CN103450305B - A kind of synthetic method being prepared steroidal compounds by 3,17-diones steroidal - Google Patents

A kind of synthetic method being prepared steroidal compounds by 3,17-diones steroidal Download PDF

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CN103450305B
CN103450305B CN201310386610.5A CN201310386610A CN103450305B CN 103450305 B CN103450305 B CN 103450305B CN 201310386610 A CN201310386610 A CN 201310386610A CN 103450305 B CN103450305 B CN 103450305B
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章亚东
冯书晓
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Zhengzhou University
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Abstract

The invention discloses the synthetic method of steroidal drug and intermediate, particularly relate to a kind of synthetic method being prepared 17-hydroxyl-20-ketone steroidal compounds by 3,17-diones steroidal, belong to pharmaceutical synthesis field.The method is with 3; 17-diones steroidal is raw material; adopt routine, environmental protection, low toxicity reagent; through C3 or (with) selective protection of C11-ketone group; the Wittig reaction of C17 position; selective oxidation 17(20) double bond; after halo displacement; easy high yield prepares steroid drugs cortisone or hydrocortisone or prednisone or Prednisolone Acetate or intermediate 17 alpha-hydroxy-2 0-ketone compounds; aftertreatment is simple, and the three wastes are less, good reaction selectivity; yield is higher, and by-product antiearly pregnancy steroid class medicine and steroid.Raw material is easy to get, and cost is lower, and synthesis technique is simple; Be applicable to suitability for industrialized production.

Description

A kind of synthetic method being prepared steroidal compounds by 3,17-diones steroidal
Technical field
The present invention relates to the synthetic method of steroidal drug and intermediate, particularly relate to a kind of synthetic method being prepared 17-hydroxyl-20-ketone steroidal compounds by 3,17-diones steroidal, belong to pharmaceutical synthesis field.
Background technology
Product after the microbial transformation of animals and plants sterol: Androstenedione (AD) or Isosorbide-5-Nitrae-Androstenedione (ADD) are the important intermediate of steroid drugs such as synthesis cortisone, prednisone etc.17-steroidal ketone raw material basis is introduced the cortin side chain containing two carbon atoms, and the constructional feature forming 17 alpha-hydroxy-2 0-ketone utilizes sterol as the key point of synthesis corticosteroid drug raw material.
At present, the method via 3,17-diones steroidal Material synthesis 17 alpha-hydroxy-2 0-ketone compounds has following several method:
One, ethynylation method
Nitta(BulletinoftheChemicalSocietyofJapan, 1985,58 (03): 981-986.) by after the ethynylation of rostadienedione (ADD) selectivity, use AgNO 317 β-nitric ether that-THF processes acetylide makes configuration inversion, and obtain 17 Alpha-hydroxy steroidals, 17 Alpha-hydroxies become ester with acetic acid, C21 bromination, displacement, obtain the C17 Protosol acetic ester (38%) of moderate yield.If by 17 Alpha-hydroxy acetic ester acetylide and I 2and peracetic acid treatment, obtain C21 iodo thing, also can obtain C17 Protosol acetic ester (total recovery about 60%) with the process of tetramethylammonium acetate.Androstenedione (AD) also can be passed through above-mentioned steps and obtains C17 Protosol acetic ester (total recovery is about 37-42%) (LiebigsAnnalenderChemie, 1987, (5): 423-426).
Kataoka(ChemistryLetters, 1990,19 (9): 1705-1708.) be raw material with AD, the ethinylation of 17-ketone group, then uses (i-Pr 2cO) 2its acidylate is obtained ester, at DME-H by 0 2under O (glycol dimethyl ether-water) and oxygen (1atm) condition, with K 2pdBr 4for catalyzer can change into corresponding aldehyde its alkynyloxy, this reaction is as with PdBr 2for catalyzer, yield only has 85%.△ is rearranged under DBU (l, 5-diaza-bicyclo), EtOAc effect 16(17)-20-ketone-21-ester products.It can be used to the intermediate synthesizing 16-replacement glucocorticosteroid.
It is higher that the method the first step introduces ethynyl productive rate, but need after introducing alkynyl to make 17 beta-hydroxy reversions, and acetylene conversion is that aldehyde needs catalyzer, be reduced into alcohol and then become acetic ester, step is more, needs to use noble metal catalyst in some situations, and condition is harsh, total recovery is lower.
