CN104292284A - Preparation method of 17-acetenyl-16-alkene steroid derivative - Google Patents
Preparation method of 17-acetenyl-16-alkene steroid derivative Download PDFInfo
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- CN104292284A CN104292284A CN201310298549.9A CN201310298549A CN104292284A CN 104292284 A CN104292284 A CN 104292284A CN 201310298549 A CN201310298549 A CN 201310298549A CN 104292284 A CN104292284 A CN 104292284A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
- C07J71/0015—Oxiranes at position 9(11)
Abstract
The invention relates to a preparation method of a 17-acetenyl-16-alkene steroid derivative (II). The derivative is characterized by being obtained by reacting a 17alpha-acetenyl-17beta-nitroester steroid derivative (I) in an organic solvent containing a monovalent silver salt or a monovalent copper salt and removing 17beta-nitroester. The reaction temperature is between 25 DEG C and a solvent reflowing temperature. The organic solvent is selected from one or more of aprotic organic solvents.
Description
Technical field
The invention belongs to steroidal synthesis technical field, relate to the de-17 β-nitro ester of 17 α-ethynyl-17 β-nitro ester steroid derivative and prepare 17-ethynyl-16-en steroids derivative.
Background technology
16,17-epoxy-DELTA4-pregn-3,20-dione and derivative thereof are the key intermediates of synthesizing steroid compound, for the manufacture of the such as steroid drugs such as dexamethasone, BETAMETHASONE, methylprednisolone, hydrocortisone, prednisone, have higher economic worth.The method that present industrial production 16,17-epoxies-DELTA4-pregn-3,20-dione and derivative thereof are commonly used is for raw material preparation with pregnant steroid-5,16-diene-20-ketone-3-hydroxyl-3-acetic ester (being called for short diene thing).Diene thing is then generated through cracking, oxidation, hydrolysis three step by diosgenin, the first, and this production process needs a large amount of sulfuric acid, easily produces a large amount of pollution to environment; Second, along with improving constantly of Environmental Protection in China consciousness, in recent years, country increases the environmental protection supervision to production of saponin enterprise, eliminate the medium and small production of saponin enterprise of part, saponin supply is becoming tight, and has caused saponin price continuous rise since 2007, to go up to 2012 more than 90 ten thousand yuan per ton by 130,000 yuan per ton at the beginning of 2007.The raising of saponin price brings extreme influence to the cost of cortin manufacturer and production and operation; 3rd, the plantation of diosgenin needs a large amount of land occupation for a long time.Therefore, develop new natural resource, find a kind of raw material of alternative diene thing, 16,17-epoxy-DELTA4-pregn-3,20-dione can be prepared with the method for lower cost and environmental protection more, have great importance concerning steroidal industry.
Last century the seventies, Marsheck, W.J. (Appl.Microbiol.23,72,1972) and Sih is waited, C.J. (J.Am.Chem.Soc.87 is waited, 1387,1965) tankage after soybean extract oil are utilized---plant sterol obtains through biological process fermentation the important intermediate Isosorbide-5-Nitrae-androstane diene-3 that can be used for producing steroid drugs with very high yield, 17-diketone (being called for short ADD) and 4-alkene androstane-3,17-diketone (being called for short 4AD).With produces at present compared with widely used diene thing, 4AD and ADD raw material is based on industrial waste, and more horn of plenty of originating is firm, and more cheaply, pollute very little in production process, be a kind of advantageous raw material to price.Meanwhile, 4AD and the ADD purity prepared with biological fermentation process is high, is conducive to the quality improving steroid drugs finished product.If the method for the synthetic route of can solve and suitability for industrialized production, the production technology level for many steroid drugss will there will be revolutionary change and significantly improve.
Since last century, the seventies obtained 4AD and ADD by fermentable, utilized 4AD and ADD to be the extremely interested problem of external chemist to synthesize the efficient cortin of high value always.Have few quantifier elimination to report again in this respect both at home and abroad, external Nitta, the people such as I have delivered and have utilized 4AD to generate pregnant Gona-4-ene-3 for 1985 on Bull.Chem.Soc.Jpn (1985,58,978), the method for 20-diketone-21-acetic ester.Issei, N. etc. (Bull.Chem.Soc.Jpn.58,981,1985) take ADD as raw material, through seven step reactions, obtain Isosorbide-5-Nitrae-pregnen diethylene-17 α, 21-dihydroxy-3,20-diketone-17 α, 21-diacetate.
