CN1053450C - Total synthesis method of 17-substituted 11 beta-substituted aromatic group-4, 9-estradiene compound - Google Patents
Total synthesis method of 17-substituted 11 beta-substituted aromatic group-4, 9-estradiene compound Download PDFInfo
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Abstract
The invention relates to a total synthesis method of 17-substituted 11 beta-substituted aryl-4, 9-estradiene compounds. Beta-naphthol is used as a starting material, beer yeast (Saccharomyces Cerevisiae) is adopted to reduce an intermediate condensate (II) into 3-methoxy-8, 14-ring-opening-1, 3, 5(10), 9(11) -estratetraene-17 beta-hydroxy-14-ketone (III) in a chiral way, 4, 9-estratetraene-17 beta-alcohol-3-ketone (VIII) is adopted as an intermediate starting material, and finally a 17-substituted 11 beta-substituted aryl-4, 9-estratediene compound is obtained, comprises 11 beta- [4- (N, N-dimethylamino) -phenyl ] -17 alpha- (1-propynyl) -4, 9-estradiene-17 beta-ol-3-one (XIV). The compound of formula (XIV) is useful as a medicament for terminating early pregnancy.
Description
The present invention relates to the preparation method of steroid drugs, particularly 17 preparation methods that replace 11 beta substitution aromatic base-4,9 estradiene steroid drugss.
17 replace 11 beta substitution aromatic base-4,9 estradiene steroidals, for example 11 β-[4-(N, N-dimethylamino)-phenyl]-17 α-(1-proyl)-4.9-estradiene-17 β-alcohol-3-ketone (Ru486; Mifepristone) and 11 β-(4-N, the N-dimethylaminophenyl)-17 α-(3-hydroxyl-1[Z]-propenyl)-4,9-estradiene-17 β-alcohol-3-ketone, in European patent (0057115), French Patent (2528434,2497807), United States Patent (USP) (4386085,4447424,4519946,4634695), German Patent (3231827,3231828) is reported in Chinese patent (86102502A) and the German Patent data such as (3347126) to some extent.These compounds have very strong avidity to the uterus PgR, have significant antiprogestin and certain Antiglucocorticoid activity, almost do not have other sexual hormoue activity, also do not have overt toxicity.Wherein Ru486 becomes the termination of early pregnancy medicine by the exploitation of Roussel-Uclaf company, and with the prostanoid drug combination, the artificial abortion rate can reach 90～95%, and French tablet goes on the market in this state, and has finished the new drug registration in China.Ru486 removes and is used for termination of early pregnancy, also can be used for treating endometriosis, mammary cancer, Ke Xing Shi disease, adrenal carcinoma, glaucoma etc.The appearance of this type of medicine is considered to a breakthrough, and is significant.China is research and development just energetically also.
The preparation of this compounds, foreign patent reported in literature mainly contain Roussel Uclaf company (EP0057115); Fr2528434; U.S 4386085 etc.) and the route of Schering company (Ger 3231827,3231828,3347126), see accompanying drawing 1.
In accompanying drawing 1:
R=H, alkane, contain heteroatoms alkane;
R
1=replacement or non-replacement alkane, alkene, alkynes, aromatic hydrocarbons;
A＝-CH
2CH
2-；-CH
2C(CH
3)
2CH
2-；
Two house journals are all from 5 (10), 9 (11)-estradienes-3,17-diketone 3-ketal (X) beginning, Roussel-Uclaf company carries out after the grignard reaction alkylation 17 of X that zone is selected and the three-dimensional oxo bridgeization of selecting gets oxygen bridge material (XII), and two steps all got the theoretical amount crude product, the former is directly used in oxo bridgeization, the latter then carries out column chromatography and handles, and Schering company is then earlier with the X oxo bridgeization, during 17 alkylations, for avoiding 5 α, 10 α-oxo bridge influenced, adopt butyllithium reagent and XII.After this two-step reaction two companies are basic identical.11 addition reactions are after column chromatography, yield 73.4% (W), protecting group is gone in hydrolysis after column chromatography, the Ru486 coarse-grain of 150 ℃ of fusing points, yield is 60.9% (W) (Ru486 elaboration fusing point should be 191～196 ℃).Roussel-Uclaf company makes this compounds from X equally via X → XI ' → XI ' → XIII → XIV.
Known preparation 5 (10), 9 (11)-estradienes-3, the method for 17-diketone 3-ketal (X) has:
German Patent is as accompanying drawing 2.
This method is not good for C13-methyl steroidal series selectivity, and purifying is trouble, and yield is lower.
Chinese patent (86102502A) name is called 11,17 two Δs that replace
4,9The synthetic method of-estradiene compound is as accompanying drawing 3.
This method has increased the selectivity cyano protection and decyanation removes to protect two-step reaction.
The then first selectivity bi-methoxyization of French Patent (2528434), exchange again after 17 alkylations XI, still simple and direct inadequately, as accompanying drawing 4.
Above-mentioned various preparation 5 (10), 9 (11)-estradienes-3, the currently known methods of 17-diketone 3-ketal (X) all is from 4,9-estradiene-3,17-diketone (14) beginning.4,9 estradienes-3,17-diketone (14) are to make (seeing accompanying drawing 5) by the intermediate carboxylic acid thing (12) of producing Norethisterone through two-step reaction.Therefore, the diosgenin that gets from the natural resource extraction, the semi-synthetic route whole process for preparing this compounds experiences 22 step chemical reaction (see figure 5)s altogether, estimates that by the yield of report total recovery is no more than 3% (W).
Other has report (China Medicine University's journal 17 (4) 282-5,1986) to begin to prepare 5 (10), 9 (11)-estradienes-3 by female phenolic ketone, 17-diketone 3-ketal (X), as accompanying drawing 6:
Female phenolic ketone generally makes (seeing accompanying drawing 5) by the midbody compound (11) of producing Norethisterone.So its whole process is not seen shortening yet.
The object of the invention is: make raw material with the compound that more cheaply is easy to get, select special microorganism, with initiator 4 in the middle of the short step preparation, 9-estradiene 17 β-alcohol-3-ketone (VIII), set up synthetic 17 as key and replace 11 beta substitution aromatic bases-4, the complete synthesis route of 9-estradiene compounds.