Two, different cyanide process
Stoelwinder(TheJournalofOrganicChemistry, 1993, 58 (14): 3687-3691.) by after the 3-keto-enol ether of Androstenedione (AD), after cyanogen methyl-phosphorous acid diethyl ester (DiethylCyanomethylphosphonate) in the basic conditions condensation, isocyanide is eliminated to obtain by phosphorus oxychloride, gaseous formaldehyde (excessive in a large number) and nitrogen are passed into its solution by a certain percentage, C21 is introduced through Witting-Horner-Emmous reaction, because this compound contains the group to acid-sensitive, by it, first in hydrochloric acid, slough blocking group becomes △ 4-3-ketone, and then generate isocyanic ester with lead tetra-acetate oxidation, finally by aluminium sesquioxide process, can △ be obtained 16-20-ketone product.It is also used to the important intermediate of synthesizing 16-replacement glucocorticosteroid.The shortcoming of this reaction is that the reagent used is rare, and total recovery is lower, and route is longer, needs gas-liquid two-phase to react, and aftertreatment is complicated.
Three, cyanohydrination method
The reaction introducing cyano group in 17-ketone group steroidal be have regioselectivity and direction narrow spectrum.Nitta(BulletinoftheChemicalSocietyofJapan; 1985; 58 (03): 978-980.) utilize Androstenedione (AD) in methyl alcohol and potassium cyanide reaction; obtain the less beta-cyano isomer of solubleness (productive rate 95%), 3-ketone group and 17 Alpha-hydroxies are protected the LiCH of rear equivalent 3after process, be hydrolyzed to obtain 17 Alpha-hydroxy Progesterone, through I 2, CaO and KOAc iodo displacement after obtain 17 alpha-hydroxy-2 0-ketone-21-acetic ester (compound S acetic ester).
Reid(TetrahedronLetters, 1990,31 (26): 3669-3672.) first by △ 9 (11)the 3-ketone group of AD is protected formation etherate; react with potassium cyanide in acetic acid and generate C17 cyano group β and a isomer mixture simultaneously; by its optionally recrystallization can obtain the β body of 95%; then formation etherate is protected to 17 Alpha-hydroxies; corresponding aldehyde is become after cyano reduction; again it is used the lithium methide addition replaced, introduce 21 carbon, C20 secondary alcohol can be oxidized further and generate 20-ketone.Its a-cyano group isomer also generates same product by another approach.First 17 Alpha-hydroxy protections are formed to the trimethylsilyl ethers of transposition; after generating aldehyde after reduction cyano group; react in tetrahydrofuran (THF) with methylene bromide, LDA (N-Lithiodiisopropylamide); in hydrochloric acid, quenching can obtain the bromo-20-ketone of 21-subsequently; its acidylate is obtained acetic acid vinegar, after hydrolysis deprotection, C17 otan acetic ester side chain can be obtained.
Livingston(JournaloftheAmericanChemicalSociety; 1990,112 (17): 6449-6450.) by after Androstenedione (AD) cyanohydrination, formation etherate is protected to its 17 Alpha-hydroxy; under highly basic effect, due to its-CH 2the volatile deprotonation of Cl group, can spontaneous Cheng Huan.It is under superacid effect, and its imines hydrolysis generation 17 alpha-hydroxy-2 0-ketone-21-chloro thing, reduction or esterification can obtain product 17 alpha-hydroxy-2 0-ketone side chain and C17 otan acetic ester side chain respectively.Wherein 17 Alpha-hydroxy Cheng Huanyi steps also can first be reduced in biphenyl lithium, tetrahydrofuran (THF), and then quenching also can obtain 17 alpha-hydroxy-2 0-ketone side chains in acid condition, but 3-ketone group need be protected.
The method adopts 4 step reactions.Shortcoming needs to use the poisonous reagents such as prussiate, and organolithium reagent, severe reaction conditions, is not suitable for industrialized production.
Four, Wittig (Wittig) reaction method
Document (Chinese Journal of New Drugs; 2010 (3): 233-235) report from Androstenedione (the AD); by etherification protection 3-ketone group; there is Wittig with the triphenylphosphine ylide (Witting reagent) of particular functional group to react; generate C21-acetic ester-C17; C20 olefinic side chains, KMnO 4oxidation generates C17, C20-glycol, PySO 3oxidation C20 secondary alcohol becomes ketone, obtains the pregnant steroid of hydrocortisone intermediate-4-alkene-17 α, 21-glycol-3,20-diketone-21-acetic ester.The method adopts 4 step synthesis, and reaction conditions is gentle, but needs to use Te Shu Phosphonium ylide reagent (Ph 3p +-CH 2cH 2oAcBr -) and toxic oxygen agent pyridine. sulfur trioxide, these reagent are expensive, and character is unstable, is difficult to obtain, and does not meet Green Chemistry requirement.
