-steroidal compounds (III), then 16- alkene -17- acetenyls-steroidal compounds (III) in acid condition with Hg2+React
To pregnant steroid -16- alkene -3,20- diketone steroid derivative（II）.
Document:Organic chemistry；Volume 25；12 phases；1556-1559 pages, 2005, it was recently reported that containing DBU（Chinese：1,
8- diazacyclos [5,4,0] hendecene -7）Benzene solvent in, POCl3With -17 α of the 18- ethyls-beta-hydroxy -4- of acetenyl -17 alkene -
Androstane -3- ketone is stirred at room temperature half an hour and then heats to backflow, and room temperature is down in reaction after two hours, add hydrochloric acid and water,
Reaction half an hour obtains dehydrate 18- ethyl -17- acetenyls -4,16- diene-androstane -3- ketone at room temperature.18- ethyl -17- second
Alkynyl -4,16- diene-androstane -3- ketone in acid condition with Hg2+React to obtain 18- ethyls -4,16- diene-pregnant steroid -3,20- bis-
Ketone.Total recovery 57.8%.
Method two, document Steroids；Volume54；Issue3；Pages321-32；1989, it was recently reported that in DMF solvent
In, trifluoro-acetic anhydride and the 17 α-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone, reaction obtain the 17 α-β of acetenyl-17-trifluoro
Acetate-4- alkene-androstane-3- ketone, the 17 α-β of acetenyl-17-triflutate-4- alkene-androstane-3- ketone in acid condition with
Hg2+React to obtain 4,16- diene-pregnant steroid -3,20- diketone.
Method three, metal（Such as ruthenium, cobalt）The reaction that complex is participated in.
Such as document Advanced Synthesis＆Catalysis;vol.348;nb.1-2;(2006);p.101-110
Ruthenium complex and the 17 α-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone are reported in the presence of trifluoroacetic acid in tetrahydrofuran
Middle heating reflux reaction 4h obtains 4,16- diene-pregnant steroid -3,20- diketone（Yield 96%）.
Such as document Pharmaceutical Chemistry Journal;vol.26;nb.3;(1992);p.285-
289;With Khimiko-Farmatsevticheskii Zhurnal;vol.26;nb.3;(1992);P.84-87 report 17 α-
The β of acetenyl -11,17 beta-dihydroxy -4- alkene-androstane -3- ketone is matched somebody with somebody in the tetrafluoride borate ether aqueous solution with cobalt octacarbonyl formation
Compound, is then obtaining the 17 α-beta-hydroxy -4,16- of acetenyl -11 diene-androstane -3- ketone, 17 α-second with ammonium ceric nitrate reaction
The beta-hydroxy -4,16- of alkynyl -11 diene-androstane -3- ketone continue in acid condition with Hg2+React to obtain 11 beta-hydroxies -4,16- bis-
Alkene-pregnant steroid -3,20- diketone.This reactions steps is more and loaded down with trivial details.
Above-mentioned is that starting material prepares pregnant steroid -16- alkene -3,20- bis- with the 17 α-beta-hydroxy of acetenyl -17 steroidal compounds (I)
Ketone steroid derivative（II）Method, yield is low, and impurity is more, is difficult to refine, and some need to pass through chromatography, and some are also used
Rare metal ruthenium, cost is high, and these methods only rest on laboratory level, there are no industrialized report at present.We lead to
Multiplicating experiment is crossed, finds these methods because the problems such as above-mentioned yield is low, impurity is more, cost is high, being not suitable for industrialized production.
The content of the invention
The present invention relates to a kind of pregnant steroid -16- alkene -3,20- diketone steroid derivative（II）Preparation method, it is characterized in that will
17 prepare the standby side hydroxy steroid derivatives I of acetenyl -17 with reagent A or the reaction of the organic solvent containing reagent A is obtained, and react warm
Degree：25 DEG C~solvent reflux temperature, the reagent A is dissolved in the solution that methanesulfonic acid is formed for 5%~15% phosphorus pentoxide
For double bond or singly-bound
R be-H orCH3OrF orF
R2For-H orBr orF
R1For==O orOH orOH
WhenR2ForBr orDuring F,R1ForOH
WhenWhen R1 is==O,R2For-H ... ... ... ... ... ... ....
A kind of described pregnant steroid -16- alkene -3,20- diketone steroid derivative（II）Preparation method, it is characterized in that described
17 α-beta-hydroxy the steroid derivative of acetenyl -17（I）For 11 beta-hydroxyl-17 alphas-β of acetenyl-17-nitro ester-4- alkene-androstane-3-
Ketone, 11 beta-hydroxyl-17 alphas-β of acetenyl-17-nitro ester-Isosorbide-5-Nitrae-diene-androstane-3- ketone, 11-17 α of the Alpha-hydroxy-β of acetenyl-17-
Nitro ester-4- alkene-androstane-3- ketone, 11-17 α of Alpha-hydroxy-β of acetenyl-17-nitro ester-Isosorbide-5-Nitrae-diene-androstane-3- ketone, 17 α-
The β of acetenyl-17-nitro ester-4- alkene-androstane-3,11- diketone or the 17 α-β of acetenyl-17-nitro ester-Isosorbide-5-Nitrae-diene-androstane-3,
11- diketone.
A kind of described pregnant steroid -16- alkene -3,20- diketone steroid derivative（II）Preparation method, it is characterized in that 17 α-second
The beta-hydroxy steroid derivative of alkynyl -17（I）Rate of charge with methanesulfonic acid is 1 for calculation in the molar ratio:4~1:8.
A kind of described pregnant steroid -16- alkene -3,20- diketone steroid derivative（II）Preparation method, it is characterized in that 17 α-second
The beta-hydroxy steroid derivative of alkynyl -17（I）Rate of charge with methanesulfonic acid is 1 for calculation in the molar ratio:6.
A kind of described pregnant steroid -16- alkene -3,20- diketone steroid derivative（II）Preparation method, it is characterized in that reaction temperature
Preferably 50~60 DEG C of degree.
A kind of described pregnant steroid -16- alkene -3,20- diketone steroid derivative（II）Preparation method, it is characterized in that reaction exist
Carried out in aprotic organic solvent.
A kind of described pregnant steroid -16- alkene -3,20- diketone steroid derivative（II）Preparation method, it is characterized in that described
Aprotic organic solvent is selected from carbon tetrachloride, chloroform, dichloromethane, 1,1- dichloroethanes, 1,2- dichloroethanes, hexamethylene
Or the one or more in n-hexane.
A kind of described pregnant steroid -16- alkene -3,20- diketone steroid derivative（II）Preparation method, it is characterized in that reagent A
The solution of methanesulfonic acid formation is dissolved in for 7% phosphorus pentoxide.
Heretofore described reagent A is the solution that 5%~15% phosphorus pentoxide is dissolved in methanesulfonic acid formation, 5 referred to
The phosphorus pentoxide of~15 percetages by weight is dissolved in the solution of methanesulfonic acid formation.
