CN103145787B - Novel preparation method of ulipristal acetate key intermediate - Google Patents
Novel preparation method of ulipristal acetate key intermediate Download PDFInfo
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Abstract
The invention discloses a novel preparation method of ulipristal acetate key intermediate 3,3,20,20-double (ethylenedioxy group)-5 alpha, 17 alpha- dihydroxyl-11 bata-[4-(N,N- dimethyl amidogen)- phenyl]-19-norprogesterone-9(11)-alkene, namely 3,3- ethylenedioxy group-17 beta-cyangroup female steroid-5(10), 9(11) diene-17 alpha-alcohol is used as a raw material, through the protection of hydroxyl, the addition of Grignard reagent and cyangroup, and the protection of ketal, and the target compound is obtained finally through 1,4 addition of alpha, beta unsaturation epoxide under the catalysis of a system of cuprous halides and dimethyl sulfide. The raw materials used in the method are safe and reliable, reaction is easy to control, reaction yield and stereoselectivity are high, and the method is applicable for industrial production.
Description
Technical field
The present invention relates to ulipristal acetate key intermediate 3,3,20,20- double (ethylenedioxy) -5 α, 17 α-dihydroxy
The preparation method of base -11 β-[4- (N, N- dimethylamino)-phenyl] -19- norpregna -9 (11)-alkene.
Background technology
Ulipristal acetate is a kind of progesterone receptor modulator, and this medicine is developed by HRA drugmaker, in May, 2009
Obtain EU Committee's approval listing, be women's unprotect sexual intercourse or the contraceptive orally using in 120 hours after contraceptive failure
Thing.Entitled 17 α of chemistry-(acetoxyl group) -11 β of ulipristal acetate-[4- (dimethylamino) phenyl] -19- norpregna -
4,9- diene -3,20- diketone, structure is as follows：
3,3,20,20- double (ethylenedioxy) -5 α, 17 alpha-dihydroxy -11 β-[4- (N, N- dimethylamino)-phenyl] -
19- norpregna -9 (11)-alkene is the key intermediate of synthetically prepared ulipristal acetate, shown in structure such as following formula (I)：
3,3,20,20- double (ethylenedioxy) -5 α, 17 alpha-dihydroxy -11 β-[4- (N, N- dimethylamino)-phenyl] -
The synthetic method of 19- norpregna -9 (11)-alkene (I), has been shown in that the route of document report has with 3,3- ethylenedioxy -17 β-cyanogen
Base female steroid -5 (10), 9 (11) diene -17 α -ol (II) is raw material, after CMDMCS chloromethyl dimethyl chlorosilane silicon etherificate, obtains 3,3-
Ethylenedioxy -17 beta-cyano -17 α-chloromethyl dimethylsilyl bis female steroid -5 (10), 9 (11) diene (III), yield 98%；
Then at -70 DEG C through Li/4,4 '-di-t-butyl biphenyl (DBB) effect hydrolyzes through hydrochloric acid after resetting, and obtains 17 Alpha-hydroxy -19- nor-
Pregnant steroid -4,9- diene -3,20- diketone (IV), yield 81%；Again after spent glycol ketal protection carbonyl, in Hexafluoro acetone catalysis
Under, introduce epoxidation with hydrogen peroxide, obtain 3,3,20,20- double (ethylenedioxy) -17 Alpha-hydroxy -5 α, 10 α-epoxy -19-
Norpregna -9 (11)-alkene (V), yield 39.1%；Under the last catalysis in Cu-lyt., 3,3,20,20- double (sub- second dioxies
Base) -17 Alpha-hydroxy -5 α, 10 α-epoxy -19- norpregna -9 (11)-alkene (V) entered with Grignard reagent 4- dimethylamino magnesium bromide
Row Isosorbide-5-Nitrae-addition, obtains target product 3,3,20,20- double (ethylenedioxy) -5 α, 17 alpha-dihydroxy -11 β-[4- (N, N- bis-
Methylamino)-phenyl] -19- norpregna -9 (11)-alkene (I), yield be 76% (Steroids, 2000,65,395～400；
US5929262A；CN1298409A；CN101466723A).Reaction equation is as follows：
This route, in preparation 17 Alpha-hydroxy -19- norpregna -4,9- diene -3, during 20- diketone (IV), need to use metal
Lithium, and lithium metal is a kind of very high alkali metal of chemical reactivity, meets water or acid can occur vigorous combustion, release hydrogen and
Heat, pole is not suitable for using in large-scale industrial production.Secondly, this route is in the Isosorbide-5-Nitrae-conjugate addition reaction of final step
Middle use cuprous chloride catalyst, the yield of reaction is only 76%, and by-product is more, causes difficulty to the purification of final products,
It is unfavorable for the raising of product quality.