, all there is the use of special reagent, some costlinesses, some severe toxicity in above 4 kinds of methods, some character is unstable, is difficult to obtain, and does not meet green chemical concept, is restricted on technical scale is produced.It is longer also to there is reaction scheme in wherein ethynylation method and different cyanide process, the shortcoming that total recovery is lower.It is shorter that Wittig (Wittig) reaction method has route, and yield is high, and the advantage that stereoselectivity is high is worthy of promotion and application, but still existing defects.
Summary of the invention
Technical problem to be solved by this invention is the defect overcoming the existence of above-mentioned prior art, provides a kind of raw material to be easy to get, and synthesis technique is simple, the method for the synthesis 17 alpha-hydroxy-2 0-ketone steroidal compounds that yield is higher.
For realizing object of the present invention, the present invention adopts following technical scheme: by 3, 17-diones steroidal raw material, comprise animals and plants sterol microbial transformation product Androstenedione (AD) or 1, 4-AD (ADD), or the hydroxyl of the C11 position of the two or ketone compound, adopt conventional, environmental protection, low toxicity reagent, through C3 or (with) selective protection of C11-ketone group, the Wittig reaction of C17 position, selective oxidation 17(20) double bond, after halo displacement, easy high yield prepares steroid drugs cortisone, or hydrocortisone, or prednisone, or Prednisolone Acetate, or intermediate 17 alpha-hydroxy-2 0-ketone.
Synthetic route of the present invention is as follows:
X=H-,HO-,O=；
Specifically comprise the steps:
Step one, 3, the 17-diones steroidals following with structure or the hydroxyl of the C11 position of the two or ketone compound, for raw material, add catalyzer, and protection reagent, through the selective protection of C3 and C11-ketone group, obtains formula 1 or formula 2 compound:
Androstenedione (AD) Isosorbide-5-Nitrae-Androstenedione (ADD),
Formula 1 formula 2
The catalyzer choosing used: anhydrous tosic acid or its monohydrate or itself and triethyl orthoformate, trimethyl orthoformate composition;
Step 2, formula 1 or formula 2 compound and Yi base triphenyl phosphonium halide salt react through Wittig, aftertreatment acid adding deprotection, and a step obtains formula 3 compound:
formula 3
Described second base triphenyl phosphonium halide salt is: ethyl triphenyl phosphonium chloride or second base three phenyl phosphonium bromide or ethyl triphenyl phosphonium iodide; Preferred second base three phenyl phosphonium bromide;
The alkali that Wittig reacts used is: sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, sodium hydrogen one of them; Preferred potassium tert.-butoxide or sodium hydrogen;
Step 3, formula 3 compound is dissolved in solvent, and under oxygenant and/or catalyzer exist, its 17 double bond of selective oxidation, obtains formula 4 compound:
formula 4
Described solvent is: ethyl acetate acetonitrile aqueous systems or chloroform aqueous systems, methylene dichloride aqueous systems, ethylene dichloride aqueous systems;
Described oxygenant is: Potassium Monopersulfate, monopersulfate sodium, Oxone(potassium peroxymonosulfate);
Described catalyzer is: RuCl 3n (H 2o), n=0-3, RuO 4; Preferred RuCl 3; Or phase-transfer catalyst n-Bu 4nBr or n-Bu 4nHSO 4;
Step 4, adds iodine or bromine or ICl or BrCl, to its C21 position halogen substiuted, after displacement, obtains following structural formula target compound in formula 4 compound:
Be preferably as follows condition: in step (1), temperature of reaction is 40-120 DEG C; Raw material is 1:2-20 with protection reagent mol ratio.
Step (2) Chinese style 1 or formula 2 compound and Yi base triphenyl phosphonium halide salt mol ratio are: 1:1-5.
The mol ratio of step (3) Chinese style 3 compound and oxygenant is: 1:5-15.
Beneficial effect of the present invention is:
(1) this synthetic method step 2 selects Yi base triphenyl phosphonium halide salt as Wittig reagent, reacted harmful by-products triphenylphosphine oxide, through reduction, generate triphenylphosphine, triphenylphosphine and halogen ethane react and generate Yi base triphenyl phosphonium halide salt, recycle, energy-saving and emission-reducing.
(2) step 3 selective oxidation reaction adopts Ru catalyzer to substitute OsO 4technique, avoids OsO 4severe toxicity, the shortcoming such as volatile; And Ru catalyzer can be recycled more than 5 times after reclaiming, and reduces cost, is convenient to suitability for industrialized production.