It the present invention relates to the use of 4AD or ADD 17 α-beta-hydroxy derivative of acetenyl -17（I）For starting material, prepare pregnant
Steroid -16- alkene -3,20- diketone steroid derivatives（II）.Sharpest edges of the present invention are to have obtained the pregnant of high-purity with high yield
Steroid -16- alkene -3,20- diketone steroid derivatives（II）, and realize industrialization.Pregnant steroid -16- alkene -3 of resulting high-purity,
20- diketone steroid derivatives（II）It is steroidal synthesis important intermediate.The present invention is realized by starting material of 4AD or ADD and prepared
Steroidal compounds, are a great technological changes for steroidal industry.Androstene two can be utilized using the technology of the present invention
It is starting material that ketone, which substitutes Chinese yam saponin, realizes that a series of product costs decline to a great extent, is more favorable to environmental protection.
Specific embodiment
Below will by embodiment, the invention will be further described, these description be not present invention is made into
The restriction of one step.Person skilled should be understood that the equivalent substitution made to the technical characteristic of the present invention, or be correspondingly improved,
Still fall within protection scope of the present invention.
Embodiment 1 prepared by starting material of the 11 beta-hydroxyl-17 alphas-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone 11 β-
Hydroxyl -4,16- diene-pregnant steroid -3,20- diketone, the content of starting material is 95% in the present embodiment.
Embodiment 1-1
700L carbon tetrachloride is put into clean five oxidations two dried in 1000L retort, then add 6.63kg15%
Phosphorus --- methanesulfonic acid stirs at room temperature.11 beta-hydroxyl-17 alphas-the beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone is put into again
3.28Kg.It is steam heated to 60 DEG C, clock reaction 1h.TLC detection raw materials disappear, and are cooled to room temperature filtering, concentration filtrate is near
It is dry, frozen water 500L is rushed, stirring is cooled to room temperature.Get rid of material.Obtain 11 beta-hydroxy -4,16- diene-pregnant steroid -3,20- diketone
2.79Kg, molar yield 85%, HPLC contents 90%.
Embodiment 1-2
700L carbon tetrachloride is put into clean five oxidations two dried in 1000L retort, then add 6.17kg7%
Phosphorus --- methanesulfonic acid stirs at room temperature.11 beta-hydroxyl-17 alphas-the beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone is put into again
3.28Kg.It is steam heated to 60 DEG C, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room temperature filtering, concentration filtrate is near
It is dry, frozen water 300L is rushed, stirring is cooled to room temperature.Get rid of material.Obtain 11 beta-hydroxy -4,16- diene-pregnant steroid -3,20- diketone
2.95Kg, molar yield 90%, HPLC contents 93%.
Embodiment 1-3
700L carbon tetrachloride is put into clean five oxidations two dried in 1000L retort, then add 6.05kg5%
Phosphorus --- methanesulfonic acid stirs at room temperature.11 beta-hydroxyl-17 alphas-the beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone is put into again
3.28Kg.It is steam heated to 60 DEG C, clock reaction 1h.TLC detection raw materials disappear, and are cooled to room temperature filtering, concentration filtrate is near
It is dry, frozen water 500L is rushed, stirring is cooled to room temperature.Get rid of material.Obtain 11 beta-hydroxy -4,16- diene-pregnant steroid -3,20- diketone
2.79Kg, molar yield 85%, HPLC contents 89%.
Embodiment 2 prepared by starting material of 11-17 α of the Alpha-hydroxy-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone 11 α-
Hydroxyl -4,16- diene-pregnant steroid -3,20- diketone, the content of starting material is 93% in the present embodiment.
Embodiment 2-1
440L chloroforms are put into clean five oxidations two dried in 1000L retort, then add 4.11kg7%
Phosphorus --- methanesulfonic acid stirs at room temperature.11-17 α of the Alpha-hydroxy-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone is put into again
3.28Kg.It is steam heated to 60 DEG C, clock reaction 1h.TLC detection raw materials disappear, and are cooled to room temperature filtering, concentration filtrate is near
It is dry, frozen water 300L is rushed, stirring is cooled to room temperature.Get rid of material.Obtain 11 Alpha-hydroxy -4,16- diene-pregnant steroid -3,20- diketone
2.79Kg, molar yield 85%, HPLC contents 92%.
Embodiment 2-2
500L chloroforms are put into clean five oxidations two dried in 1000L retort, then add 6.17kg7%
Phosphorus --- methanesulfonic acid stirs at room temperature.11-17 α of the Alpha-hydroxy-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone is put into again
3.28Kg.It is steam heated to 60 DEG C, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room temperature filtering, concentration filtrate is near
It is dry, frozen water 300L is rushed, stirring is cooled to room temperature.Get rid of material.11 Alpha-hydroxy -4,16- diene-pregnant steroid -3,20- diketone 2.8Kg is obtained,
Molar yield 90%, HPLC contents 93%.
Embodiment 2-3
500L chloroforms are put into clean five oxidations two dried in 1000L retort, then add 8.22kg7%
Phosphorus --- methanesulfonic acid stirs at room temperature.11-17 α of the Alpha-hydroxy-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone 3.28Kg.
It is steam heated to 60 DEG C, clock reaction 1h.TLC detection raw materials disappear, and are cooled to room temperature filtering, and concentration filtrate rushes ice near dry
Water 300L, stirring is cooled to room temperature.Get rid of material.11 Alpha-hydroxy -4,16- diene-pregnant steroid -3,20- diketone 2.8Kg is obtained, mole receipts
Rate 85%, HPLC contents 93%.
Embodiment 2-4
500L chloroforms are put into clean five oxidations two dried in 1000L retort, then add 3kg7%
Phosphorus --- methanesulfonic acid stirs at room temperature.11-17 α of the Alpha-hydroxy-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone 3.28Kg.
It is steam heated to 60 DEG C, clock reaction 1h.TLC detection raw materials disappear, and are cooled to room temperature filtering, and concentration filtrate rushes ice near dry
Water 300L, stirring is cooled to room temperature.Get rid of material.Obtain 6 Alpha-Methyls-Isosorbide-5-Nitrae, 9（11）, 16- tetraenes-pregnant steroid -3,20- diketone
2.67Kg, molar yield 81%, HPLC contents 85%.
Embodiment 2-5
500L chloroforms are put into clean five oxidations two dried in 1000L retort, then add 10kg7%
Phosphorus --- methanesulfonic acid stirs at room temperature.11-17 α of the Alpha-hydroxy-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone 3.28Kg.
It is steam heated to 60 DEG C, clock reaction 1h.TLC detection raw materials disappear, and are cooled to room temperature filtering, and concentration filtrate rushes ice near dry
Water 300L, stirring is cooled to room temperature.Get rid of material.11 Alpha-hydroxy -4,16- diene-pregnant steroid -3,20- diketone 2.6Kg is obtained, mole receipts
Rate 80%, HPLC contents 85%.
Embodiment 3 is prepared by starting material of the 11 beta-hydroxyl-17 alphas-beta-hydroxy of acetenyl-17-Isosorbide-5-Nitrae-diene-androstane-3- ketone
11 beta-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone, the content of starting material is 93% in the present embodiment.