Caused domestic and international steroid chemical men to pay close attention to widely although prepare steroidal compounds with 4AD and ADD for starting raw material, but its industrialization is undecided all the time.
The present invention relates to 17 α-ethynyl-17 β-nitro ester steroid derivative (I) utilizing 4AD or ADD is initiator, prepares 17-ethynyl-16-ene derivative (II) by 17 de-17 β-nitro ester.
Compound (I) is for prepared by initiator with 4AD or ADD; can reference Bull.Chem.Soc.Jpn.V58; P981; the method of 1985 can introduce 17 α-ethynyl-17 β-nitro ester at 17; or reference Biol.Pharm.Bull.23 (9) 1059 ~ 1065(2000) method can introduce 6 Alpha-Methyls; or the method for references to U.S. patent US4383947 can introduce 6 α-fluorine or 6 β-fluorine; or reference " Steroids; 71 (11-12), 979-983; 2006 " method 11 introduce Alpha-hydroxies, then with 11 Alpha-hydroxy derivatives for initiator, the method for reference " CN102040639 ", 11 introduce double bonds or generate 9,11 epoxy derivative.
With compound (II) for initiator, reference Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1991), (7), the method of 1709-10 report, just can obtain 16,17-epoxy-3,20-derovatives (III).Compound (III) is 16,17-epoxy-pregnant Gona-4-ene-3,20-diketone or derivatives thereof is the key intermediate of synthesizing steroid compound, can manufacture as steroid drugss such as dexamethasone, BETAMETHASONE, methylprednisolone, hydrocortisone, prednisones by reacting further.
The preparation method of current 17-ethynyl-16-en steroids derivative mainly contains following three kinds:
Method one, 17 α-ethynyl-17 beta-hydroxy steroidal compounds and dewatering agent react prepares 16-alkene-17-ethynyl-steroidal compounds, and dewatering agent can be POCl
3(such as document Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1989), (12), 2810-15.; Steroids; Volume 58; Issue 5; Pages 220-4; 1993; Journal of the American Chemical Society, Volume 73, Pages 5073-6,1951), SOCl
2(such as document Journal fuer Praktische Chemie (Leipzig) (1988), 330 (2), 309-12), formic acid (such as document Journal of the American Chemical Society (1951), 73,5073-6), specifically following formula is seen:
Such as document Steroids; Volume 58; Issue 5; Pages 220-4; 1993, report in the toluene solvant containing 2,4-lutidine, POCl
3with 17 α-ethynyl-17 beta-hydroxy-4-alkene-androstane-3-ketone at 100 DEG C, react and within 3.5 hours, obtain 17-ethynyl-4,16-diene-androstane-3-ketone, yield 61%.
Such as document Journal fuer Praktische Chemie (Leipzig) (1988), 330 (2), 309-12, reports and at room temperature adds 17 α-ethynyl-17 beta-hydroxy-4-alkene-androstane-3-ketone anhydrous tetrahydrofuran solution containing SOCl
2and in the anhydrous tetrahydrofuran solution of N, N'-sulfinyl diimidazole, be then heated to 60 DEG C, react and within 1.5 hours, obtain 17-ethynyl-4,16-diene-androstane-3-ketone, yield 71%.
Such as document Journal of the American Chemical Society, 114,5579-5584; 1992; report 17 α-ethynyl-17 beta-hydroxy-4-alkene-androstane-3-ketone (2.60g; 8.32mmol) under nitrogen protection with anhydrous cupric sulfate (6.64g; 41.6mmol) in liquid paraffin,light, be heated to 160 ~ 180 DEG C; react 1 hour; first final product utilizes pillar layer separation, and then recrystallization obtains 0.69g 17-ethynyl-4,16-diene-androstane-3-ketone.