The present invention seeks to reach like this: with basic chemical industry raw material 2-Naphthol is starting raw material, production method according to the 18-methylnorethindron prepares tetralin enol (I) (609 pages in national bulk drug technology compilation), get 4 with the most rational approach, 9-estradiene-17 β-alcohol-3-ketone (VIII), and then acquisition final product XIV comprises 11 β-[4-(N, the N-dimethylamino)-and phenyl]-17 α-(1-proyl)-4,9-estradiene-17 β-alcohol-3-ketone (XIV).
The present invention is described in detail below in conjunction with drawings and Examples.
The final product of gained of the present invention is 17 and replaces 11 beta substitution aromatic bases-4,9-estradiene compounds, and the compounds X IV in its structural formula such as the accompanying drawing 1,
Wherein, R is H or NR
2R
3, wherein, R
2And R
3Represent H or C
1-C
4Alkyl;
R
1Be the C that is replaced by hydroxyl not essentially
1-C
4The alkynes base.
Particularly comprising: 11 β-[4-(N, N-dimethylamino)-phenyl]-17 α-(1-proyl)-4,9-estradiene-17 β-alcohol-3-ketone (XIV).
Complete synthesis estradiol once had report (Liebigs Ann chem 701.199,1967; Ibid 701,206.1967), main reference of the present invention prepares the experience of optics 18-methylnorethindron, selects special microorganism, with initiator 4 in the middle of the short step preparation, 9-estradiene-17 β-alcohol-3-ketone (VIII).As key, set up the complete synthesis route (seeing accompanying drawing 7) of synthetic this compounds.Existing division is as follows:
With basic chemical industry raw material 2-Naphthol is starting raw material, according to the production method of 18-methylnorethindron (609 pages in national bulk drug technology compilation) through beta-hydroxy methyl-etherified, active nickel low pressure shortening, chromic acid oxidation three go on foot tetralone, get tetralin enol (I) with the addition of vinylchlorid Grignard reagent again.
Tetralin enol (I) gets 3-methoxyl group-8 with methyl cyclopentanedione addition condensation under solutions of weak acidity, 14-open loop-1,3,5 (10), 9 (11)-female steroid tetraenes-14,17-diketone (II), II carries out the chirality micro-reduction and gets optical activity 3-methoxyl group-8,14-open loop-1,3,5 (10), 9 (11)-female steroid tetraene-17 beta-hydroxies-14-ketone (III).III is under strong acid such as PTS catalysis, and cyclization gets 3-methoxyl group-17 β-acetoxyl group-1,3 in aceticanhydride, 5 (10), 8,14-female steroid pentaene (IV), add catalyzer preferably the direct catalytic hydrogenation of active nickel get 3-methoxyl group-17 β-acetoxyl group-1,3,5 (10), 8-female steroid tetraene (V), again through lithium ammonia reduce 1,4-dihydro-3,17 beta estradiol 3-methyl ether (VI).VI gets 5 (10)-female steroid alkene-17 β-alcohol-3 ketone (VII) through the weak acid hydrolysis.VII generates crucial middle initiator 4,9-estradiene-17 β-alcohol-3-ketone (VIII) with mistake bromopyridine reactant salt in pyridine.
Wherein, condensation reaction, the optical activity product 3-methoxyl group-8 of tetralin enol (I) and methyl cyclopentanedione, 14-open loop-1, the ring-closure reaction and the 3-methoxyl group-17 β-acetoxyl group-1 of 3,5 (10), 9 (11)-female steroid tetraene-17 beta-hydroxies-14-ketone (III), 3,5 (10), 8, the hydrogenation of 14-female steroid pentaene (IV) is to carry out with reference to described document method.
3-methoxyl group-17 β-acetoxyl group-1,3,5 (10), 8-female steroid tetraene (V) is selected conditions suitable in the system of liquefied ammonia and metallic lithium, 8 (9) two keys and fragrant A ring reduced simultaneously and 1,4-dihydro-3,17 beta estradiol 3-methyl ether (VI), the solvent of selecting for use are ethers, comprise ether, tetrahydrofuran (THF) etc., temperature of reaction is-60～-30 ℃.
Compound VI under mild acid conditions, as oxalic acid-acetone system, acetic acid-water system, 15～50 ℃ of temperature of reaction, careful hydrolysis gets compound VI I.
Compound VI I carries out 5 (10) addition, eliminates reaction with mistake bromopyridine salt in pyridine.The addition reaction temperature is eliminated 50～100 ℃ of temperature of reaction for 0～30 ℃.The treated promptly crucial middle initiator 4 in reaction back, 9-estradiene-17 β-alcohol-3-ketone (VIII).
The microorganism of selecting for use is cereuisiae fermentum (Saccharomyces cerevisiae), and it is reduced to 3-methoxyl group-8 with intermediate condenses II chirality, 14-open loop-1,3,5 (10), 9 (11)-female steroid tetraene-17 β-alcohol-14-ketone (III).
Fermentation culture conditions: substratum consists of glucose 3～5%, corn steep liquor 2～4%, inoculum size 10～20%, air capacity 1: 0.33, and tank pressure 0.05MPa, 25～30 ℃ of jar temperature, incubation time: 10～15 hours, concentration fed intake: 1～2.5%.