Embodiment 3-1
800L hexamethylenes are put into clean five oxidations two dried in 1000L retort, then add 6.17kg7%
Phosphorus --- methanesulfonic acid stirs at room temperature.11 beta-hydroxyl-17 alphas-beta-hydroxy-Isosorbide-5-Nitrae-diene-androstane-of acetenyl -17 is put into again
3- ketone 3.26Kg.It is steam heated to 50~60 DEG C, clock reaction 1h.TLC detection raw materials disappear, and are cooled to room temperature filtering, concentration
Filtrate rushes frozen water 700L near dry, and stirring is cooled to room temperature.Get rid of material.Obtain 11 beta-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20-
Diketone 2.9kg, molar yield 90%, HPLC contents 92%.
Embodiment 3-2
800L hexamethylenes are put into clean five oxidations two dried in 1000L retort, then add 6.17kg7%
Phosphorus --- methanesulfonic acid stirs at room temperature.11 beta-hydroxyl-17 alphas-beta-hydroxy-Isosorbide-5-Nitrae-diene-androstane-of acetenyl -17 is put into again
3- ketone 3.26Kg.It is steam heated to backflow, clock reaction 1h.TLC detection raw materials disappear, and are cooled to room temperature filtering, concentrate filtrate
To near dry, frozen water 700L is rushed, stirring is cooled to room temperature.Get rid of material.Obtain 11 beta-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone
2.77Kg, molar yield 85%, HPLC contents 93%.
Embodiment 3-3
800L hexamethylenes are put into clean five oxidations two dried in 1000L retort, then add 6.17kg7%
Phosphorus --- methanesulfonic acid stirs at room temperature.11 beta-hydroxyl-17 alphas-beta-hydroxy-Isosorbide-5-Nitrae-diene-androstane-of acetenyl -17 is put into again
3- ketone 3.26Kg.Stirring reaction, clock reaction 4h at room temperature.TLC detection raw materials disappear, and are cooled to room temperature filtering, concentrate filtrate
To near dry, frozen water 700L is rushed, stirring is cooled to room temperature.Get rid of material.Obtain 11 beta-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone
2.8Kg, molar yield 86%, HPLC contents 92%.
Embodiment 4 is prepared by starting material of 11-17 α of the Alpha-hydroxy-beta-hydroxy of acetenyl-17-Isosorbide-5-Nitrae-diene-androstane-3- ketone
11 Alpha-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone, the content of starting material is 93% in the present embodiment.
By 500L1,1- dichloroethanes puts into clean five oxygen dried in 1000L retort, then add 6.17kg7%
Change two phosphorus --- methanesulfonic acid stirs at room temperature.11-17 α of the Alpha-hydroxy-beta-hydroxy of acetenyl-17-Isosorbide-5-Nitrae-diene-hero is put into again
Steroid -3- ketone 3.26Kg.It is steam heated to 50~60 DEG C, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room temperature filtering, dense
Contracting filtrate rushes frozen water 300L near dry, and stirring is cooled to room temperature.Get rid of material.Obtain 11 Alpha-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,
20- diketone 2.9Kg, molar yield 90%, HPLC contents 93%.
Embodiment 5 is that starting material prepares Isosorbide-5-Nitrae with the 17 α-beta-hydroxy of acetenyl-17-Isosorbide-5-Nitrae-diene-androstane-3,11- diketone,
16- triolefins-pregnant steroid -3,20- diketone, the content of starting material is 93% in the present embodiment.
By 4.42kg15% phosphorus pentoxide --- methanesulfonic acid is put into clean dry 500L retort, is then added
Stir at room temperature.17 α-beta-hydroxy-Isosorbide-5-Nitrae-the diene-of acetenyl -17 androstane -3,11- diketone 3.24Kg is put into again.Steam adds
Heat is to 50-60 DEG C, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room temperature filtering, and concentration filtrate rushes frozen water near dry
300L, stirring is cooled to room temperature.Get rid of material.Obtain Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone 2.59Kg, molar yield 80%,
HPLC contents 87%.
Embodiment 6 is that starting material prepares 4,16- bis- with the 17 α-beta-hydroxy of acetenyl-17-4- alkene-androstane-3,11- diketone
Alkene-pregnant steroid -3,20- diketone, the content of starting material is 95% in the present embodiment.
500L hexamethylenes are put into clean five oxidations two dried in 1000L retort, then add 6.17kg7%
Phosphorus --- methanesulfonic acid stirs at room temperature.17 α-the beta-hydroxy of acetenyl-17-4- alkene-androstane-3,11- diketone is put into again
3.26Kg.25 DEG C are stirred at room temperature reaction, clock reaction 5h.TLC detection raw materials disappear, and are cooled to room temperature filtering, concentration filtrate is extremely
It is near dry, frozen water 300L is rushed, stirring is cooled to room temperature.Get rid of material.4,16- diene-pregnant steroid -3,20- diketone 2.77Kg is obtained, mole receipts
Rate 85%, HPLC contents 90%.
Embodiment 7 prepares 6 by starting material of 6-17 α of the Alpha-Methyl-beta-hydroxy of acetenyl-17-4- alkene-androstane-3,11- diketone
Alpha-Methyl 4,16- diene-pregnant steroid -3,20- diketone, the content of starting material is 94% in the present embodiment.
By 8.8kg15% phosphorus pentoxide --- methanesulfonic acid is put into clean dry 500L retort, is stirred at room temperature
Uniformly.6-17 α of the Alpha-Methyl-beta-hydroxy of acetenyl-17-4- alkene-androstane-3,11- diketone 3.40Kg is put into again.It is steam heated to 50
~60 DEG C, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room temperature filtering, and concentration filtrate is rushed frozen water 300L, stirred near dry
Mix and be cooled to room temperature.Get rid of material.Obtain 6 Alpha-Methyls 4,16- diene-pregnant steroid -3,20- diketone 2.8Kg, molar yield 83%, HPLC contains
Amount 85%.
Embodiment 8 is with 6-17 α of the Alpha-Methyl-beta-hydroxy of acetenyl-17-Isosorbide-5-Nitrae-diene-androstane-3,11- diketone for starting material
Prepare 6 Alpha-Methyls-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone, the content of starting material is 94% in the present embodiment.
By 8.22kg7% phosphorus pentoxide --- methanesulfonic acid is put into clean dry 500L retort, then adds room
Stirred under temperature.6-17 α of the Alpha-Methyl-beta-hydroxy-Isosorbide-5-Nitrae-diene-of acetenyl-17 androstane-3,11- diketone 3.38Kg is put into again.
Stirring reaction, clock reaction 3h at room temperature.TLC detection raw materials disappear, and are cooled to room temperature filtering, and concentration filtrate rushes ice near dry
Water 300L, stirring is cooled to room temperature.Get rid of material.Obtain 6 Alpha-Methyls-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone 2.77Kg, mole
Yield 82%, HPLC contents 90%.
Embodiment 9 prepared by starting material of the 6 α-fluoro- 17 α-beta-hydroxy of acetenyl-17-4- alkene-androstane-3,11- diketone 6 α-
Fluoro- 4,16- diene-pregnant steroid -3,20- diketone, the content of starting material is 93% in the present embodiment.