Inhoffen etc., at document Berichte, report in 1938,71:1024 ~ 1032 and utilize 17-hydroxyl-17-ethynyl-4-alkene-androstane-3-ketone and formic acid to react to prepare 17-ethynyl-4,16-diene-androstane-3-ketone.But there is arguement in experimental result, (the Steroids such as Dvolaitzky etc. (Bull soc chim france 62-71,1963) and Iren Vincze; Volume 58; Issue5; Pages220-4; 1993) by repeating the experiment of Inhoffen, and find that the final product obtained is not 17-ethynyl-4,16-diene-androstane-3-ketone through structural identification research, but obtain D ring-fragrant homosteroid.
Method two, the 17-hydroxyl-17-ethynyl-steroidal compounds dehydration reaction of transition metal (such as ruthenium, cobalt etc.) catalysis.Such as document Organometallics, 2002,21 (1), 203-209; Report 17-hydroxyl-17-ethynyl-steroidal compounds (2a-c) to be first obtained by reacting (4a-c) and (3a-c) with ruthenium complexe (1), (4a-c) and (3a-c) reflux in acetonitrile prepared finally obtains 16-alkene-17-ethynyl-steroidal compounds (7a-c), the finished product, by purification by column chromatography, are specifically shown in following formula:
Method three: the de-nitro ester reaction of 17 transition metal-catalyzed α-ethynyl-17 β-nitryl ester derivant.Document Bulletin of the Chemical Society of Japan, Volume 58, Issue 3, Pages 981-6,1985, report compound 17 α-ethynyl-17 β-nitro ester-1,4-androstane diene-3-ketone, in the mixed solvent of tetrahydrofuran (THF) and water, adds catalyst A gNO
3or CuCl, normal temperature or heated and stirred a few hours obtain compound 16 Alpha-hydroxy-17 α-ethynyl-Isosorbide-5-Nitrae-androstane diene-3-ketone and compound 17-ethynyl-Isosorbide-5-Nitrae, the mixture of 16-androstane triolefin-3-ketone.When with AgNO
3for catalyzer, react 72 hours at 20 DEG C, the yield of 16 Alpha-hydroxy-17 α-ethynyl-Isosorbide-5-Nitrae-androstane diene-3-ketone is 88.9%, 17-ethynyl-Isosorbide-5-Nitrae, and the yield of 16-androstane triolefin-3-ketone is only 6.5%.When taking CuCl as catalyzer, react 4 hours at 65 DEG C, the yield of 16 Alpha-hydroxy-17 α-ethynyl-Isosorbide-5-Nitrae-androstane diene-3-ketone is 63%, 17-ethynyl-Isosorbide-5-Nitrae, and the yield of 16-androstane triolefin-3-ketone is only 32%.When being catalyzer with CuCl, and when adding pyridine, 17-ethynyl-Isosorbide-5-Nitrae, the yield of 16-androstane triolefin-3-ketone brings up to 65.8%.All this reaction has been participated according to document description water and catalyzer.Specifically see following formula:
。
Above-mentioned with 4AD or ADD derivative for initiator prepares the method for 17-ethynyl-16-en steroids derivative, yield is low, impurity is many, not easily refine, some need through chromatography, and some has also used rare metal ruthenium, and cost is high, these methods only rest on laboratory level at present, there are no industrialized report.We pass through repeatedly revision test, find that these methods are because above-mentioned yield is low, impurity is many, high in cost of production problem, are not suitable for suitability for industrialized production.
Summary of the invention
The present invention relates to a kind of preparation method of 17-ethynyl-16-en steroids derivative (II), it is characterized in that: 17 α-ethynyl-17 β-nitro ester steroid derivative (I) is reacted in the organic solvent containing monovalence silver salt or cuprous salt, slough 17 β-nitro ester to obtain, temperature of reaction: 25 DEG C ~ solvent reflux temperature; Organic solvent be selected from aprotic organic solvent one or more.
。
A kind of preparation method of 17-ethynyl-16-en steroids derivative (II), it is characterized in that 17 described α-ethynyl-17 β-nitro ester steroid derivative (I) is 17 α-ethynyl-17 β-nitro ester-4,9(11)-diene-androstane-3-ketone, 9 β, 11 beta epoxide-17 α-ethynyl-17 β-nitro ester-4-alkene-androstane-3-ketone, 9 β, 11 beta epoxide-17 α-ethynyl-17 β-nitro ester-1,4-diene-androstane-3-ketone or 17 α-ethynyl-17 β-nitro ester-1,4,9(11)-triolefin-androstane-3-ketone.