Content of the invention
It is an object of the invention to provide 3,3,20,20- double (ethylenedioxy) -5 α, 17 alpha-dihydroxy -11 β-[4- (N,
N- dimethylamino)-phenyl] -19- norpregna -9 (11)-alkene (I) preparation method it is intended to overcome in above-mentioned synthetic method
Shortcoming.
It is hydrolyzed using after Grignard reagent and nitrile addition, be to prepare one of classical way of ketone (March ' s again
AdvancedOrganic Chemistry, 5thEd, 2001, p1217.), just have classics in Organic Synthesis
Example report (OrganicSyntheses, 1955, CV3,562；Organic Syntheses, 1973, CV5,520).Research table
Bright, in this class functional group conversions reaction, often it is catalyzed (J Org Chem, 1987,52,3901.) using cuprous ion, and
It is widely used in organic synthesiss and the synthesis of sky hot.It is next synthetically prepared that Matsuda et al. reports application the method
Jasmonoid class compound (JOrg Chem, 1980,45,237.).Rinehart et al. also reports application the method to close
Become natural product Eudistomins (JAm Chem Soc, 1987,109,3378.).
In α, in the Isosorbide-5-Nitrae-conjugate addition reaction of β unsaturated epoxide and Grignard reagent, Cu-lyt. is conventional urging
Agent.But show in the research of Marshall et al., the reaction of this class is as in the presence of Hydro-Giene (Water Science). and dimethyl sulphide
With in ether solvent, not only contribute to the stereo selectivity reacted, and be more beneficial for raising (the J Am Chem of reaction yield
Soc, 1983,105,3360.；J Am Chem Soc, 1983,105,6515.；J Am Chem Soc, 1984,106,723.；J
Am Chem Soc, 1984,106,6006.；J Org Chem, 1984,49,1707.；J Org Chem, 1987,52,
1106.).
Under the inspiration of above method, the present invention designs and implements double (the sub- second dioxy of following synthesis 3,3,20,20-
Base) -5 α, the method road of 17 alpha-dihydroxy -11 β-[4- (N, N- dimethylamino)-phenyl] -19- norpregna -9 (11)-alkene
Line：With 3,3- ethylenedioxy -17 beta-cyano female steroid -5 (10), 9 (11) diene -17 α -ol (II) is raw material, through chloromethyl two
3,3- ethylenedioxy -17 beta-cyano -17 α-chloromethyl (dimethyl) siloxy female steroid -5 is obtained after methylchlorosilane protection
(10), 9 (11) diene (III), III and methyl-magnesium-bromide carry out additive reaction, and obtain 17 Alpha-hydroxy -19- after acid hydrolysis
Norpregna -4,9- diene -3,20- diketone (IV), IV is carried out after ketal protection through 1，2-ethandiol, under Hexafluoro acetone catalysis
Oxidized obtain 3,3,20,20- double (ethylenedioxy) -17 Alpha-hydroxy -5 α, 10 α-epoxy -19- norpregna -9 (11)-alkene
(V), V and equimolar 4- dimethylaminophenyl magnesium bromide obtain 3,3,20,20- double (ethylenedioxy) -5 α through Isosorbide-5-Nitrae-addition,
17 alpha-dihydroxy -11 β-[4- (N, N- dimethylamino)-phenyl] -19- norpregna -9 (11)-alkene (I).The following institute of reaction equation
Show：
Specifically, the preparation method that the present invention provides includes following content：
In tetrahydrofuran solvent, in the presence of DMAP and triethylamine, 3,3- ethylenedioxy -17 β -
Cyano group female steroid -5 (10), 9 (11) diene -17 α -ol (II) and CMDMCS chloromethyl dimethyl chlorosilane, carry out silicon etherificate anti-at room temperature
Should, obtain 3,3- ethylenedioxy -17 beta-cyano -17 α-chloromethyl (dimethyl) siloxy female steroid -5 (10), 9 (11) diene
(III).