By 10kg15% phosphorus pentoxide --- methanesulfonic acid is put into clean dry 500L retort, and 6 are then put into again
α-fluoro- 17 α-the beta-hydroxy of acetenyl-17-4- alkene-androstane-3,11- diketone 3.44Kg.It is steam heated to 90 DEG C, clock reaction 1h.
TLC detection raw materials disappear, and are cooled to room temperature filtering, and concentration filtrate rushes frozen water 300L near dry, and stirring is cooled to room temperature.Get rid of material.
Obtain 6 α-fluoro- 4,16- diene-pregnant steroid -3,20- diketone 2.75kg, molar yield 80%, HPLC contents 86%.
Embodiment 10 is with the 6 α-fluoro- 17 α-beta-hydroxy of acetenyl-17-Isosorbide-5-Nitrae-diene-androstane-3,11- diketone for starting material system
Standby 6 α-fluoro- Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone, the content of starting material is 94% in the present embodiment.
By 10kg5% phosphorus pentoxide --- methanesulfonic acid is put into clean dry 500L retort, is stirred at room temperature down again
Put into the 6 α-fluoro- 17 α-beta-hydroxy-Isosorbide-5-Nitrae-diene-of acetenyl -17 androstane -3,11- diketone 3.24Kg.It is steam heated to 50-60
DEG C, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room temperature filtering, and concentration filtrate rushes frozen water 300L, stirring drop near dry
Warm to room temperature.Get rid of material.Obtain 6 α-fluoro- Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone 2.6Kg, molar yield 81%, HPLC contents
85%。
Embodiment 11 prepares 6 by starting material of the 6 β-fluoro- 17 α-beta-hydroxy of acetenyl-17-4- alkene-androstane-3,11- diketone
β-fluoro- 4,16- diene-pregnant steroid -3,20- diketone, the content of starting material is 94% in the present embodiment.
500L carbon tetrachloride is put into clean five oxidations two dried in 1000L retort, then add 4.42kg15%
Phosphorus --- methanesulfonic acid stirs at room temperature.6 β-fluoro- 17 α-the beta-hydroxy of acetenyl-17-4- alkene-androstane-3,11- two is put into again
Ketone 3.44Kg.Stir at room temperature, clock reaction 5h.TLC detects that raw material disappears, and is cooled to room temperature filtering, and concentration filtrate is done near,
Frozen water 300L is rushed, stirring is cooled to room temperature.Get rid of material.6 β-fluoro- 4,16- diene-pregnant steroid -3,20- diketone 2.75Kg is obtained, mole
Yield 80%, HPLC contents 85%.
Embodiment 12 is with the 6 β-fluoro- 17 α-beta-hydroxy of acetenyl-17-Isosorbide-5-Nitrae-diene-androstane-3,11- diketone for starting material system
Standby 6 β-fluoro- Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone, the content of starting material is 94% in the present embodiment.
500L n-hexanes are put into clean five oxidations two dried in 1000L retort, then add 4.1kg7%
Phosphorus --- methanesulfonic acid stirs at room temperature.6 β-fluoro- 17 α-the beta-hydroxy of acetenyl-17-Isosorbide-5-Nitrae-diene-androstane-3 are put into again,
11- diketone 3.42Kg.Stirred at room temperature at 25 DEG C, clock reaction 5h.TLC detection raw materials disappear, and are cooled to room temperature filtering, concentration
Filtrate rushes frozen water 300L near dry, and stirring is cooled to room temperature.Get rid of material.Obtain 6 β-fluoro- Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- bis-
Ketone 2.9Kg, molar yield 85%, HPLC contents 85%.
Embodiment 13 is using-17 α of Alpha-hydroxy of 6 Alpha-Methyl-11-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone as starting material
Alpha-hydroxy-4, the 16- diene of 6 Alpha-Methyl-11-pregnant steroid-3,20- diketone is prepared, the content of starting material is 95% in the present embodiment.
600L hexamethylenes are put into clean five oxidations two dried in 1000L retort, then add 8.22kg7%
Phosphorus --- methanesulfonic acid stirs at room temperature.- 17 α of Alpha-hydroxy of 6 Alpha-Methyl-11-beta-hydroxy of acetenyl-17-4- alkene-hero is put into again
Steroid -3- ketone 3.42Kg.It is steam heated to 50-60 DEG C, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room temperature filtering, dense
Contracting filtrate rushes frozen water 300L near dry, and stirring is cooled to room temperature.Get rid of material.Obtain the beta-hydroxy -4- of -11 Alpha-hydroxy of 6 Alpha-Methyl -17
Alkene-pregnant steroid -3,20- diketone 2.87Kg, molar yield 84%, HPLC contents 87%.
Embodiment 14 is using 6-11 beta-hydroxyl-17 alphas of the Alpha-Methyl-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone as starting material
Beta-hydroxy-4, the 16- diene of 6 Alpha-Methyl-11-pregnant steroid-3,20- diketone is prepared, the content of starting material is 95% in the present embodiment.
500L chloroforms are put into clean five oxidations two dried in 1000L retort, then add 8.8kg15%
Phosphorus --- methanesulfonic acid stirs at room temperature.6-11 beta-hydroxyl-17 alphas of the Alpha-Methyl-beta-hydroxy of acetenyl-17-4- alkene-hero is put into again
Steroid -3- ketone 3.42Kg.It is steam heated to solvent refluxing, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room temperature filtering, dense
Contracting filtrate rushes frozen water 300L near dry, and stirring is cooled to room temperature.Get rid of material.Obtain beta-hydroxy-4, the 16- diene of 6 Alpha-Methyl-11-pregnant
Steroid -3,20- diketone 2.7Kg, molar yield 80%, HPLC contents 91%.
Embodiment 15 is using 6 α-- 17 α of the fluoro- 11 Alpha-hydroxy-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone as starting material system
Standby 6 α-fluoro- 11 Alpha-hydroxy -4,16- diene-pregnant steroid -3,20- diketone, the content of starting material is 95% in the present embodiment.
500L dichloromethane is put into clean five oxidations two dried in 1000L retort, then add 8.07kg5%
Phosphorus --- methanesulfonic acid stirs at room temperature.6 α-- 17 α of the fluoro- 11 Alpha-hydroxy-beta-hydroxy of acetenyl-17-4- alkene-hero is put into again
Steroid -3- ketone 3.46Kg.It is steam heated to backflow, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room temperature filtering, concentration filter
Liquid rushes frozen water 300L near dry, and stirring is cooled to room temperature.Get rid of material.6 α-fluoro- 11 Alpha-hydroxy -4,16- diene-pregnant steroid -3 are obtained,
20- diketone 2.9Kg, molar yield 85%, HPLC contents 84%.
Embodiment 16 is using the 6 α-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone as starting material system
Standby 6 α-fluoro- 11 beta-hydroxy -4,16- diene-pregnant steroid -3,20- diketone, the content of starting material is 95% in the present embodiment.