A kind of preparation method of 17-ethynyl-16-en steroids derivative (II), is characterized in that described monovalence silver salt or cuprous salt are selected from AgNO
3, AgCl, AgF, AgBr, AgI, Ag
2cO
3, CF
3cO
2ag, CF
3sO
3ag, CuBr, CuCl or CuI, preferred AgNO
3.
A kind of preparation method of 17-ethynyl-16-en steroids derivative (II), it is characterized in that the feed ratio of described monovalence silver salt or cuprous salt and 17 α-ethynyl-17 β-nitro ester steroid derivative (I) calculates as 1:50 to 1:1 in molar ratio, preferred 3:7.
A kind of preparation method of 17-ethynyl-16-en steroids derivative (II), is characterized in that described temperature of reaction preferably 60 ~ 70 DEG C.
A kind of preparation method of 17-ethynyl-16-en steroids derivative (II), it is characterized in that described organic solvent is selected from dimethyl sulfoxide (DMSO), N, dinethylformamide, acetonitrile, ethyl acetate and tetrahydrofuran (THF), Isosorbide-5-Nitrae-ether solvent such as dioxane, methyl tertiary butyl ether, preferred tetrahydrofuran (THF).
A kind of preparation method of 17-ethynyl-16-en steroids derivative (II), the feed ratio that it is characterized in that described 17 α-ethynyl-17 β-nitro ester steroid derivative (I) and solvents tetrahydrofurane by weight volume ratio is calculated as 1:10 to 1:3, preferred 1:5.
Consider the yield of product, content, reaction times, cost and to problems such as the aftertreatments of metal-salt, our preferred 1:50 to 1:1 of the mol ratio of monovalence silver salt or cuprous salt and initiator, more preferably 3:7 doubly.There is monovalence silver salt or the cuprous salt of katalysis, preferred Silver Nitrate.The preferred tetrahydrofuran (THF) of reaction solvent.In technical solution of the present invention, monovalence silver salt or cuprous salt, by environmental protection treatment, reclaim.
The present invention and document Bulletin of the Chemical Society of Japan, Volume 58, Issue 3, Pages 981-6, maximum not being both of the de-nitro ester reaction of transition metal-catalyzed 17 α-ethynyl-17 β-nitryl ester derivant of 1985 reports, do not use water to make solvent in the present invention, document uses the mixed solvent of THF and water, and wherein water take part in reaction process.In addition, the yield preparing 17-ethynyl-16-en steroids derivative according to the method for this bibliographical information is lower, especially when taking Silver Nitrate as catalyzer.
17 α-ethynyl-17 β-nitro ester steroid derivative (I) that the present invention relates to a kind of 4AD of utilization or ADD prepares the method for 17-ethynyl-16-en steroids derivative (II) by 17 de-17 β-nitro ester.Sharpest edges of the present invention obtain high purity 17-ethynyl-16-en steroids derivative (II) with high productive rate, and achieve industrialization.Highly purified 17-ethynyl-16-en steroids derivative (II) obtained, can obtain steroidal important intermediate 16,17-epoxy-pregnant Gona-4-ene-3 by literature method, 20-diketone and derivative or 16 thereof, 17-epoxy-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone and derivative thereof.Present invention achieves with 4AD or ADD for initiator prepares steroidal compounds, be a great technological change for steroidal industry.Utilize the technology of the present invention that Androstenedione can be utilized to substitute diosgenin for starting material, realize a series of product cost and decline to a great extent, be also more conducive to environment protection.
Specific embodiment
Below will the invention will be further described by embodiment, these descriptions are not be further limited content of the present invention.Person skilled should be understood that the equivalent replacement done technical characteristic of the present invention, or improves accordingly, still belongs within protection scope of the present invention.
In the following embodiments: THF is tetrahydrofuran (THF), DMSO is dimethyl sulfoxide (DMSO), and DMF is DMF, and dioxane is Isosorbide-5-Nitrae-dioxane, and DMI is 1.3-dimethyl 2-imidazolidone.
ayield: refer to product molar yield;
bcontent: refer to product HPLC content; C, this reaction adopts the retort of 1000L.