In the presence of cuprous halide, 3,3- ethylenedioxy -17 beta-cyano -17 α-chloromethyl (dimethyl) siloxy is female
Steroid -5 (10), 9 (11) diene (III) are reacted in suitable organic solvent with methyl-magnesium-bromide, then acidic hydrolysises obtain
17 Alpha-hydroxy -19- norpregna -4,9- diene -3,20- diketone (IV).Wherein cuprous halide is selected from Cu-lyt., cuprous bromide
Or Hydro-Giene (Water Science)., organic solvent is selected from one of ether, diisopropyl ether, tertiary butyl ether, oxolane, benzene,toluene,xylene or many
Plant mixture, reaction temperature is 10～100 DEG C, 3,3- ethylenedioxy -17 beta-cyano -17 α-chloromethyl (dimethyl) siloxy
Female steroid -5 (10), 9 (11) diene are 1: 0.05～1 with the mol ratio of cuprous halide.
In dichloromethane, in the presence of triethyl orthoformate and p-methyl benzenesulfonic acid, 17 Alpha-hydroxy -19- norpregnas -
4,9- diene -3,20- diketone (IV) and ethylene glycol, through being dehydrated into after ketal, after conventional post processing, then exist in Hexafluoro acetone
Under, obtain 3,3,20,20- double (ethylenedioxy) -17 Alpha-hydroxy -5 α through hydrogen peroxide oxidation, 10 α-epoxy -19- norpregna -
9 (11)-alkene (V).
In the presence of dimethyl sulphide and cuprous halide, 3,3,20,20- double (ethylenedioxy) -17 Alpha-hydroxy -5 α, 10
α-epoxy -19- norpregna -9 (11)-alkene (V), in suitable organic solvent, occurs 1 with 4- dimethylaminophenyl magnesium bromide,
4- additive reaction, obtains 3,3,20,20- double (ethylenedioxy) -5 α, 17 alpha-dihydroxy -11 β-[4- (N, N- dimethylamino
Base)-phenyl] -19- norpregna -9 (11)-alkene；Wherein cuprous halide is selected from cuprous bromide, Hydro-Giene (Water Science)., and organic solvent is selected from
One or more of ether, diisopropyl ether, tertiary butyl ether, oxolane, benzene,toluene,xylene mixture, reaction temperature is -10
～100 DEG C.
The raw material that used of method that the present invention provides is more safe and reliable, and reaction is more easy to control, the yield of reaction and choosing
Selecting property is higher, is more suitable for industrialized production.
Specific embodiment
Following exemplary embodiments are used for illustrating the present invention, the letter that technical staff in the art is done to the present invention
Single replacement or improvement etc. belong within the technical scheme that the present invention is protected.
Embodiment 1：3,3- ethylenedioxy -17 beta-cyano -17 α-chloromethyl (dimethyl) siloxy female steroid -5 (10), 9
(11) preparation (III) of diene
By 3,3- ethylenedioxy -17 beta-cyano female steroid -5 (10), 9 (11) diene -17 α -ol (II) 170.5g and 5L tetra-
Hydrogen furan is added sequentially in reaction bulb, opens stirring, is cooled to 5 DEG C, adds DMAP 12.2g, triethylamine
96.5mL, Deca CMDMCS chloromethyl dimethyl chlorosilane 79.0mL, are stirred at room temperature reaction 12h.It is evaporated to dry under room temperature, add two
Chloromethanes 1500mL, under stirring pours reactant liquor in 800mL saturated sodium bicarbonate aqueous solution into.Divide liquid, dense under organic faciess decompression
It is reduced to dry, adds diisopropyl ether 500mL, filter, filter cake forced air drying obtains off-white powder 219.5g, yield 98.0%.