Initiator VIII is under strong acid such as tosic acid (PTS) catalysis in the middle of crucial, with dibasic alcohol preferably ethylene glycol 60～100 ℃ of ketalizations simultaneously migration of the double bond get 5 (10), 9 (11)-estradienes-17 beta-hydroxies-3-ketone 3-ketal (IX).IX carries out the Wo Shi oxidation with aluminum isopropylate, pimelinketone, and medium is fragrant alkane or halogenated alkanes such as benzene, toluene, and temperature of reaction is 50～100 ℃, gets 5 (10), 9 (11)-estradienes-3,17-diketone 3-ketal (X).X gets the compounds X I of nearly theoretical amount through 17 alkylations of grignard reaction.When 17 acetylides of preparation, earlier with haloalkane (comprising monobromethane, halogen butane, chlorocyclohexane etc.) and magnesium chips prepared in reaction haloalkane Grignard reagent, 20～50 ℃ of temperature of reaction, exchange at logical alkynes under-10～10 ℃ of low temperature and carry out 17 addition reactions again in ethers (tetrahydrofuran (THF), ether etc.) after the haloalkane Grignard reagent is transformed fully, temperature of reaction is 0～30 ℃.XI is under weakly alkaline and Perfluoroacetone or hexachloroacetone catalysis, reacted 15～30 hours at-5～25 ℃ with 30% hydrogen peroxide, 5 (10) pairs of key generation area are selected and the three-dimensional oxygen emigrantization of selecting, and get 5 (10) oxygen bridge material XII, and wherein αYi Gouti and beta isomer ratio are about 7: 3.XII under univalent copper ion such as cuprous chloride catalysis 11 carry out unusual Ge Shi addition and get compounds X III; Reaction solvent is ethers such as tetrahydrofuran (THF), and Grignard reagent is made under 20～60 ℃ temperature by the halogenated aromatic based compound of magnesium chips and replacement.The addition reaction temperature is-10～30 ℃; Perhaps 5 (10), 9 (11)-estradienes-17 β-alcohol-3-ketone 3-ketal (IX) carries out 5 (10) two key oxo bridgeizations under these conditions earlier, 11 unusual Ge Shi additions, and 17 hydroxyl Wo Shi oxidation, 17 Ge Shi addition alkylations get compounds X III.At last with compounds X III in 10～80 ℃ in acetic acid or with strong acid catalysis, in alcohol (methyl alcohol, ethanol) dehydration go protecting group must go up the object XIV of array structure.
Above-mentioned complete synthesis process, from the optical activity product III of microorganism chirality reduction gained, it is all consistent with reported in literature after measured that each goes on foot the specific optical rotation and the Main physical constant of intermediate and end product.From hydrolyzate VII, each goes on foot intermediate specific optical rotation and Main physical constant, and the respective compound while blank determination with the semi-synthetic path of preparing of special usefulness all obtains consistent data.
The effect of the inventive method is:
1, different with semi-synthetic route, the present invention adopts 4, and 9-estradiene-17 β-alcohol-3-ketone (VIII) is middle initiator; in preparation 5 (10); 9 (11)-estradienes-3 do not have the problem of 17 ketone groups of first selective protection, thereby have shortened reactions steps during 17-diketone 3-ketal (X).And semi-synthetic route since when 17 methyl ketone side chains of early stage excision of process 17 ketone; the middle initiator that obtains after the some reactions of process is 4; 9-estradiene-3; 17-diketone (14) (see figure 2); must add protection earlier to 17 ketone groups; remove protecting group again after waiting to introduce required group, this is a more relatively reason of semi-synthetic route steps.
2, different with other routes, initiator 4 in the middle of of the present invention, 9-estradiene-17 β-alcohol-3-ketone (VIII) be can't help female phenolic ketone and is produced, but by tetralin enol (I) through condensation, the reduction of microorganism chirality, cyclization, hydrogenation, lithium ammonia reduction five steps reaction make 1,4-dihydro-3,17 beta estradiol 3-methyl ether (VI), again through hydrolysis, Δ
4,9The generation two-step reaction makes.This is to obtain 4 at present, the most reasonable simple and direct approach of 9-estradiene-17 β-alcohol-3-ketone (VIII).
3, select cereuisiae fermentum (Saccharomyces cerevisiae) for use, (taking from Institute of Microorganism, Academia Sinica) is reduced to 3-methoxyl group-8 with intermediate condenses (II) chirality, 14-open loop-1,3,5 (10), 9 (11)-female steroid tetraene-17 β-alcohol-14 ketone (III), efficient height, yield height.
4, foreign patent respectively goes on foot intermediate and product all through column chromatographic isolation and purification, and the present invention does not need the complicated operation of column chromatography, and technology is greatly simplified, be applicable to produce actual.
To sum up, complete synthesis route of the present invention, whole process begins to experience 17 step main reaction (see figure 7) total recoverys from basic chemical industry raw material 2-Naphthol and reaches 5% (W).Last four step 17 alkylations get nearly theoretical amount crude product, can be directly used in the next step.Also get the theoretical amount crude product after 5 (10) oxo bridgeizations, be used for the next step, needn't pass through column chromatography with the general method processing.Handle yield 80% (W) with general method after 11 addition reactions, hydrolysis go after the protecting group the Ru486 crude product of nearly theoretical amount, yield 87% (W), getting fusing point with the refining purifying of general method is 192-196 ℃ qualified product, the rate of recovery 75～85% (W).With semi-synthetic route ratio, step is shorter, and total recovery is higher, and cost is lower, and more significant potential economic benefit is arranged, and process optimization is convenient to produce the industrialized practical value of tool.And the intermediate of this route still can be used for preparing some important 19-demethyl steroid drugss.From the prospect of diosgenin natural resource growing tension, the reasonable disposition of the steroid drugs resources of production is also had than important practical sense.
17 of the present invention replace 11 beta substitution aromatic bases-4,11 β of one of end product that the complete synthesis route of 9-estradiene compounds makes-(4 (N, the N-dimethylamino)-and phenyl)-17 α-(1-proyl)-4, the biomedical test-results of 9-estradiene-17 β-alcohol-3-ketone (XIV):
Oral administration stops mouse early pregnancy ED50:0.67mg/kg
Oral administration stops rat early pregnancy ED50:2.46mg/kg
Rabbit uterus endochylema PgR bonding force is better than nearly 3 times of progesterone;
McGinty test: no progestin, the obvious antiprogestational action of tool;
Rats'liver endochylema glucocorticoid receptor there is certain bonding force.
Its mouse oral LD50＞5g/kg, rat oral LD50＞2.5g/kg.
Rat 200mg/kg/ day per os administration January, do not see the overt toxicity reaction.
Macaque 10～80mg/kg/ day per os administration January, do not see the overt toxicity reaction.
Cause prominent, the teratogenic test feminine gender.