Embodiment 1 is with 6 Alpha-Methyl-17 α-ethynyl-17 β-nitro ester-4,9(11)-diene-androstane-3-ketone is that initiator prepares 6 Alpha-Methyl-17-ethynyls-4,9(11), 16-triolefin-androstane-3-ketone
Initiator 6 Alpha-Methyl-17 α-ethynyl-17 β-nitro ester-4,9(11 in the present embodiment) content of-diene-androstane-3-ketone is 95%.
Embodiment 1-1
By 259LTHF, 0.25Kg AgNO
3put in clean dry 500L retort, stirred at ambient temperature is even.Drop into 6 Alpha-Methyl-17 α-ethynyl-17 β-nitro ester-4,9(11 again)-diene-androstane-3-ketone 51.7Kg.Be steam heated to reaction solution backflow, clock reaction 48h.TLC detects raw material and disappears, and is cooled to room temperature and filters, and concentrated filtrate is near dry, and bath 150L, stirs and be cooled to room temperature.Get rid of material.Obtain 6 Alpha-Methyl-17-ethynyls-4,9(11), 16-triolefin-androstane-3-ketone 36.4Kg, molar yield 85%.HPLC content 80%.
Embodiment 1-2 ~ embodiment 1-39
Operating process is with reference to embodiment 1-1, and the charging capacity of initiator is 51.7Kg.When selecting monovalence silver salt (except AgNO
3time outward), react and detect raw material disappearance to TLC, be cooled to room temperature and filter, concentrated filtrate, near dry, rushes 10% ammoniacal liquor 200L.When selecting cuprous salt, reaction is carried out under a nitrogen atmosphere, and react and detect raw material disappearance to TLC, be cooled to room temperature and filter, concentrated filtrate, near dry, rushes 10% ammoniacal liquor 200L.
Embodiment 2 with 6 Alpha-Methyl-17 α-ethynyl-17 β-nitro ester-Isosorbide-5-Nitrae, 9(11)-triolefin-androstane-3-ketone is that initiator prepares 6 Alpha-Methyl-17-ethynyl-Isosorbide-5-Nitraes, 9(11), 16-tetraene-androstane-3-ketone
Embodiment 2-1 ~ embodiment 2-39
Operating process is with reference to embodiment 1, and the charging capacity of initiator is 51.4Kg, and content is 93%.
Embodiment 3 is with 17 α-ethynyl-17 β-nitro ester-4,9(11)-diene-androstane-3-ketone is that initiator prepares 17-ethynyl-4,9(11), 16-triolefin-androstane-3-ketone
Embodiment 3-1 ~ embodiment 3-39
Operating process is with reference to embodiment 1, and the charging capacity of initiator is 49.7Kg, and content is 94%.
Embodiment 4 with 17 α-ethynyl-17 β-nitro ester-Isosorbide-5-Nitrae, 9(11)-triolefin-androstane-3-ketone is that initiator prepares 17-ethynyl-Isosorbide-5-Nitrae, 9(11), 16-tetraene-androstane-3-ketone
Embodiment 4-1 ~ embodiment 4-39
Operating process is with reference to embodiment 1, and the charging capacity of initiator is 49.4Kg, and content is 95%.
Embodiment 5 with 6 α-fluoro-17 α-ethynyl-17 β-nitro ester-Isosorbide-5-Nitrae, 9(11)-triolefin-androstane-3-ketone is that initiator prepares 6 α-fluoro-17-ethynyl-Isosorbide-5-Nitrae, 9(11), 16-tetraene-androstane-3-ketone
Embodiment 5-1 ~ embodiment 5-39
Operating process is with reference to embodiment 1, and the charging capacity of initiator is 52Kg, and content is 93%.
Embodiment 6 is with 6 α-fluoro-17 α-ethynyl-17 β-nitro ester-4,9(11)-diene-androstane-3-ketone is that initiator prepares 6 α-fluoro-17-ethynyl-4,9(11), 16-triolefin-androstane-3-ketone
Embodiment 6-1 ~ embodiment 6-39
Operating process is with reference to embodiment 1, and the charging capacity of initiator is 52.2Kg, and content is 95%.