(3) by product 17, the 20-dihydroxy steroid of step 3 selective oxidation reaction and 17,20-epoxy steroid compounds are very important anti-early pregnancy drug and intermediate.Another by product 17-ketosteroid compound is the starting raw material of step one, recycles, improves the utilising efficiency of raw material.And the proportion of composing of primary product can be controlled by the amount adjusting oxygenant.
(4) displacement of step 4 halo adopts ICl to substitute conventional iodine foundry skill, improves the utilising efficiency of atomic iodine, economical and efficient; Bromine and BrCl adopt without iodine technique, greatly reduce enterprise's production cost;
(5) three wastes are less, good reaction selectivity, and by product is few, and yield is higher; Raw material is easy to get, and cost is lower, and synthesis technique is simple; Be applicable to suitability for industrialized production.
Detail of the present invention describes in detail in embodiment below, but embodiment should not be construed as restriction protection scope of the present invention.
Embodiment
In order to the present invention will be described better, enumerate embodiment as follows:
Embodiment 1
(1) step one: after being mixed with 2-20 part ethylene glycol by 1 part of 4-AD (Androstenedione, 4AD), adds 0.01-10% part tosic acid monohydrate (TsOHH 2o) catalysts and solvents toluene 50mL, stirs, at oil bath medium 50-120 DEG C of temperature, and reacting by heating 2-10h, stopped reaction, cooling; In impouring 1:20-50 part water, filter, washing solid.Purifying recrystallizing methanol.Productive rate 85%.TLC detection reaction (PE:EtOAc=3:1, the smoked colour developing of iodine, Rf=0.72).
C 23h 34o 4, white powdery solids.mp.160-162℃
=0.80（petroleumether(30–60)/EtOAc=3/2）。
1HNMR(400MHz,CDCl 3)δ5.36(s,1H,H-6),3.93（m,8H,2×OCH 2CH 2O）,2.57(d,1H,J H-H=14Hz,H-9),2.14-1.10(m,18H,skeletonprotons),1.04(s,3H,H-19),0.87(s,3H,H-18).
13CNMR(101MHz,CDCl 3)δ140.14,121.93,119.51,109.44,65.16,64.57,64.46,64.22,50.53,49.50,45.77,41.81,36.75,36.31,34.25,32.27,31.16,31.07,30.61,22.84,20.46,18.89,14.21.
ESI-MS,m/z:397.3[M+Na] +，771.5[2M+Na] +。
By above-mentioned solid, add in the aqueous acetone solution of 10:1 mixing, dilute hydrochloric acid adjust pH 1-6, stopped reaction after stirring 1-10h, in impouring 1:20-50 part water, filter, washing solid.Purifying acetone recrystallization.Productive rate 55%.Point plate detection reaction (PE:EtOAc=3:1, the smoked colour developing of iodine, Rf=0.64).
C 21h 30o 3, white powdery solids.mp.194-196℃
=0.72（petroleumether(30–60)/EtOAc=3/2）。
1HNMR(400MHz,CDCl 3)δ5.39(s,1H,H-6),4.04–3.85(m,4H,OCH 2CH 2O),2.59(d,1H,J=14.1Hz,H-9),2.46(dd,J=19.2,8.8Hz,1H,H-8),2.23-1.08(m,17H,skeletonprotons),1.06(s,3H,H-19),0.89(s,3H,H-18).
13CNMR(101MHz,CDCl 3)δ221.11,140.42,121.41,109.30,64.45,64.25,51.75,49.83,47.55,41.81,36.77,36.26,35.84,31.52,31.44,31.00,30.66,21.89,20.34,18.91,13.56.
ESI-MS,m/z:353.3[M+Na] +，683.5[2M+Na] +。
(2) step 2: take 1-10 part second base three phenyl phosphonium bromide, under nitrogen protection, add 10-50 part THF solvent, stirring and dissolving; Take 2-20 part potassium tert.-butoxide, add in above-mentioned solution in batches, stir 0.5-2h, solution colour is orange; Take above-mentioned steps one product 3-ketal to be dissolved in 10-50 part THF, slowly join in above-mentioned solution, and reflux 1-10h, react complete, be cooled to room temperature, add in 50-200 part frozen water, filter, solid adds dehydrated alcohol recrystallization and obtains white solid, drying, weighs, productive rate about 95%.
C 23h 34o 2, yellow needles solid.