Embodiment 2：17 Alpha-hydroxy -19- norpregna -4,9- diene -3, the preparation (IV) of 20- diketone
By 3,3- ethylenedioxy -17 beta-cyano -17 α-chloromethyl (dimethyl) siloxy female steroid -5 (10), 9 (11) two
Alkene (III) 219.5g is added in 500mL toluene and the mixed solvent of 500mL oxolane, after stirring 15min under room temperature, plus
Enter cuprous bromide 7.0g, Deca under room temperature.Continue stirring reaction 23h after completion of dropping, remove solvent under reduced pressure, be slowly added to
The dilute hydrochloric acid of 300mL 5%, after continuing 30min is stirred at room temperature, extracts secondary (500mL × 2) with dichloromethane, organic faciess
Respectively washed once with 300mL saturated aqueous common salt, water successively, filter after being dried through anhydrous magnesium sulfate, filtrate is concentrated to dryness, and obtains product
142.2g, yield 92.3%.
Embodiment 3：3,3,20,20- double (ethylenedioxy) -17 Alpha-hydroxy -5 α, 10 α-epoxy -19- norpregna -9
(11) preparation (V) of-alkene
By 17 Alpha-hydroxy -19- norpregna -4,9- diene -3,20- diketone 138.7g (IV), 122.9mL ethylene glycol and
Stirring is opened, under room temperature, the 200mL dichloromethane of Deca triethyl orthoformate (220.4mL) is molten after the mixing of 1500mL dichloromethane
Liquid.Drip and finish, add 5.1g p-methyl benzenesulfonic acid, after continuing stirring under room temperature 18 hours, be slowly added dropwise 700mL saturated sodium bicarbonate molten
Liquid.Drip and finish, point liquid, organic faciess are respectively washed once with saturated aqueous common salt, water 700mL successively.After organic faciess are dried through anhydrous magnesium sulfate,
Filter, in gained dichloromethane filtrate, add 71.2g Hexafluoro acetone, open stirring and be cooled to 4 DEG C, Deca 30% hydrogen peroxide
(125mL) disodium hydrogen phosphate (25g) mixed solution, drips and finishes, and continues stirring 25min, 10% sodium sulfide solution of 4 DEG C of Deca
1000mL.Divide liquid, organic faciess extract (1000mL × 2) with dichloromethane.Merge organic interdependent secondary saturated aqueous common salt, water
800mL respectively washes once.After organic faciess are dried through anhydrous magnesium sulfate, filter, filtrate is concentrated to dryness, in residue, add 400mL first
Base tertbutyl ether, 4 DEG C of stirring 1h, filtration drying obtains product 198.8g, yield 56%.
Embodiment 4：3,3,20,20- double (ethylenedioxy) -5 α, 17 alpha-dihydroxy -11 β-[4- (N, N- dimethylamino
Base)-phenyl] -19- norpregna -9 (11)-alkene preparation (I)
By 3,3,20,20- double (ethylenedioxy) -17 Alpha-hydroxy -5 α, 10 α-epoxy -19- norpregna -9 (11)-alkene
(V) 138.5g, Hydro-Giene (Water Science). 6.3g, dimethyl sulphide 25mL are added to 1500mL oxolane.Open stirring, Deca under room temperature
The tetrahydrofuran solution (500mL) of the 4- dimethylaminophenyl magnesium bromide of 73.6g, continues stirring 1～2h, TLC detection is up to instead
Should be completely.Deca 20% ammonium chloride solution 2000mL, is stirred vigorously 10min.Separate oxolane phase, add 1000mL dichloro
Methane extracts, point liquid, and organic faciess be washed once with 20% ammonium chloride solution, each 1000mL of 2N sodium hydroxide solution successively.Organic
After being dried through anhydrous magnesium sulfate, filter, filtrate is concentrated to dryness and obtains off-white powder 166.1g, yield 93%.