By 500L1,2- dichloroethanes puts into clean five oxygen dried in 1000L retort, then add 4.03kg5%
Change two phosphorus --- methanesulfonic acid stirs at room temperature.Put into again the 6 α-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy -4- of acetenyl -17 alkene -
Androstane -3- ketone 3.46Kg.It is steam heated to 50-60 DEG C, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room temperature filtering,
Filtrate is concentrated near dry, frozen water 300L is rushed, stirring is cooled to room temperature.Get rid of material.Obtain 6 α-fluoro- 11 beta-hydroxy -4,16- diene-pregnant
Steroid -3,20- diketone 2.9Kg, molar yield 85%, HPLC contents 85%.
Embodiment 17 is using 6 β-- 17 α of the fluoro- 11 Alpha-hydroxy-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone as starting material system
Standby 6 β-fluoro- 11 Alpha-hydroxy -4,16- diene-pregnant steroid -3,20- diketone, the content of starting material is 94% in the present embodiment.
500L dichloromethane is put into clean five oxidations two dried in 1000L retort, then add 3.17kg15%
Phosphorus --- methanesulfonic acid stirs at room temperature.6 β-- 17 α of the fluoro- 11 Alpha-hydroxy-beta-hydroxy of acetenyl-17-4- alkene-hero is put into again
Steroid -3- ketone 3.46Kg.Backflow, clock reaction 2h.TLC detects that raw material disappears, and is cooled to room temperature filtering, and concentration filtrate is done near,
Frozen water 300L is rushed, stirring is cooled to room temperature.Get rid of material.Obtain 6 β-fluoro- 11 Alpha-hydroxy -4,16- diene-pregnant steroid -3,20- diketone
2.77Kg, molar yield 80%, HPLC contents 86%.
Embodiment 18 is using the 6 β-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone as starting material system
Standby 6 β-fluoro- 11 beta-hydroxy -4,16- diene-pregnant steroid -3,20- diketone, the content of starting material is 94% in the present embodiment.
By 500L1,1- dichloroethanes puts into clean five oxygen dried in 1000L retort, then add 4.11kg7%
Change two phosphorus --- methanesulfonic acid stirs at room temperature.Put into again the 6 β-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy -4- of acetenyl -17 alkene -
Androstane -3- ketone 3.46Kg.Backflow, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room temperature filtering, concentration filtrate is near
It is dry, frozen water 300L is rushed, stirring is cooled to room temperature.Get rid of material.Obtain 6 β-fluoro- 11 beta-hydroxy -4,16- diene-pregnant steroid -3,20- diketone
2.9Kg, molar yield 85%, HPLC contents 89%.
Embodiment 19 using-17 α of Alpha-hydroxy of 6 Alpha-Methyl-11-beta-hydroxy of acetenyl-17-Isosorbide-5-Nitrae-diene-androstane-3- ketone as rise
Beginning thing prepares 6-11 Alpha-hydroxies of Alpha-Methyl-Isosorbide-5-Nitrae, the content of 16- triolefins-pregnant steroid-3,20- diketone, in the present embodiment starting material
For 94%.
By 700L1,2- dichloroethanes puts into clean five oxidations dried in 1000L retort, then add 8.2kg7%
Two phosphorus --- methanesulfonic acid stirs at room temperature.- 17 α of Alpha-hydroxy of 6 Alpha-Methyl-11-beta-hydroxy-Isosorbide-5-Nitrae-of acetenyl-17 is put into again
Diene-androstane -3- ketone 3.40Kg.Backflow, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room temperature filtering, concentrate filtrate
To near dry, frozen water 300L is rushed, stirring is cooled to room temperature.Get rid of material.Obtain 6-11 Alpha-hydroxies of Alpha-Methyl-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid-
3,20- diketone 2.89Kg, molar yield 85%, HPLC contents 90%.
Embodiment 20 using 6-11 beta-hydroxyl-17 alphas of the Alpha-Methyl-beta-hydroxy of acetenyl-17-Isosorbide-5-Nitrae-diene-androstane-3- ketone as rise
Beginning thing prepares 6-11 beta-hydroxies of Alpha-Methyl-Isosorbide-5-Nitrae, the content of 16- triolefins-pregnant steroid-3,20- diketone, in the present embodiment starting material
For 93%.
500L hexamethylenes are put into clean five oxidations two dried in 1000L retort, then add 6.17kg7%
Phosphorus --- methanesulfonic acid stirs at room temperature.6-11 beta-hydroxyl-17 alphas of the Alpha-Methyl-beta-hydroxy of acetenyl-17-Isosorbide-5-Nitrae-two is put into again
Alkene-androstane -3- ketone 3.40Kg.Backflow, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room temperature filtering, concentration filtrate is extremely
It is near dry, frozen water 300L is rushed, stirring is cooled to room temperature.Get rid of material.Obtain 6-11 beta-hydroxies of Alpha-Methyl-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid-3,
20- diketone 3.1Kg, molar yield 90%, HPLC contents 87%.
Embodiment 21 is using 6 α-- 17 α of the fluoro- 11 Alpha-hydroxy-beta-hydroxy of acetenyl-17-Isosorbide-5-Nitrae-diene-androstane-3- ketone as starting
Thing prepare 6 α-fluoro- 11 Alpha-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone, in the present embodiment the content of starting material be
93%。
By 8.8kg10% phosphorus pentoxide --- methanesulfonic acid is put into clean dry 500L retort, is stirred at room temperature
Uniformly.6 α--17 α of the fluoro- 11 Alpha-hydroxy-beta-hydroxy-Isosorbide-5-Nitrae-diene-androstane -3- ketone of acetenyl -17 3.44Kg is put into again.At room temperature
Stirring, clock reaction 4h.TLC detection raw materials disappear, and are cooled to room temperature filtering, and concentration filtrate is rushed frozen water 300L near dry, stirred
It is cooled to room temperature.Get rid of material.Obtain 6 α-fluoro- 11 Alpha-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone 2.8Kg, molar yield
83%, HPLC content 85%.
Embodiment 22 is using the 6 α-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy of acetenyl-17-Isosorbide-5-Nitrae-diene-androstane-3- ketone as starting
Thing prepare 6 α-fluoro- 11 beta-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone, in the present embodiment the content of starting material be
95%。
500L carbon tetrachloride is put into clean five oxidations two dried in 1000L retort, then add 6.63kg15%
Phosphorus --- methanesulfonic acid stirs at room temperature.6 α-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy-Isosorbide-5-Nitrae-diene-of acetenyl -17 is put into again
Androstane -3- ketone 3.44Kg.Backflow, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room temperature filtering, concentration filtrate is near
It is dry, frozen water 300L is rushed, stirring is cooled to room temperature.Get rid of material.Obtain 6 α-fluoro- 11 beta-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- bis-
Ketone 3.0Kg, molar yield 88%, HPLC contents 85%.
Embodiment 23 is using 6 β-- 17 α of the fluoro- 11 Alpha-hydroxy-beta-hydroxy of acetenyl-17-Isosorbide-5-Nitrae-diene-androstane-3- ketone as starting
Thing prepare 6 β-fluoro- 11 Alpha-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone, in the present embodiment the content of starting material be
93%。
500L chloroforms are put into clean five oxidations two dried in 1000L retort, then add 8.84kg15%
Phosphorus --- methanesulfonic acid stirs at room temperature.6 β--17 α of fluoro- 11 Alpha-hydroxy-beta-hydroxy-Isosorbide-5-Nitrae-diene-of acetenyl -17 is put into again
Androstane -3- ketone 3.44Kg.Backflow, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room temperature filtering, concentration filtrate is near
It is dry, frozen water 300L is rushed, stirring is cooled to room temperature.Get rid of material.Obtain 6 β-fluoro- 11 Alpha-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- bis-
Ketone 3.0Kg, molar yield 88%, HPLC contents 88%.