Rat, the test of macaque oral administration pharmacokinetics, each parameter and time front of blood concentration meet two-compartment model, absorb rapidly, and the prototype medicine is very few through renal excretion.
Above result is consistent with the finished product control experiment result of Roussel-Uclaf company product and homemade semi-synthesis method.
Embodiment
The open loop-1,3 of example 1:3-methoxyl group-8,14,5 (10), 9 (11)-female steroid tetraenes-14, the preparation of 17-diketone (II):
21 parts of methyl cyclopentanediones that in tetralin enol (I) alcoholic solution, add calculated amount, under mild acid conditions, stirred for several hour.Reclaim ethanol, lower the temperature, leave standstill, filtration, crystallization be with ethanol drip washing, dry 3-methoxyl group-8,14-open loop-1,3,5 (10), 9 (11)-female steroid tetraenes-14,17-diketone (II).Yield 120% (to tetralone weight meter), mp.77-79 ℃.
Example 2:3-methoxyl group-8,14-open loop-1,3, the preparation of 5 (10), 9 (11)-female steroid tetraene-17 β-alcohol-14-ketone (III):
By shaking bottle, seed tank culture is received fermentor tank again and is carried out fermentation culture with saccharomyces cerevisiae, inoculum size 15%, and air capacity 1: 0.33, tank pressure 0.05MPa, 28 ℃ of jar temperature were cultivated 12 hours, transformed with major ingredient.
Substratum is formed: glucose 4.5%, and corn steep liquor 2.5%, the concentration 1.5～2% that feeds intake, reaction terminating control transformation efficiency gets final product discharging about 90%.Centrifugally get rid of filter.Extract filter cake with the ethanol gradation, filtrate decompression concentrates, crystallization, filtration, drying:
3-methoxyl group-8,14-open loop-1,3-5 (10), 9 (11)-female steroid tetraene-17 β-alcohol-14-ketone (III).Yield 75% (W).MP.112～116 ℃ (α) D-39 ° (dioxane).
Example 3:3-methoxyl group-17 β-acetoxyl group-1,3,5 (10), the preparation of 8-female steroid tetraene (V):
A) with 3-methoxyl group-8,14 open loop-1,3,0.5 part of 10 parts of 5 (10), 9 (11)-female steroid tetraene-17 β-alcohol-14-ketone (III) and tosic acid are dissolved in the retort with aceticanhydride, in below 55 ℃, stoichiometric number hour, reclaim under reduced pressure goes out a certain amount of solvent, cooling, add the water elutriation, filtration, washing, drying, air-dry get 3-methoxyl group-17 β-acetoxyl group-1,3,5 (10), 8,14-female steroid pentaene (IV) cyclisation thing.(IV) uses dissolve with ethanol with this cyclocomplex, active nickel catalysis, and atmospheric hydrogenation, reaction ends, the filtering active nickel.Concentrating under reduced pressure, crystallization, filtration, and, get 3-methoxyl group-17 β-acetoxyl group-1,3 with small amount of ethanol drip washing, 5 (10), 8-female steroid tetraene (V), yield 80%, mp.113～114 ℃ [α] D20-51 °; Or
B) cyclocomplex (IV) (1 part) is in benzene (10 parts), add 5% palladium/lime carbonate (0.15 part) atmospheric hydrogenation after, leach catalyzer, boil off solvent, alcohol crystal gets compound V, mp.110～112 ℃, (α)
D 20-54 °.
Example 4:1, the preparation of 4-dihydro-3,17 beta estradiol 3-methyl ether (VI):
A) in lithium ammonia jar, feeding 180 parts in liquefied ammonia about-40 ℃, add 4.8 parts of metallic lithiums, stirring and dissolving, in addition with an amount of ether with 3-methoxyl group-17 β-acetoxyl group-1,3,5 (10), 8-female steroid tetraene (V) 6.5 dissolvings, and adding in the retort.Stirred 1 hour, add dehydrated alcohol again, after 20 minutes, with tap water, the most ammonia of steam flood, catch up with clean back to add 30% aqueous acetic acid and an amount of water respectively, filtration, washing, alcohol are washed, drying, get 1,4-dihydro-3,17 beta estradiol 3-methyl ether (VI) yield 74%, mp.111-114.5 ℃ (α)
D 20+ 109 °; Or
B) heavily steam adding metallic lithium (0.8 part) in the liquefied ammonia (25 parts) to drying, after the dissolving, add 3-methoxyl group-17 β-acetoxyl groups-1,3-at-50 ℃, 5 (10), the tetrahydrofuran solution of 8-female steroid tetraene (V) (1 part) and aniline (1 part), stirring reaction 30 minutes adds dehydrated alcohol, drive away ammonia, add dilute acetic acid, filter, washing, alcohol is washed, drying, get 1,4-dihydro-3,17 beta estradiol 3-methyl ether (VI), yield 73% (weight), mp.110～114 ℃, (α)
D 20+ 108 °.
Example 5:5 (10)-female steroid alkene-17 β-alcohol-3-ketone (VII):
A) with 1,4-dihydro-3,17 beta estradiol 3-methyl ether (VI) is used the acetone heating for dissolving for 1 part, reduces to room temperature.1.5 parts of ethanolic solns of the oxalic acid that contains calculated amount are being added below 45 ℃, keeping this temperature to stir 2.5 hours.Reaction solution with cold water elutriation, filtration, is washed till neutrality, air-dry:
5 (10)-female steroid alkene-17 β-alcohol-3-ketone (VII).Yield 80%, mp.175～185 ℃, [α]
D+ 187 °, HPLC content 97%; Or
B) 1,1 part of 4-dihydro-3,17 beta estradiol 3-methyl ether (XI), in 25 parts of 90% acetic acid, 25～30 ℃ of stirring reactions 1 hour add water (25 parts), filter, and are washed till neutrality, after doing compound VI I, yield 71 (weight) %, mp.185～190 ℃.