Embodiment 7 is with 6 β-fluoro-17 α-ethynyl-17 β-nitro ester-4,9(11)-diene-androstane-3-ketone is that initiator prepares 6 β-fluoro-17-ethynyl-4,9(11), 16-triolefin-androstane-3-ketone
Embodiment 7-1 ~ embodiment 7-39
Operating process is with reference to embodiment 1, and the charging capacity of initiator is 52.2Kg, and content is 95%.
Embodiment 8 with 6 β-fluoro-17 α-ethynyl-17 β-nitro ester-Isosorbide-5-Nitrae, 9(11)-triolefin-androstane-3-ketone is that initiator prepares 6 β-fluoro-17-ethynyl-Isosorbide-5-Nitrae, 9(11), 16-tetraene-androstane-3-ketone
Embodiment 8-1 ~ embodiment 8-39
Operating process is with reference to embodiment 1, and the charging capacity of initiator is 52Kg, and content is 93%.
Embodiment 9 is with 9 β, and 11 beta epoxide-17 α-ethynyl-17 β-nitro ester-4-alkene-androstane-3-ketone is that initiator prepares 9 β, 11 beta epoxide-17-ethynyl-4,16-diene-androstane-3-ketone
Embodiment 9-1 ~ embodiment 9-39
Operating process is with reference to embodiment 1, and the charging capacity of initiator is 52Kg, and content is 93%.
Embodiment 10 is with 9 β, and 11 beta epoxide-17 α-ethynyl-17 β-nitro ester-Isosorbide-5-Nitrae-diene-androstane-3-ketone is that initiator prepares 9 β, 11 beta epoxide-17-ethynyl-Isosorbide-5-Nitraes, 16-triolefin-androstane-3-ketone
Embodiment 10-1 ~ embodiment 10-39
Operating process is with reference to embodiment 1, and the charging capacity of initiator is 51.6Kg, and content is 93%.
Embodiment 11 is with 9 β, and 11 beta epoxide-6 Alpha-Methyl-17 α-ethynyl-17 β-nitro ester-4-alkene-androstane-3-ketone are that initiator prepares 9 β, 11 beta epoxide-6 Alpha-Methyl-17-ethynyl-4,16-diene-androstane-3-ketone
Embodiment 11-1 ~ embodiment 11-39
Operating process is with reference to embodiment 1, and the charging capacity of initiator is 53.9Kg, and content is 94%.
Embodiment 12 is with 9 β, and 11 beta epoxide-6 Alpha-Methyl-17 α-ethynyl-17 β-nitro ester-Isosorbide-5-Nitrae-diene-androstane-3-ketone is that initiator prepares 9 β, 11 beta epoxide-6 Alpha-Methyl-17-ethynyl-Isosorbide-5-Nitraes, 16-triolefin-androstane-3-ketone
Embodiment 12-1 ~ embodiment 12-39
Operating process is with reference to embodiment 1, and the charging capacity of initiator is 53.6Kg, and content is 94%.
Embodiment 13 is with 9 β, and 11 beta epoxide-6 α-fluoro-17 α-ethynyl-17 β-nitro ester-4-alkene-androstane-3-ketone is that initiator prepares 9 β, 11 beta epoxide-6 α-fluoro-17-ethynyl-4,16-diene-androstane-3-ketone
Embodiment 13-1 ~ embodiment 13-39
Operating process is with reference to embodiment 1, and the charging capacity of initiator is 54.5Kg, and content is 93%.
Embodiment 14 is with 9 β, and 11 beta epoxide-6 α-fluoro-17 α-ethynyl-17 β-nitro ester-Isosorbide-5-Nitrae-diene-androstane-3-ketone is that initiator prepares 9 β, 11 beta epoxide-6 α-fluoro-17-ethynyl-Isosorbide-5-Nitrae, 16-triolefin-androstane-3-ketone
Embodiment 14-1 ~ embodiment 14-39
Operating process is with reference to embodiment 1, and the charging capacity of initiator is 54.2Kg, and content is 93%.