Embodiment 24 is using the 6 β-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy of acetenyl-17-Isosorbide-5-Nitrae-diene-androstane-3- ketone as starting
Thing prepare 6 β-fluoro- 11 beta-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone, in the present embodiment the content of starting material be
95%。
500L dichloromethane is put into clean five oxidations two dried in 1000L retort, then add 4.42kg15%
Phosphorus --- methanesulfonic acid stirs at room temperature.6 β-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy-Isosorbide-5-Nitrae-diene-of acetenyl -17 is put into again
Androstane -3- ketone 3.44Kg.It is steam heated to 50~60 DEG C, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room temperature filtering,
Filtrate is concentrated near dry, frozen water 300L is rushed, stirring is cooled to room temperature.Get rid of material.Obtain 6 β-fluoro- 11 beta-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-
Pregnant steroid -3,20- diketone 3.0Kg, molar yield 88%, HPLC contents 90%.
Embodiment 25 is with the α of 6 Alpha-Methyl-9-bromo- 11 beta-hydroxyl-17 alphas-beta-hydroxy of acetenyl-17-Isosorbide-5-Nitrae-diene-androstane-3-
Ketone is that starting material prepares 6 Alpha-Methyl -9 α-bromo- 11 beta-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone, in the present embodiment
The content of starting material is 93%.
By 700L1,1- dichloroethanes puts into clean five oxidations dried in 1000L retort, then add 10kg15%
Two phosphorus --- methanesulfonic acid stirs at room temperature.The α of 6 Alpha-Methyl-9-bromo- 11 beta-hydroxyl-17 alphas-β of acetenyl-17-hydroxyl is put into again
Base-Isosorbide-5-Nitrae-diene-androstane -3- ketone 4.18Kg.It is steam heated to 50~60 DEG C, clock reaction 2h.TLC detection raw materials disappear, cold
But filtered to room temperature, concentration filtrate rushes frozen water 300L near dry, and stirring is cooled to room temperature.Get rid of material.Obtain the α of 6 Alpha-Methyl-9-bromo-
11 beta-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone 3.67Kg, molar yield 87%, HPLC contents 90%.
Embodiment 26 is with 6 α-fluoro- 9 α-bromo- 11 beta-hydroxyl-17 alphas-beta-hydroxy-Isosorbide-5-Nitrae-diene-androstane -3- ketone of acetenyl -17
6 α-fluoro- 9 α-bromo- 11 beta-hydroxies-Isosorbide-5-Nitrae is prepared for starting material, 16- triolefins-pregnant steroid -3,20- diketone are originated in the present embodiment
The content of thing is 95%.
By 500L1,2- dichloroethanes puts into clean five oxidations dried in 1000L retort, then add 3kg15%
Two phosphorus --- methanesulfonic acid stirs at room temperature.Put into again 6 α-fluoro- 9 α-bromo- 11 beta-hydroxyl-17 alphas-beta-hydroxy of acetenyl-17-
Isosorbide-5-Nitrae-diene-androstane -3- ketone 4.22Kg.It is steam heated to 50~60 DEG C, clock reaction 2h.TLC detection raw materials disappear, and are cooled to
Room temperature is filtered, and concentration filtrate rushes frozen water 300L near dry, and stirring is cooled to room temperature.Get rid of material.Obtain 6 α-fluoro- 9 α-bromo- 11 β-hydroxyl
Base-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone 3.7Kg, molar yield 88%, HPLC contents 87%.
Embodiment 27 is with 6 β-fluoro- 9 α-bromo- 11 beta-hydroxyl-17 alphas-beta-hydroxy-Isosorbide-5-Nitrae-diene-androstane -3- ketone of acetenyl -17
6 β-fluoro- 9 α-bromo- 11 beta-hydroxies-Isosorbide-5-Nitrae is prepared for starting material, 16- triolefins-pregnant steroid -3,20- diketone are originated in the present embodiment
The content of thing is 94%.
500L hexamethylenes are put into clean five oxidations two dried in 1000L retort, then add 10kg5%
Phosphorus --- methanesulfonic acid stirs at room temperature.6 β-fluoro- 9 α-bromo- 11 beta-hydroxyl-17 alphas-beta-hydroxy -1 of acetenyl -17 is put into again,
4- diene-androstane -3- ketone 4.22Kg.It is steam heated to backflow, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room temperature mistake
Filter, concentration filtrate rushes frozen water 300L near dry, and stirring is cooled to room temperature.Get rid of material.6 β-fluoro- 9 α-bromo- 11 beta-hydroxy -1 is obtained,
4,16- triolefins-pregnant steroid -3,20- diketone 3.5Kg, molar yield 83%, HPLC contents 85%.
Embodiment 28 is with the α of 6 Alpha-Methyl-9-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy of acetenyl-17-Isosorbide-5-Nitrae-diene-androstane-3-
Ketone is that starting material prepares 6 Alpha-Methyl -9 α-fluoro- 11 beta-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone, in the present embodiment
The content of starting material is 94%.
By 8.8kg12% phosphorus pentoxide --- methanesulfonic acid is put into clean dry 500L retort, is stirred at room temperature
Uniformly.The α of 6 Alpha-Methyl-9-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy-Isosorbide-5-Nitrae-diene-androstane-3- ketone of acetenyl-17 is put into again
3.58Kg.It is steam heated to 50~60 DEG C, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room temperature filtering, concentrate filtrate
To near dry, frozen water 300L is rushed, stirring is cooled to room temperature.Get rid of material.Obtain the α of 6 Alpha-Methyl-9-fluoro- 11 beta-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-
Pregnant steroid -3,20- diketone 2.9Kg, molar yield 82%, HPLC contents 83%.
Embodiment 29 is with 6 α-fluoro- 9 α-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy-Isosorbide-5-Nitrae-diene-androstane -3- ketone of acetenyl -17
6 α-fluoro- 9 α-fluoro- 11 beta-hydroxies-Isosorbide-5-Nitrae is prepared for starting material, 16- triolefins-pregnant steroid -3,20- diketone are originated in the present embodiment
The content of thing is 94%.
500L carbon tetrachloride is put into clean five oxidations two dried in 1000L retort, then add 4.11kg12%
Phosphorus --- methanesulfonic acid stirs at room temperature.6 α-fluoro- 9 α-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy -1 of acetenyl -17 is put into again,
4- diene-androstane -3- ketone 3.62Kg.It is steam heated to 50~60 DEG C, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room
Temperature filtering, concentration filtrate rushes frozen water 300L near dry, and stirring is cooled to room temperature.Get rid of material.Obtain 6 α-fluoro- 9 α-fluoro- 11 β-hydroxyl
Base-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone 3.2Kg, molar yield 88%, HPLC contents 89%.