Example 6:4, the preparation of 9-estradiene-17 β-alcohol-3-ketone (VII):
A) 1 part of 5 (10)-female steroid alkene-17 β-alcohol-3-ketone (VII) is dissolved in 12 parts of the pyridines, under nitrogen protection, room temperature added pyridinium bromide hydrobromate pyridine solution, stirred 0.5 hour.Heat up about 90 ℃, be incubated 0.5 hour.With this reaction solution with the water elutriations, filtration, drying of six amounts, crude product.With an amount of re-crystallizing in ethyl acetate, get 4,9-estradiene-17 β-alcohol-3-ketone (VIII) again.Yield 58 (weight) %, mp.184-187 ℃, (α)
D-295 °, HPLC content 96%～97%; Or
B) 5 (10)-female steroid alkene-17 β-pure 3-ketone (VII) (1 part) is dissolved in pyridine (7 parts), dripped pyridine (10 parts) solution of the hydrobromate (1.2 parts) of pyridinium bromide under 0 ℃, 25 ℃ were reacted 1 hour, 70 ℃ of reactions hour, the reaction solution impouring contains in the water of calculated amount acid, filters, get crude product, get compound VIII with methanol crystallization again, mp.185～187 ℃, (α)
D-296 °.
Example 7:3,3-(1, the preparation of 2-enedioxy (base)-5 (10), 9 (11)-estradiene-17 β-alcohol (IX):
A) with 4,9-estradiene-17 β-alcohol-3-ketone (VIII) (1 part) is dissolved in the ethylene glycol (50 parts), adds tosic acid (0.1 part).70～80 ℃ of heating underpressure distillation treat that most of liquid steams, and stop distillation.Reaction solution is with a large amount of water water foldings, and the leaching crystallization gets 3,3-(1, the 2-ethylene two oxy)-5 (10), 9 (11)-estradiene-17 β-alcohol (IX).Yield 100%, content 98%; Or
B) with 4,9-estradiene-17 β-alcohol-3-ketone (VIII) (1 part) is dissolved in the benzene (20 parts), add ethylene glycol (7.5 parts) and tosic acid (0.05 part), 110 ℃ of reflux dewaterings reactions of outer bath 3～4 hours add 5% sodium hydrogen carbonate solution, tell the benzene layer, anhydrous magnesium sulfate drying, boil off solvent, get nearly theoretical amount compound 1X, content 95 (weight) %.
Example 8:3, the preparation of 3-(1, the 2-ethylene two oxy)-5 (10), 9 (11)-estradienes-17-ketone (X):
A) with 3,3-(1, the 2-ethylene two oxy)-5 (10), 9 (11)-estradiene-17 β-alcohol (IX) (1 part) is dissolved in an amount of benzene, and refluxes band water till the clarification of distilled benzene liquid.Cooling adds aluminum isopropylate (1 part), pimelinketone (5 parts), refluxes 4 hours.Decompression steams most of benzene.Change steam distillation into, do not have the benzene flavor, add 10% sodium hydroxide solution, cooling, leaching crystallization until the liquid that steams.Again with this crude product with ethanol bubble wash, filter, drying, 3,3-(1, the 2-ethylene two oxy)-5 (10), 9 (11)-estradienes-17-ketone (X).Yield 80%, mp.148-152 ℃, [α]
D+ 304.8.Content 97%;
B) Compound I X (1 part) is dissolved in toluene (15 parts), 110 ℃ are distilled to distillate clarification, cooling, add aluminum isopropylate (1 part), pimelinketone (5 parts), reacting by heating 2～3 hours, decompression steams most of solvent, water vapor heats up in a steamer the removal pimelinketone, add 10% sodium hydroxide solution, cooling is filtered, alcohol crystal, get compounds X, mp.148-153℃。
Example 9:3,3-(1, the 2-ethylene two oxy)-17 α-(1-proyl)-5 (10), 9 (11)-estradiene-17 β-alcohol (XI):
A) magnesium chips adds tetrahydrofuran (THF) in a small amount for 0.46 part under the logical nitrogen of low temperature, drips monobromethane in a small amount and brings out reaction.At the tetrahydrofuran solution of 1.4 parts in 30～40 ℃ of dripping bromine ethane, stirring makes and reacts completely again.Earlier at the logical propine gas of low temperature, rise to room temperature again and continue logical propine and made in 1～2 hour and react completely.Drip 3 under the stirring at room, the THF solution of 3-(1, the 2-ethylene two oxy)-5 (10), 9 (11)-estradienes-17-ketone (X) (1 part) continues to stir to make to react completely.In impouring trash ice and the saturated ammonium chloride solution, tell organic layer, anhydrous magnesium sulfate drying, removal of solvent under reduced pressure gets nearly theoretical amount 3, and 3-(1, the 2-ethylene two oxy)-17 α-(1-proyl)-5 (10), 9 (11)-estradiene-17 β-alcohol (XI), content 95%; Or
B) magnesium chips (0.46 part) adds a small amount of tetrahydrofuran (THF), drip small amount of bromine ethane under the nitrogen gas stream and bring out reaction, the tetrahydrofuran solution of 30 ℃ of following dripping bromine ethane (1.3 parts), stirring makes and reacts completely, the logical acetylene gas of elder generation's low temperature rises to room temperature again and continues logical acetylene gas, makes exchange fully, 25～30 ℃ drip 3, the tetrahydrofuran solution of 3-(1, the 2-ethylene two oxy)-5 (10), 9 (11)-estradienes-17-ketone (X) (1 part), stirred 30 minutes, in the impouring refrigerative ammonium chloride solution, tell organic layer, with anhydrous magnesium sulfate drying, removal of solvent under reduced pressure, get nearly theoretical amount 3,3-(1, the 2-ethylene two oxy)-17 α-ethynyl-5 (10), 9 (11)-estradienes-17 β-alcohol, content 95%.