=0.70（petroleumether(30–60)/EtOAc=3/2）。
1HNMR(400MHz,CDCl 3)δ5.41-5.36（m,1H,H-6）,5.16(dt,1H,J=7.1,2.0Hz,H-20),4.03-3.92(m,4H,OCH 2CH 2O),2.60(dd,1H,J=14.2,2.7Hz,H-9),2.39-1.08(m,18H,skeletonprotons),1.68(dt,3H,J=7.1,1.9Hz,H-21),1.06(s,3H,H-19),0.92(s,3H,H-18).
13CNMR(101MHz,CDCl 3)δ150.26,140.17,122.08,113.46,109.46,77.25,64.44,64.22,56.46,49.69,44.06,41.79,36.97,36.69,36.28,31.57,31.43,31.07,24.48,21.20,18.84,16.62,13.14.
(3) step 3: take 1 part of above-mentioned steps two product (17Z)-pregnant steroid-4,17 (20)-diene-3-ketal, be dissolved in 10-50 part THF, under stirring, slowly add 0.5-50% part protonic acid (hydrochloric acid or sulfuric acid), stir 0.1-2h, add in 50-200 part frozen water, filter, clear yellow viscous thing acetonitrile/water recrystallization, obtains yellow solid, dry, weigh, productive rate about 100%.
C 21h 30o, white needles.mp.104-106℃
=0.65（petroleumether(30–60)/EtOAc=3/2）。
1HNMR(400MHz,CDCl 3)δ5.73(s,1H,H-4),5.15-5.05(m,1H,H-20),2.44-0.92(m,19H,skeletonprotons),1.65(d,3H,J=7.1Hz,H-21),1.21(s,3H,H-19),0.92(s,3H,H-18).
13CNMR(101MHz,CDCl 3)δ199.40,171.26,149.51,123.83(d,J=5.0Hz),113.68,55.58,53.75,44.00,38.57,36.78,35.69(d,J=7.1Hz),35.06,33.94,32.82,31.83,31.26,24.33,21.13,17.36(d,J=7.1Hz),16.73,13.11.
ESI-MS,m/z:299.3[M+H] +，321.3[M+Na] +，619.5[2M+Na] +。
By the clear yellow viscous thing containing above-mentioned substance, join containing 1-10 part NaHCO 3, 0.01-5% part RuCl 3, 10-20 part aqueous solvent/CH 3cN/EtOAc(volume ratio is 1/6/6), in the glassy yellow suspension of 5-15 part potassium peroxymonosulfate (Oxone), now, reaction solution is cooled to temperature required (-20-30 DEG C), reaction 10min-12h, after reacting completely, by in reaction solution impouring 50-100 part water, water layer EtOAc extracts (3 × 30 parts), merges organic layer, removal of solvent under reduced pressure, obtains crude product.Crude product obtains sterling through re-crystallizing in ethyl acetate.Productive rate 70%.By product 17(20)-algestone productive rate 20%, 17-ketone product 10%(4AD, can be used as starting raw material and recycle).
C 21h 30o 3, white powdery solids.Mp.200-202 DEG C (ethyl acetate)
=0.45（petroleumether(30–60)/EtOAc=3/2）。
1HNMR(400MHz,CDCl 3)δ5.74(s,1H,H-4),2.84-0.76(m,20H,skeletonprotons),2.28(s,3H,H-21),1.13(s,3H,H-19),0.76(s,3H,H-18).
13CNMR(101MHz,CDCl 3)δ211.64,199.53,170.98,123.97,89.79,53.30,49.95,48.21,38.57,35.70,35.47,33.93,33.52,32.82,32.00,30.02,27.91,23.95,20.49,17.40,15.43.
ESI-MS,m/z:353.3[M+Na] +，683.5[2M+Na] +。
HRMS331.2269[M+H] +(calculatedforC 21H 30O 3330.2195).
C 21h 32o 3, white powdery solids.mp.186-188℃
=0.35（petroleumether(30–60)/EtOAc=3/2）。
1HNMR(400MHz,CDCl 3)δ5.73(s,1H,H-4),3.86-3.85(d,1H,H-20),2.43-0.97(m,21H,skeletonprotons),1.23(s,3H,H-21),1.21(s,3H,H-19),0.78(s,3H,H-18).
13CNMR(101MHz,CDCl 3)δ199.63,171.37,123.87,85.39,77.24,72.28,53.28,50.55,45.64,38.54,37.70,35.69(d,J=20.2Hz),33.95,32.89,31.97,30.95,23.36,20.50,18.54,17.40,14.08.