Embodiment 30 is with 6 β-fluoro- 9 α-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy-Isosorbide-5-Nitrae-diene-androstane -3- ketone of acetenyl -17
6 β-fluoro- 9 α-fluoro- 11 beta-hydroxies-Isosorbide-5-Nitrae is prepared for starting material, 16- triolefins-pregnant steroid -3,20- diketone are originated in the present embodiment
The content of thing is 94%.
500L chloroforms are put into clean five oxidations two dried in 1000L retort, then add 4.11kg7%
Phosphorus --- methanesulfonic acid stirs at room temperature.6 β-fluoro- 9 α-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy -1 of acetenyl -17 is put into again,
4- diene-androstane -3- ketone 3.62Kg.Stirring reaction, clock reaction 5h at room temperature.TLC detection raw materials disappear, and are cooled to room temperature mistake
Filter, concentration filtrate rushes frozen water 300L near dry, and stirring is cooled to room temperature.Get rid of material.6 β-fluoro- 9 α-fluoro- 11 beta-hydroxy -1 is obtained,
4,16- triolefins-pregnant steroid -3,20- diketone 3.2Kg, molar yield 88%, HPLC contents 85%.
Embodiment 31 is using the 9 α-bromo- 11 beta-hydroxyl-17 alphas-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone as starting material system
Standby 9 α-bromo- 11 beta-hydroxy -4,16- diene-pregnant steroid -3,20- diketone, the content of starting material is 93% in the present embodiment.
500L dichloromethane is put into clean five oxidations two dried in 1000L retort, then add 8.22kg7%
Phosphorus --- methanesulfonic acid stirs at room temperature.9 α-bromo- 11 beta-hydroxyl-17 alphas-the beta-hydroxy of acetenyl-17-4- alkene-hero is put into again
Steroid -3- ketone 4.06Kg.Under 25 DEG C of room temperature conditions, clock reaction 4h.TLC detection raw materials disappear, and are cooled to room temperature filtering, concentration
Filtrate rushes frozen water 300L near dry, and stirring is cooled to room temperature.Get rid of material.Obtain 9 α-bromo- 11 beta-hydroxy -4,16- diene-pregnant steroid -
3,20- diketone 3.5Kg, molar yield 87%, HPLC contents 89%.
Embodiment 32 using the α of 6 Alpha-Methyl-9-bromo- 11 beta-hydroxyl-17 alphas-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone as
Starting material prepares the α of 6 Alpha-Methyl-9-bromo- 11 beta-hydroxy-4,16- diene-pregnant steroid-3,20- diketone, in the present embodiment starting material
Content be 93%.
By 700L1,1- dichloroethanes puts into clean five oxidations dried in 1000L retort, then add 10kg7%
Two phosphorus --- methanesulfonic acid stirs at room temperature.The α of 6 Alpha-Methyl-9-bromo- 11 beta-hydroxyl-17 alphas-β of acetenyl-17-hydroxyl is put into again
Base -4- alkene-androstane -3- ketone 4.20Kg.Under 25 DEG C of room temperature conditions, clock reaction 4h.TLC detection raw materials disappear, and are cooled to room
Temperature filtering, concentration filtrate rushes frozen water 500L near dry, and stirring is cooled to room temperature.Get rid of material.Obtain the α of 6 Alpha-Methyl-9-bromo- 11 β-hydroxyl
Base -4,16- diene-pregnant steroid -3,20- diketone 3.36Kg, molar yield 80%, HPLC contents 85%.
Embodiment 33 using the 6 α-fluoro- 9 α-bromo- 11 beta-hydroxyl-17 alphas-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone as rise
Beginning thing prepares 6 α-fluoro- 9 α-bromo- 11 beta-hydroxy -4,16- diene-pregnant steroid -3,20- diketone, and starting material contains in the present embodiment
Measure as 94%.
500L n-hexanes are put into clean five oxidations two dried in 1000L retort, then add 6.63kg15%
Phosphorus --- methanesulfonic acid stirs at room temperature.6 α-fluoro- 9 α-bromo- 11 beta-hydroxyl-17 alphas-the beta-hydroxy of acetenyl-17-4- is put into again
Alkene-androstane -3- ketone 4.24Kg.Under 25 DEG C of room temperature conditions, clock reaction 4h.TLC detection raw materials disappear, and are cooled to room temperature mistake
Filter, concentration filtrate rushes frozen water 300L near dry, and stirring is cooled to room temperature.Get rid of material.6 α-fluoro- 9 α-bromo- 11 beta-hydroxy -4 are obtained,
16- diene-pregnant steroid -3,20- diketone 3.6Kg, molar yield 85%, HPLC contents 85%.
Embodiment 34 using the 6 β-fluoro- 9 α-bromo- 11 beta-hydroxyl-17 alphas-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone as rise
Beginning thing prepares 6 β-fluoro- 9 α-bromo- 11 beta-hydroxy -4,16- diene-pregnant steroid -3,20- diketone, and starting material contains in the present embodiment
Measure as 94%.
500L hexamethylenes are put into clean five oxidations two dried in 1000L retort, then add 3kg15%
Phosphorus --- methanesulfonic acid stirs at room temperature.6 β-fluoro- 9 α-bromo- 11 beta-hydroxyl-17 alphas-the beta-hydroxy of acetenyl-17-4- is put into again
Alkene-androstane -3- ketone 4.24Kg.Under 25 DEG C of room temperature conditions, clock reaction 5h.TLC detection raw materials disappear, and are cooled to room temperature mistake
Filter, concentration filtrate rushes frozen water 300L near dry, and stirring is cooled to room temperature.Get rid of material.6 β-fluoro- 9 α-bromo- 11 beta-hydroxy -4 are obtained,
16- diene-pregnant steroid -3,20- diketone 3.7Kg, molar yield 82%, HPLC contents 86%.
Embodiment 35 using the α of 6 Alpha-Methyl-9-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone as
Starting material prepares the α of 6 Alpha-Methyl-9-fluoro- 11 beta-hydroxy-4,16- diene-pregnant steroid-3,20- diketone, in the present embodiment starting material
Content be 93%.
By 4.4kg15% phosphorus pentoxide --- methanesulfonic acid is put into clean dry 500L retort, is stirred at room temperature
Uniformly.The α of 6 Alpha-Methyl-9-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone 3.60Kg is put into again.
Under 25 DEG C of room temperature conditions, clock reaction 3h.TLC detection raw materials disappear, and are cooled to room temperature filtering, and concentration filtrate rushes ice near dry
Water 300L, stirring is cooled to room temperature.Get rid of material.Obtain the α of 6 Alpha-Methyl-9-fluoro- 11 beta-hydroxy-4,16- diene-pregnant steroid-3,20- bis-
Ketone 2.88Kg, molar yield 80%, HPLC contents 83%.
Embodiment 36 using the 6 α-fluoro- 9 α-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone as rise
Beginning thing prepares 6 α-fluoro- 9 α-fluoro- 11 beta-hydroxy -4,16- diene-pregnant steroid -3,20- diketone, and starting material contains in the present embodiment
Measure as 93%.