Claims (4)
1. one kind prepares 3,3,20,20- double (ethylenedioxy) -5 α, and 17 alpha-dihydroxy -11 β-[4- (N, N- dimethylamino) -
Phenyl] -19- norpregna -9 (11)-alkene method it is characterised in that described preparation method comprises the following steps：
(a) in tetrahydrofuran solvent, in the presence of DMAP and triethylamine, (17 α) -3,3- [1,2- second two
Base is double-and (oxygen)] -17- hydroxy-estra -5 (1), 9 (11)-diene -17- cyano group and CMDMCS chloromethyl dimethyl chlorosilane carry out silicon etherificate
Reaction, obtains 3,3- ethylenedioxy -17 beta-cyano -17 α-chloromethyl (dimethyl) siloxy female steroid -5 (10), 9 (11) two
Alkene；
B (), in the presence of cuprous halide, 3,3- ethylenedioxy -17 beta-cyano -17 α-chloromethyl (dimethyl) siloxy is female
Steroid -5 (10), 9 (11) diene and methyl-magnesium-bromide are reacted in suitable organic solvent, then acidic hydrolysises obtain 17 α-hydroxyl
Base -19- norpregna -4,9- diene -3,20- diketone；Wherein cuprous halide be selected from cuprous bromide, organic solvent be selected from ether,
One or more of diisopropyl ether, tertiary butyl ether, oxolane, benzene,toluene,xylene mixture, reaction temperature is 10～100
DEG C, 3,3- ethylenedioxy -17 beta-cyano -17 α-chloromethyl (dimethyl) siloxy female steroid -5 (10), 9 (11) diene and halogenation
Cuprous mol ratio is 1: 0.05～1；
(c) in dichloromethane, in the presence of triethyl orthoformate and p-methyl benzenesulfonic acid, 17 Alpha-hydroxy -19- norpregnas -
4,9- diene -3,20- diketone and ethylene glycol through being dehydrated into after ketal, after conventional post processing, then in the presence of Hexafluoro acetone, warp
Hydrogen peroxide oxidation obtains 3,3,20,20- double (ethylenedioxy) -17 Alpha-hydroxy -5 α, 10 α-epoxy -19- norpregna -9
(11)-alkene；
(d) in the presence of dimethyl sulphide and cuprous halide, 3,3,20,20- double (ethylenedioxy) -17 Alpha-hydroxy -5 α, 10 α -
Epoxy -19- norpregna -9 (11)-alkene in suitable organic solvent, with 4- dimethylaminophenyl magnesium bromide occur Isosorbide-5-Nitrae-plus
Become reaction, obtain 3,3,20,20- double (ethylenedioxy) -5 α, 17 alpha-dihydroxy -11 β-[4- (N, N- dimethylamino)-benzene
Base] -19- norpregna -9 (11)-alkene；Wherein cuprous halide is selected from Hydro-Giene (Water Science)., and organic solvent is selected from ether, diisopropyl ether, uncle
One or more of butyl ether, oxolane, benzene,toluene,xylene mixture, reaction temperature is -10～100 DEG C.
2. method according to claim 1 is it is characterised in that organic solvent is in ether or oxolane in step (b)
A kind of or both solvents mixing.
3. method according to claim 1 it is characterised in that in step (b) 3,3- ethylenedioxy -17 beta-cyano -17
α-chloromethyl (dimethyl) siloxy female steroid -5 (10), 9 (11) diene is 1: 0.05～0.3 with the mol ratio of cuprous halide.
4. method according to claim 1 is it is characterised in that organic solvent is in ether or oxolane in step (d)
A kind of or both solvents mixing.
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| CN107200770B (en) * | 2016-03-18 | 2019-11-01 | 华东师范大学 | In the synthesis of special plast ketone eposide isomers efficiently separate and circulation utilization method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1298409A (en) * | 1998-03-06 | 2001-06-06 | 研究三角协会 | 20-keto-11&beta, -arylsteroids and their derivatives having agonist or antagonist hormonal properties |
| CN101466723A (en) * | 2006-06-14 | 2009-06-24 | 吉瑞工厂 | Industrial process for the synthesis of 17 alpha-acetoxy-11 beta- [ 4- (N, N-dimethyl-amino) -phenyl ] -19-norpregna-4, 9-diene-3, 20-dione and novel intermediates used in said process |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1298409A (en) * | 1998-03-06 | 2001-06-06 | 研究三角协会 | 20-keto-11&beta, -arylsteroids and their derivatives having agonist or antagonist hormonal properties |
| CN101466723A (en) * | 2006-06-14 | 2009-06-24 | 吉瑞工厂 | Industrial process for the synthesis of 17 alpha-acetoxy-11 beta- [ 4- (N, N-dimethyl-amino) -phenyl ] -19-norpregna-4, 9-diene-3, 20-dione and novel intermediates used in said process |
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