HRMS333.2426[M+H] +(calculatedforC 21H 32O 3332.2351).
C 19h 26o 2, white powdery solids, mp.166-168 DEG C.
=0.45（petroleumether(30–60)/EtOAc=3/2）。
1HNMR(400MHz,CDCl 3)：δ0.92(s,3H,H-18),1.22(s,3H,H-19),5.75(s,1H,H-4),0.99-2.52(m,19H,skeletonprotons).
13CNMR(101MHz,CDCl 3)：δ220.09(C-17),198.96(C-3),170.26(C-5),123.95(C-4),53.69(C-9),50.70(C-14),47.35(C-13),38.54(C-10),35.63,35.57,35.00,33.82,32.46,31.19,30.64,21.63,20.21,17.28(C-19),13.62(C-18).
(4) step 4: step 3 oxidation products is added in chloroform and calcium chloride-methanol solution in there-necked flask, be stirred to entirely molten, there-necked flask is put into low temperature thermostat bath, CaO is added under low temperature, the ICl liquid be dissolved in calcium chloride methanol solution is dripped under low temperature, in dropping process, high should the stopping of temperature drips, drip 2h, drip off rear continuation stirring reaction, TLC detection reaction terminal, after raw material reaction is complete, add aqueous ammonium chloride solution freezing in advance, 20min layering is left standstill after stirring, divide in separating funnel and get organic layer, water layer chloroform washes three times, the organic phase merged is filtered, concentrated after filtration, continuing to add methyl alcohol after concentrated is concentrated into dry, thickening temperature can not be too high, in case iodo thing decomposes, dry after concentrated, recrystallization, weigh, yield 98%.
Anhydrous potassium carbonate is dissolved in DMF, acetic acid and diacetyl oxide is added under stirring, stirring at room temperature for some time, then slowly intensification 1h to 100 DEG C, insulation 30min, make it to generate Potassium ethanoate, then less than 25 DEG C are cooled to, add above-mentioned iodo thing, progressively heat up, slow intensification 2h is to the follow-up continuous insulation reaction of certain temperature, TLC endpoint detection, after reacting completely, reaction solution is cooled, crystallization is had after cooling, filtered, mother liquor flush cake again after filtering, rinse with the mixture of DMF and water again, finally with hot water wash extremely neutral (pH=7), dry in an oven, drying temperature is less than or equal to 120 DEG C, recrystallization, obtain 11-deoxy-acetic acid cortisone, weigh, yield 98%.
Embodiment 2
(1) step one: the Androstenedione taking 1 part is dissolved in 10-100 part THF solution, and constantly stirs, and adds the dehydrated alcohol of 1-500 part, the triethyl orthoformate of 1-5 part, the tosic acid of 0.05-10% part, N 2protection, reaction solution is at 25-50 DEG C of reaction 1-12h, and after reacting completely, by reaction solution impouring 50-100 part water, filter, solid, with containing pyridine/ethyl alcohol recrystallization, obtains white powdery solids, dry, weighs, productive rate about 95%. =0.73 (sherwood oil (30-60 DEG C)/EtOAc=3/2).
C 21h 30o 2, white powdery solids.mp.144-146℃
=0.80（petroleumether(30–60)/EtOAc=3/2）。
1HNMR(400MHz,CDCl 3)δ5.25(s,1H,H-6),5.14(s,1H,H-4),3.81-3.78（t,2H,OCH 2CH 3）,2.52-2.45(m,1H,H-9),2.32-1.10(m,16H,skeletonprotons),1.32(t,3H,OCH 2CH 3),1.02(s,3H,H-19),0.93(s,3H,H-18).
13CNMR(101MHz,CDCl 3)δ220.98,154.60,141.16,117.07,98.87,62.17,51.94,48.42,47.65,35.84,35.26,33.74,31.50,31.45,30.71,25.45,21.82,20.47,18.97,14.65,13.66.
ESI-MS,m/z:315.3[M+H] +，337.3[M+Na] +。
(2) step 2: take 1-10 part second base three phenyl phosphonium bromide and 1 part of above-mentioned steps one product, under nitrogen protection, add THF, stirring and dissolving; Take the potassium tert.-butoxide of 2-20 part, be added in above-mentioned solution in batches, stir 0.5-3h, and 40-70 DEG C of oil bath heating 1-12h, react complete, be cooled to room temperature, add in 100-500 part frozen water, filter, solid adds dehydrated alcohol recrystallization and obtains white solid, dry, weighs, productive rate about 95%.