Example 9-1:3,3-(1, the 2-ethylene two oxy)-11 β-(4-(N, N-dimethylamino-phenyl)-17 α-(3-(tetrahydropyrans-2 '-the oxygen base)-proyl)-9-female steroid alkene-5 α, 17-isoallopregnane-3:
Magnesium chips (0.43 part) adds a small amount of tetrahydrofuran (THF), drip small amount of bromine ethane under the nitrogen gas stream and bring out reaction, the tetrahydrofuran solution of 30 ℃ of following dripping bromine ethane (1.35 parts), stirring makes and reacts completely, low temperature drips the tetrahydrofuran solution of propiolic alcohol tetrahydropyranyl ethers (2.75 parts) down, stirring at room makes conversion fully, add 3, the tetrahydrofuran solution of 3-(1, the 2-ethylene two oxy)-11 β-(4-(N, N-dimethylamino)-phenyl)-9-female steroid alkene-5 α-alcohol-17-ketone (1 part), stir to make in 30 minutes and react completely, by epimere example 9 methods handle theoretical amount 3,3-(1, the 2-ethylene two oxy)-11 β-(4,-N, the N-dimethylamino)-and phenyl)-17 α-(3-(tetrahydropyrans-2 '-the oxygen base)-proyl)-9-female steroid alkene-5 α, 17-isoallopregnane-3, content 90%.
Example 10:3,3-(1, the 2-ethylene two oxy)-5 α, 10 alpha-epoxy-17 α-(1-proyl)-9 (11)-female steroid alkene-17 β-alcohol (XII):
A) with 3,3-(1, the 2-ethylene two oxy)-17 α-(1-proyl)-5 (10), 9 (11)-estradiene-17 β-alcohol (XI) is dissolved in methylene dichloride, adds 0.5 part in the hydrogen peroxide of hexachloroacetone (0.5 part), pyridine 30%, and 0～20 ℃ is stirred to and reacts completely.Add hypo solution and stir, tell organic layer, washing, drying are used ethyl acetate and normal hexane crystallization behind the removal solvent.Yield-80% (W).Content 75～80%; Or
B) compounds X I (1 part) is dissolved in methylene dichloride (5 parts), 0 ℃ drips Perfluoroacetone (0.06 part) down, a small amount of pyridine and 30% hydrogen peroxide (0.5 part), stir under 0 ℃ to make in 24 hours and react completely, add hypo solution, tell organic layer, washing, anhydrous magnesium sulfate drying, remove solvent, use ethyl acetate-petroleum ether crystallization, treat compounds X II, yield 80% (W), content 75～80%.
Example 10-1:3,3-(1, the 2-ethylene two oxy)-5 α, 10 alpha-epoxy-17 α-ethynyls-9 (11)-female steroid alkene-17 β-alcohol
3,3-(1, the 2-ethylene two oxy)-17 α-ethynyl-5 (10), 9 (11)-estradienes-17 β-alcohol (1 part) is dissolved in methylene dichloride, add hexachloroacetone (0.5 part), a small amount of pyridine and 30% hydrogen peroxide (0.5 part), 10～20 ℃ are stirred to and react completely, adding hypo solution stirs, tell organic layer, washing, drying are used ethyl acetate and normal hexane crystallization behind the removal solvent, get 3,3-(1, the 2-ethylene two oxy)-5 α, 10 alpha-epoxy-17 α-ethynyls-9 (11)-female steroid alkene-17 β-alcohol, yield 78% (W), content 75～80%.
Example 10-2:3,3-(1, the 2-ethylene two oxy)-5 α, 10 α-epoxy-9 (11)-female steroid alkene-17-ketone (XI ')
3,3-(1, the 2-ethylene two oxy)-5 (10), 9 (11)-estradienes-17-ketone (X) (1 part) is dissolved in methylene dichloride, adds Perfluoroacetone (0.4 part), a small amount of pyridine and 30% hydrogen peroxide (0.5 part), 10～20 ℃ are stirred to and react completely, handle by routine 10-1 method, get 3,3-(1, the 2-ethylene two oxy)-5 α, 10 α-epoxy-9 (11)-female steroid alkene-17-ketone, yield 80% (W), content 75～80%.
Example 11:3,3-(1, the 2-ethylene two oxy)-11 β-[4-(N, N-dimethylamino)-phenyl]-17 α-(1-proyl)-9-female steroid alkene-5 α, 17-isoallopregnane-3 (XIII):
Magnesium chips (0.3 part), low temperature leads to nitrogen in THF, and the THF solution that drips xylene bromide amine (2.5 parts) brings out the continuation dropping of reaction back in a small amount, keeps 30～40 ℃, stirs to make to react completely.
Add chlorination cuprous (0.1 part), stir evenly, drip 3 at low temperatures, 3-(1, the 2-ethylene two oxy)-5 α, the THF solution of 10 alpha-epoxy-17 α-(1-proyl)-9 (11)-female steroid alkene-17 β-alcohol (XII) (1 part) adds and rises to room temperature and make and react completely, the ice-cold saturated ammonium chloride solution of impouring, tell organic layer, washing, drying are removed solvent, yield-100% (W), the crude product crystallization gets 3,3-(1, the 2-ethylene two oxy)-11 β-[4-(N, the N-dimethylamino)-and phenyl)-17 α-(1～proyl)-9-female steroid alkene-5 α, 17-isoallopregnane-3 (VIII).Yield～80% (W), content 98%.
Example 11-1:3,3-(1, the 2-ethylene two oxy)-11 β-(4-(N, N-dimethylamino)-phenyl)-17 α-ethynyl-9-female steroid alkene-5 α, 17-isoallopregnane-3 (XIII),
Magnesium chips (0.3 part) is logical nitrogen in a small amount of THF, after dropping is brought out reaction on a small quantity to THF (12 parts) solution of bromo-dimethylaniline (2.4 parts), continue to drip, keep 30～40 ℃, stirring makes and reacts completely, and adds chlorination cuprous (0.1 part), drip 3 at 10～20 ℃, 3-(1, the 2-ethylene two oxy)-5 α, the THF solution of 10 alpha-epoxy-17 α-ethynyls-9 (11)-female steroid alkene-17 β-alcohol (1 part), continue reaction 30 minutes, handle by example 11 methods, recrystallize gets 3, and 3-(1, the 2-ethylene two oxy)-11 β-(4-(N, the N-dimethylamino)-phenyl)-17 α-ethynyl-9-female steroid alkene-5 α, 17-isoallopregnane-3, yield 90% (W).