500L carbon tetrachloride is put into clean five oxidations two dried in 1000L retort, then add 4.42kg15%
Phosphorus --- methanesulfonic acid stirs at room temperature.6 α-fluoro- 9 α-fluoro- 11 beta-hydroxyl-17 alphas-the beta-hydroxy of acetenyl-17-4- is put into again
Alkene-androstane -3- ketone 3.64Kg.Under 25 DEG C of room temperature conditions, clock reaction 5h.TLC detection raw materials disappear, and are cooled to room temperature mistake
Filter, concentration filtrate rushes frozen water 300L near dry, and stirring is cooled to room temperature.Get rid of material.6 α-fluoro- 9 α-fluoro- 11 beta-hydroxy -4 are obtained,
16- diene-pregnant steroid -3,20- diketone 3.05Kg, molar yield 84%, HPLC contents 86%.
Embodiment 37 using the 6 β-fluoro- 9 α-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone as rise
Beginning thing prepares 6 β-fluoro- 9 α-fluoro- 11 beta-hydroxy -4,16- diene-pregnant steroid -3,20- diketone, and starting material contains in the present embodiment
Measure as 93%.
700L chloroforms are put into clean five oxidations two dried in 1000L retort, then add 8.84kg15%
Phosphorus --- methanesulfonic acid stirs at room temperature.6 β-fluoro- 9 α-fluoro- 11 beta-hydroxyl-17 alphas-the beta-hydroxy of acetenyl-17-4- is put into again
Alkene-androstane -3- ketone 3.64Kg.Under 25 DEG C of room temperature conditions, clock reaction 4h.TLC detection raw materials disappear, and are cooled to room temperature mistake
Filter, concentration filtrate rushes frozen water 500L near dry, and stirring is cooled to room temperature.Get rid of material.6 β-fluoro- 9 α-fluoro- 11 beta-hydroxy -4 are obtained,
16- diene-pregnant steroid -3,20- diketone 3.2Kg, molar yield 87%, HPLC contents 85%.
Embodiment 38 is using the 9 α-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy of acetenyl-17-4- alkene-androstane-3- ketone as starting material system
Standby 9 α-fluoro- 11 beta-hydroxy -4,16- diene-pregnant steroid -3,20- diketone, the content of starting material is 93% in the present embodiment.
500L dichloromethane is put into clean five oxidations two dried in 1000L retort, then add 10kg5%
Phosphorus --- methanesulfonic acid stirs at room temperature.9 α-fluoro- 11 beta-hydroxyl-17 alphas-the beta-hydroxy of acetenyl-17-4- alkene-hero is put into again
Steroid -3- ketone 3.46Kg.Backflow, clock reaction 2h.TLC detects that raw material disappears, and is cooled to room temperature filtering, and concentration filtrate is done near,
Frozen water 300L is rushed, stirring is cooled to room temperature.Get rid of material.Obtain 9 α-fluoro- 11 beta-hydroxy -4,16- diene-pregnant steroid -3,20- diketone
3.0Kg, molar yield 87%, HPLC contents 86%.
Embodiment 39 is using the 9 α-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy of acetenyl-17-Isosorbide-5-Nitrae-diene-androstane-3- ketone as starting
Thing prepare 9 α-fluoro- 11 beta-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone, in the present embodiment the content of starting material be
93%。
By 500L1,1- dichloroethanes puts into clean five oxygen dried in 1000L retort, then add 6.05kg5%
Change two phosphorus --- methanesulfonic acid stirs at room temperature.9 α-fluoro- 11 beta-hydroxyl-17 alphas-beta-hydroxy-Isosorbide-5-Nitrae-of acetenyl -17 is put into again
Diene-androstane -3- ketone 3.44Kg.Backflow, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room temperature filtering, concentrate filtrate
To near dry, frozen water 300L is rushed, stirring is cooled to room temperature.Get rid of material.Obtain 9 α-fluoro- 11 beta-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,
20- diketone 2.9Kg, molar yield 85%, HPLC contents 85%.
Embodiment 40 is using the 9 α-bromo- 11 beta-hydroxyl-17 alphas-beta-hydroxy of acetenyl-17-Isosorbide-5-Nitrae-diene-androstane-3- ketone as starting
Thing prepare 9 α-bromo- 11 beta-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,20- diketone, in the present embodiment the content of starting material be
93%。
By 500L1,2- dichloroethanes puts into clean five oxygen dried in 1000L retort, then add 6.17kg7%
Change two phosphorus --- methanesulfonic acid stirs at room temperature.9 α-bromo- 11 beta-hydroxyl-17 alphas-beta-hydroxy-Isosorbide-5-Nitrae-of acetenyl -17 is put into again
Diene-androstane -3- ketone 4.04Kg.Backflow, clock reaction 2h.TLC detection raw materials disappear, and are cooled to room temperature filtering, concentrate filtrate
To near dry, frozen water 300L is rushed, stirring is cooled to room temperature.Get rid of material.Obtain 9 α-bromo- 11 beta-hydroxies-Isosorbide-5-Nitrae, 16- triolefins-pregnant steroid -3,
20- diketone 3.6Kg, molar yield 90%, HPLC contents 90%.
Claims (7)
1. a kind of pregnant steroid -16- alkene -3,20- diketone steroid derivative II preparation method, it is characterized in that by 17 α-acetenyl -17
Beta-hydroxy steroid derivative I is with reagent A or the reaction of the organic solvent containing reagent A is obtained, reaction temperature：25 DEG C ~ solvent refluxing
Temperature, the reagent A is dissolved in the solution that methanesulfonic acid is formed for 5% ~ 15% phosphorus pentoxide
。
2. a kind of pregnant steroid -16- alkene -3,20- diketone steroid derivative II preparation method as claimed in claim 1, its feature
The rate of charge for being 17 α-beta-hydroxy steroid derivative I of acetenyl -17 and methanesulfonic acid is 1 for calculation in the molar ratio:4~1:8.
3. a kind of pregnant steroid -16- alkene -3,20- diketone steroid derivative II preparation method as claimed in claim 2, its feature
The rate of charge for being 17 α-beta-hydroxy steroid derivative I of acetenyl -17 and methanesulfonic acid is 1 for calculation in the molar ratio:6.
4. a kind of pregnant steroid -16- alkene -3,20- diketone steroid derivative II preparation method as claimed in claim 1, its feature
It is that the phosphorus pentoxide that the reagent A is 7% is dissolved in the solution of methanesulfonic acid formation.
5. a kind of pregnant steroid -16- alkene -3,20- diketone steroid derivative II preparation method as claimed in claim 1, its feature
It is preferably 50 ~ 60 DEG C of reaction temperature.
6. a kind of pregnant steroid -16- alkene -3,20- diketone steroid derivative II preparation method as claimed in claim 1, its feature
It is that reaction is carried out in aprotic organic solvent.
7. a kind of pregnant steroid -16- alkene -3,20- diketone steroid derivative II preparation method as claimed in claim 6, its feature
It is that described aprotic organic solvent is selected from carbon tetrachloride, chloroform, dichloromethane, 1,1- dichloroethanes, the chloroethenes of 1,2- bis-
One or more in alkane, hexamethylene or n-hexane.
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