C 23h 34o, yellow needles solid.mp.90-93℃
=0.72（petroleumether(30–60)/EtOAc=3/2）。
1HNMR(400MHz,CDCl 3)δ5.25-5.23(t,1H,H-6),5.17-5.16(t,1H,H-4),5.14(s,1H,H-20),3.84-3.76(m,2H,OCH 2CH 3),2.44-1.07(m,17H,skeletonprotons),1.66(t,3H,OCH 2CH 3),1.33(t,3H,H-21),1.04(s,3H,H-19),0.97(s,3H,H-18).
13CNMR(101MHz,CDCl 3)δ154.47,150.23,140.99,118.00,113.45,99.03,62.16,56.68,48.31,44.18,37.02,35.22,33.86,33.79,31.69,31.46(d,J=5.0Hz),25.54,24.43,21.36,19.01,18.94,16.76,14.70,13.17.
(3) step 3: above-mentioned steps two product taking 1 part, joins containing 2-15 part Oxone(potassium peroxymonosulfate) or KHSO 5, and 10-200 part methylene chloride and water, and the RuCl of 0.5%-5% part 3, and 10-100% part n-Bu 4nHSO 4, stirring at room temperature reaction 0.1-12h, after reacting completely, by reaction solution impouring 100-500 part water, water layer is with dichloromethane extraction (3 × 30 parts), and merge organic layer, removal of solvent under reduced pressure, obtains crude product.Crude product obtains sterling through re-crystallizing in ethyl acetate.Productive rate 70%.By product 17(20)-epoxy progesterone productive rate 20%, 17-ketone product 10%(4AD, can be used as starting raw material and recycle).
C 21h 30o 3, white powdery solids.Mp.200-202 DEG C (ethyl acetate)
=0.45（petroleumether(30–60)/EtOAc=3/2）。
1HNMR(400MHz,CDCl 3)δ5.74(s,1H,H-4),2.84-0.76(m,20H,skeletonprotons),2.28(s,3H,H-21),1.13(s,3H,H-19),0.76(s,3H,H-18).
13CNMR(101MHz,CDCl 3)δ211.64,199.53,170.98,123.97,89.79,53.30,49.95,48.21,38.57,35.70,35.47,33.93,33.52,32.82,32.00,30.02,27.91,23.95,20.49,17.40,15.43.
ESI-MS,m/z:353.3[M+Na] +，683.5[2M+Na] +。
HRMS331.2269[M+H] +(calculatedforC 21H 30O 3330.2195).
C 21h 30o 2, white powdery solids.mp.126-128℃
=0.65（petroleumether(30–60)/EtOAc=3/2）。
1HNMR(400MHz,CDCl 3)δ5.74(s,1H,H-4),2.99-2.98(d,1H,H-20),2.98-1.00(m,19H,skeletonprotons),1.37(d,3H,H-21),1.19(s,3H,H-19),0.93(s,3H,H-18).
13CNMR(101MHz,CDCl 3)δ199.45,171.02,123.93,73.04,57.05,53.37,53.36,41.62,38.53,35.66,35.42,33.92,33.75,32.77,32.12,31.61,23.93,20.54,17.37,14.71,14.63.
HRMS315.2320[M+H] +(calculatedforC 21H 30O 2314.2246).
C 19h 26o 2, white powdery solids, mp.166-168 DEG C.
=0.45（petroleumether(30–60)/EtOAc=3/2）。
13CNMR(101MHz,CDCl 3)：δ220.09(C-17),198.96(C-3),170.26(C-5),123.95(C-4),53.69(C-9),50.70(C-14),47.35(C-13),38.54(C-10),35.63,35.57,35.00,33.82,32.46,31.19,30.64,21.63,20.21,17.28(C-19),13.62(C-18).
(4) step 4: above-mentioned steps three product taking 1 part, add 5-50 part ethanol, 1-5 part tetramethyleneimine, 0-50 DEG C is stirred 0.1-12h, adds 1-5 part concentrated hydrochloric acid, stir 1-6h, slowly add the ethanolic soln of 1-5 part bromine, add complete continuation reaction 1-12h, after reacting completely, removal of solvent under reduced pressure, add 5-50 part acetone again, 2-20 part Glacial acetic acid potassium, 1-10 part Glacial acetic acid and 2-10 part potassiumiodide, 20-60 DEG C of stirring reaction 0.5-6h, react complete, removal of solvent under reduced pressure, chloroform extraction, removal of solvent under reduced pressure, obtains 11-deoxy-acetic acid cortisone.Yield 98%.