Example 11-2:3,3-(1, the 2-ethylene two oxy)-11 β-(4-(N, N-dimethylamino)-phenyl)-9-female steroid alkene-5 α-alcohol-17-ketone (XII '),
Magnesium chips (0.29 part) is logical nitrogen in a small amount of THF, drips THF (12 parts) solution to xylene bromide amine (2.45 parts) and bring out the reaction back on a small quantity and continue to drip, and keeps 35 ℃ of stirrings and make and react completely.
Add chlorination cuprous (0.1 part), drip 3 at 0 ℃, 3-(1, the 2-ethylene two oxy)-5 α, the THF solution of 10 α-epoxy-9 (11)-female steroid alkene-17-ketone (1 part) continues reaction 30 minutes, handles by example 11 methods, recrystallize gets 3,3-(1, the 2-ethylene two oxy)-11 β-(4-(N, N-dimethylamino)-phenyl)-9-female steroid alkene-5 α-alcohol-17-ketone (XII '), mp.171-176 ℃, yield 85% (W).
Example 12:11 β-(4-N, N-dimethylamino)-phenyl)-17 α-(1-proyl)-4,9-estradiene-17 β-alcohol-3-ketone (XIV):
A) with 3,3-(1, the 2-ethylene two oxy)-11 β-(4-(N, the N-dimethylamino)-and phenyl)-17 α-(1-proyl)-9-female steroid alkene-5 α, 17-isoallopregnane-3 (XIII) (1 part) is suspended in 20 parts of the methyl alcohol, add 0.5 part of concentrated hydrochloric acid, stirring at room 30 minutes, with diluted sodium hydroxide solution handle the theoretical amount crude product; Or
B) compounds X III (1 part), ethanol (20 parts) stirs evenly down and adds tosic acid (0.3 part), 70～80 ℃ of stirring reactions 1 hour, by a) method handle the theoretical amount crude product; Or
C) compounds X III (1 part) is in 70% acetic acid (10 parts), and 50～60 ℃ of stirred for several hour make and to react completely, handle with diluted sodium hydroxide solution, after filtration, washing, the drying the theoretical amount crude product.
Process for purification:
1, with the feed intake hydrolysis reaction product of gained of the thick product of addition reaction, by silicagel column, with hexanaphthene-eluent ethyl acetate, ethyl acetate-normal hexane crystallization, get 11 β-(4-N, N-dimethylamino)-phenyl)-17 α (1-proyl)-4,9-estradiene-17 β-alcohol-3-ketone (XIV).Mp.191-196 ℃ (not proofreading and correct); Or
2, do not carry out column chromatography with the feed intake thick product of hydrolysis reaction of gained of the smart product of addition reaction, get 11 β-(4-(N with ethyl acetate-normal hexane or sherwood oil crystallization after treatment, the N-dimethylamino)-and phenyl)-17 α-(1-proyl)-4,9-estradiene-17 β-alcohol-3-ketone (XIV).Mp.191-196 ℃ of (not proofreading and correct) yield 75% (W).
Example 12-1:11 β-(4-(N, N-dimethylamino)-phenyl)-17 α-ethynyl-4,9-estradiene-17 β-alcohol-3-ketone,
3,3-(1, the 2-ethylene two oxy)-11 β-(4-(N, the N-dimethylamino)-phenyl)-17 α-ethynyl-9-female steroid alkene-5 α, 17-isoallopregnane-3 (1 part) is dissolved in methyl alcohol (25 parts), add 2N hydrochloric acid (4 parts), stirring at room 30 minutes, diluted sodium hydroxide solution is handled, dichloromethane extraction, remove behind the solvent crude product, through refining 11 β-(4-(N, N-dimethylamino)-phenyl)-17 α-ethynyl-4,9-estradiene-17 β-alcohol-3-ketone, yield 75% (W), mp.173 ℃, purity 97.7%.
Example 12-2:11 β-(4-(N, N-dimethylamino)-phenyl)-17 α-(3-hydroxypropyn base)-4,9-estradiene-17 β-alcohol-3-ketone
3,3-(1, the 2-ethylene two oxy)-11 β-(4-(N, the N-dimethylamino)-and phenyl)-17 α-(3-(tetrahydropyrans-2 '-the oxygen base)-proyl)-9-female steroid alkene-5 α, 17-isoallopregnane-3 (1 part) is in 70% acetic acid (10 parts), and 50 ℃ are stirred down, reacted 2 hours, cooling, the ammoniacal liquor neutralization, ethyl acetate extraction is removed the back of desolvating and is made with extra care, get 11 β-(4-(N, the N-dimethylamino)-and phenyl)-17 α-(3-hydroxypropyn base)-4,9-estradiene-17 β-alcohol-3-ketone, yield 40% (W), mp.220-223 ℃, purity 98%.
Claims (7)
1,17 replace 11 beta substitution aromatic bases-4, the complete synthesizing process of 9-estradiene compounds, with the 2-Naphthol is starting raw material, production method according to the 18-methylnorethindron obtains tetralin enol (I), it is characterized in that: adopt cereuisiae fermentum 3-methoxyl group-8,14-open loop-1,3,5 (10), 9 (11)-female steroid tetraenes-14,17-diketone (II) chirality is reduced to 3-methoxyl group-8,14-open loop-1,3,5 (10), 9 (11)-female steroid tetraene-17 beta-hydroxies-14-ketone (III) adopt 4, and 9-estradiene-17 β-alcohol-3-ketone (VIII) is middle initiator preparation 5 (10), 9 (11)-estradienes-3,17-diketone-3-ketal (X) obtains 17 at last and replaces 11 beta substitution aromatic bases-4,9-estradiene compounds (XIV):
Wherein: R is H or NR
2R
3, wherein, R
2And R
3Represent H or C
1-C
4Alkyl;
R
1Be the C that is replaced by hydroxyl not essentially
1-C
4The alkynes base.