Embodiment 15 is with 9 β, and 11 beta epoxide-6 β-fluoro-17 α-ethynyl-17 β-nitro ester-Isosorbide-5-Nitrae-diene-androstane-3-ketone is that initiator prepares 9 β, 11 beta epoxide-6 β-fluoro-17-ethynyl-Isosorbide-5-Nitrae, 16-triolefin-androstane-3-ketone
Embodiment 15-1 ~ embodiment 15-39
Operating process is with reference to embodiment 1, and the charging capacity of initiator is 54.2Kg, and content is 93%.
Embodiment 16 is with 9 β, and 11 beta epoxide-6 β-fluoro-17 α-ethynyl-17 β-nitro ester-4-alkene-androstane-3-ketone is that initiator prepares 9 β, 11 beta epoxide-6 β-fluoro-17-ethynyl-4,16-diene-androstane-3-ketone
Embodiment 16-1 ~ embodiment 16-39
Operating process is with reference to embodiment 1, and the charging capacity of initiator is 54.5Kg, and content is 93%.
Claims (10)
1. the preparation method of 17-ethynyl-16-en steroids derivative (II), 17 α-ethynyl-17 β-nitro ester steroid derivative (I) is it is characterized in that to react in the organic solvent containing monovalence silver salt or cuprous salt, slough 17 β-nitro ester to obtain, temperature of reaction: 25 DEG C ~ solvent reflux temperature; Organic solvent be selected from aprotic organic solvent one or more
。
2. the preparation method of a kind of 17-ethynyl-16-en steroids derivative (II) as claimed in claim 1, it is characterized in that 17 described α-ethynyl-17 β-nitro ester steroid derivative (I) is 17 α-ethynyl-17 β-nitro ester-4,9(11)-diene-androstane-3-ketone, 17 α-ethynyl-17 β-nitro ester-1,4,9(11)-triolefin-androstane-3-ketone, 9 β, 11 beta epoxide-17 α-ethynyl-17 β-nitro ester-4-alkene-androstane-3-ketone or 9 β, 11 beta epoxide-17 α-ethynyl-17 β-nitro ester-Isosorbide-5-Nitrae-diene-androstane-3-ketone.
3. the preparation method of a kind of 17-ethynyl-16-en steroids derivative (II) as claimed in claim 1, is characterized in that described monovalence silver salt or cuprous salt are selected from AgNO
3, AgCl, AgF, AgBr, AgI, Ag
2cO
3, CF
3cO
2ag, CF
3sO
3ag, CuBr, CuCl or CuI.
4. the preparation method of a kind of 17-ethynyl-16-en steroids derivative (II) as claimed in claim 3, is characterized in that described monovalence silver salt is AgNO
3.
5. the preparation method of a kind of 17-ethynyl-16-en steroids derivative (II) as described in claim 1 ~ 4, is characterized in that the feed ratio of described monovalence silver salt or cuprous salt and 17 α-ethynyl-17 β-nitro ester steroid derivative (I) calculates in molar ratio as 1:50 to 1:1.
6. the preparation method of a kind of 17-ethynyl-16-en steroids derivative (II) as claimed in claim 5, is characterized in that the feed ratio of described monovalence silver salt or cuprous salt and 17 α-ethynyl-17 β-nitro ester steroid derivative (I) calculates in molar ratio as 3:7.
7. as claim 1,2,3,4,6 arbitrary as described in a kind of preparation method of 17-ethynyl-16-en steroids derivative (II), it is characterized in that described temperature of reaction is 60 ~ 70 DEG C.
8. as claim 1,2,3,4,6 arbitrary as described in a kind of preparation method of 17-ethynyl-16-en steroids derivative (II), it is characterized in that described organic solvent is selected from dimethyl sulfoxide (DMSO), N, dinethylformamide, ethyl acetate, acetonitrile and tetrahydrofuran (THF), Isosorbide-5-Nitrae-ether solvent such as dioxane, methyl tertiary butyl ether.
9. the preparation method of a kind of 17-ethynyl-16-en steroids derivative (II) as claimed in claim 8, is characterized in that described organic solvent is tetrahydrofuran (THF).
10. the preparation method of a kind of 17-ethynyl-16-en steroids derivative (II) as claimed in claim 9, the feed ratio that it is characterized in that described 17 α-ethynyl-17 β-nitro ester steroid derivative (I) and solvents tetrahydrofurane by weight volume ratio is calculated as 1:10 to 1:3.
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