Nuclear magnetic data:
1HNMR(CDCl 3)：δ=0.85(3H，H-19)，1.14(3H，H-18)，1.95(1H，17-OH)，2.14(3H，21-OCOCH 3)，5.25(2H，H-21)，5.75(1H，H-4)。
13CNMR(CDCl 3)：δ=206.8,198.9,170.2,170.2,124.0,90.8,67.7,53.7,49.5,48.0,38.6,35.7,35.2,34.1,33.2,32.5,31.6,30.2,23.8,21.1,20.4,19.0,16.4。
Embodiment 3
With Isosorbide-5-Nitrae-Androstenedione (ADD) for raw material, according to the method described in embodiment 1, the obtained following compound of structural formula:
Nuclear magnetic data:
1HNMR(CDCl 3)：δ=0.94(3H，H-19)，1.18(3H，H-18)，2.15(3H，21-OCOCH 3)，5.24(2H，H-21)，6.12(1H，H-4),6.35(1H，H-1),6.69(1H，H-2)。
13CNMR(CDCl 3)：δ=90.8,48.0,49.6,33.2,23.8,185.7,35.8,30.3,168.1,124.2,128.3,155.4,43.4,52.3,31.7,22.8,32.9,170.2,206.8,67.7,16.4,18.7,20.4。
Embodiment 4
Be raw material with alternative Isosorbide-5-Nitrae-Androstenedione (ADD), according to the method described in embodiment 1, the obtained following compound of structural formula:
Nuclear magnetic data:
1HNMR(CDCl 3)：δ=1.00(3H，H-19)，1.18(3H，H-18)，2.15(3H，21-OCOCH 3)，5.24(2H，H-21)，6.12(1H，H-4),6.35(1H，H-1),6.69(1H，H-2)。
13CNMR(CDCl 3)：δ=211.5,206.8,185.7,170.2,165.3,154.3,128.3,124.2,90.3,67.7,61.5,51.2,49.4,47.8,42.2,35.3,32.6,32.6,31.2,23.5,20.4,19.0,15.8。

Claims (4)

1. prepared the synthetic method of steroidal compounds by 3,17-diones steroidal for one kind, it is characterized in that, specifically comprise the steps:
Step one, with following 3, the 17-diones steroidals of structure for raw material, adds catalyzer, and protection reagent, through the selective protection of C3 ketone group, obtains formula 1 or formula 2 compound:
Androstenedione (AD) Isosorbide-5-Nitrae-Androstenedione (ADD)
Formula 1 formula 2
The catalyzer choosing used: anhydrous tosic acid or its monohydrate or itself and triethyl orthoformate or trimethyl orthoformate composition;
Step 2, formula 1 or formula 2 compound and Yi base triphenyl phosphonium halide salt react through Wittig, aftertreatment link acid adding deprotection, and a step obtains formula 3 compound:
Formula 3
Described second base triphenyl phosphonium halide salt is: ethyl triphenyl phosphonium chloride or second base three phenyl phosphonium bromide or ethyl triphenyl phosphonium iodide;
The alkali that Wittig reacts used is: sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydrogen one of them;
Step 3, formula 3 compound is dissolved in solvent, and under oxygenant and/or catalyzer exist, its 17 double bond of selective oxidation, obtains formula 4 compound:
Formula 4
Described solvent is: ethyl acetate acetonitrile aqueous systems, chloroform aqueous systems, methylene dichloride aqueous systems or ethylene dichloride aqueous systems;
Described oxygenant is: Potassium Monopersulfate, monopersulfate sodium or potassium peroxymonosulfate;
Described catalyzer is: RuCl 3n (H 2o), n=0-3;
Step 4, adds iodine or bromine or ICl or BrCl, to its C21 position halogen substiuted, after displacement, obtains following structural formula target compound in formula 4 compound:
。
2. the synthetic method being prepared steroidal compounds by 3,17-diones steroidal as claimed in claim 1, it is characterized in that, in step one, temperature of reaction is 40-120 DEG C; Raw material is 1:2-20 with protection reagent mol ratio.
3. the as claimed in claim 1 synthetic method being prepared steroidal compounds by 3,17-diones steroidal, is characterized in that, step 2 Chinese style 1 or formula 2 compound and Yi base triphenyl phosphonium halide salt mol ratio are: 1:1-5.
4. the synthetic method being prepared steroidal compounds by 3,17-diones steroidal as claimed in claim 1, it is characterized in that, the mol ratio of step 3 Chinese style 3 compound and oxygenant is: 1:5-15.
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