2,17 according to claim 1 replace 11 beta substitution aromatic bases-4, the complete synthesizing process of 9-estradiene compounds, and it is characterized in that: synthesis step is as follows:
A) tetralin enol (I) obtains 3-methoxyl group-8,14-open loop-1,3,5 (10), 9 (11)-female steroid tetraenes-14,17-diketone (II) with methyl cyclopentanedione addition condensation under acidic conditions;
B) with cereuisiae fermentum with 3-methoxyl group-8,14-open loop-1,3,5 (10), 9 (11)-female steroid tetraenes-14,17-diketone (II) chirality is reduced to 3-methoxyl group-8,14-open loop-1,3,5 (10), 9 (11)-female steroid tetraene-17 beta-hydroxies-14-ketone (III);
C) 3-methoxyl group-8,14-open loop-1,3,5 (10), 9 (11)-female steroid tetraene-17 beta-hydroxies-14-ketone (III) is under strong acid catalysis, and cyclization in aceticanhydride obtains 3-methoxyl group-17 β-acetoxyl group-1,3, and 5 (10), 8,14-female steroid pentaene (IV);
D) add catalyzer in this compound (IV), directly catalytic hydrogenation obtains 3-methoxyl group-17 β-acetoxyl group-1,3, and 5 (10), 8,14-female steroid tetraene (V);
E) this compound (V) obtains 1,4-dihydro-3,17 beta estradiols-3-methyl ether (VI) through the reduction of lithium ammonia;
F) this compound (VI) obtains 5 (10)-female steroid alkene-17 β-alcohol-3-ketone (VII) through the weak acid hydrolysis;
G) this compound (VII) in pyridine with cross the bromopyridine reactant salt, generate 4,9-estradiene 17 β-alcohol-3-ketone (VIII).
H) with 4,9-female steroid tetraene-17 β-alcohol-3-ketone (VIII) under strong acid catalysis, with dibasic alcohol 60～100 ℃ of ketalizations, simultaneously migration of the double bond obtains 5 (10), 9 (11)-estradienes-17 beta-hydroxies-3-ketone-3-ketal (IX);
I) compound 5 (10), 9 (11)-estradienes-17 beta-hydroxies-3-ketone-3-ketal (IX) is used Virahol, pimelinketone carries out the Wo Shi oxidation, medium is fragrant alkane or halogenated alkane, 50～100 ℃ of temperature of reaction, obtain 5 (10), 9 (11)-estradienes-3,7-diketone-3-ketal (X), this compound (X) obtains 3 through 17 alkylations of grignard reaction, and 3-(1, the 2-ethylene two oxy)-17 α-(1-proyl)-5 (10), 9 (11)-estradienes-17 β-alcohol (XI), this compound reacted 15～30 hours down at-5～25 ℃ with hydrogen peroxide under slightly acidic and Perfluoroacetone catalysis, obtain 5 (10) oxygen bridge materials (XII), this compound (XII) carries out unusual Ge Shi addition at 11 under univalent copper ion catalysis, the addition reaction temperature is-10～30 ℃, obtain compound 3,3-(1, the 2-ethylene two oxy)-11 β-[4-(N, N-dimethylamino)-phenyl]-17 α-(1-proyl)-9-female steroid alkene-5 α, 17-isoallopregnane-3 (XIII)
J) compound 3; 3-(1, the 2-ethylene two oxy)-11 β-[4-(N, N-dimethylamino)-phenyl]-17 α-(1-proyl)-9-female steroid alkene-5 α; 17-isoallopregnane-3 (XIII) in 10～80 ℃, in acetic acid or with strong acid catalysis, in alcohol the dehydration go protecting group to obtain object (XIV).
3,17 according to claim 2 replace 11 beta substitution aromatic bases-4, the complete synthesizing process of 9-estradiene compounds, it is characterized in that: i) in the step, compound 5 (10), 9 (11)-estradienes-17 beta-hydroxies-3-ketone-3-ketal (IX) carries out 5 (10) two key oxo bridgeizations earlier, carry out 11 unusual Ge Shi additions again, 17 hydroxyl Wo Shi oxidation and 17 Ge Shi addition alkylations obtain compound 3,3-(1, the 2-ethylene two oxy)-11 β-[4-(N, the N-dimethylamino)-and phenyl]-17 α-(1-proyl)-9-female steroid alkene-5 α, 17-isoallopregnane-3 (XIII).
4,17 according to claim 2 replace 11 beta substitution aromatic bases-4, and the complete synthesizing process of 9-estradiene compounds is characterized in that: h) used dibasic alcohol is an ethylene glycol in the step.
5,17 according to claim 2 replace 11 beta substitution aromatic bases-4, and the complete synthesizing process of 9-estradiene compounds is characterized in that: i) in the step in said 5 (10) oxygen bridge materials (XII), the ratio of αYi Gouti and beta isomer is 7: 3.
6,17 according to claim 2 replace 11 beta substitution aromatic bases-4, and the complete synthesizing process of 9-estradiene compounds is characterized in that: j) used alcohol is methyl alcohol or ethanol in the step.
7,17 according to claim 1 and 2 replace 11 beta substitution aromatic bases-4, the complete synthesizing process of 9-estradiene compounds, it is characterized in that: this compound (XIV) is 11 β-[4-(N, the N-dimethylamino)-and phenyl]-17 α-(1-proyl)-4,9-estradiene-17 β-alcohol-3-ketone.
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| CN102617691B (en) * | 2012-01-18 | 2014-05-14 | 上海新华联制药有限公司 | Improved preparation method for mifepristone intermediate |
| CA2966753A1 (en) | 2014-11-17 | 2016-05-26 | Arno Therapeutics, Inc. | Onapristone extended-release compositions and methods |
| WO2017053793A1 (en) | 2015-09-25 | 2017-03-30 | Arno Therapeutics, Inc. | Methods of making onapristone intermediates |
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| EP0053978A1 (en) * | 1980-12-05 | 1982-06-16 | Roussel-Uclaf | Estra-4,9-diene derivatives, process for their preparation and their utilization as medicines |
| CN85102147A (en) * | 1985-04-01 | 1986-10-29 | 施林股份公司 | Prepare method of 11 beta-arylestradienes and uses thereof |
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| EP0053978A1 (en) * | 1980-12-05 | 1982-06-16 | Roussel-Uclaf | Estra-4,9-diene derivatives, process for their preparation and their utilization as medicines |
| CN85102147A (en) * | 1985-04-01 | 1986-10-29 | 施林股份公司 | Prepare method of 11 beta-arylestradienes and uses thereof |
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