CN103145787A - 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, two (ethylenedioxy)-5 α of 20-, the preparation method of 17 alpha-dihydroxy-s-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 obtains EU Committee's approval listing by the exploitation of HRA drugmaker in May, 2009, is the sexual intercourse of women's unprotect or the contraceptive that orally uses in 120 hours after contraceptive failure.The chemistry of ulipristal acetate is called 17 α-(acetoxyl group)-11 β-[4-(dimethylamino) phenyl]-19-norpregna-4,9-diene-3, and the 20-diketone, structure is as follows:
3,3,20, two (ethylenedioxy)-5 α of 20-, 17 alpha-dihydroxy-s-11 β-[4-(N, N-dimethylamino)-phenyl]-19-norpregna-9 (11)-alkene is the key intermediate of synthetic preparation ulipristal acetate, and structure is as shown in the formula shown in (I):
3,3,20, two (ethylenedioxy)-5 α of 20-, 17 alpha-dihydroxy-s-11 β-[4-(N, the N-dimethylamino)-phenyl]-synthetic method of 19-norpregna-9 (11)-alkene (I), the route of having seen bibliographical information has with 3,3-ethylenedioxy-17 beta-cyano female steroid-5 (10), 9 (11) diene-17 α-alcohol (II) is raw material, after CMDMCS chloromethyl dimethyl chlorosilane silicon etherificate, obtain 3,3-ethylenedioxy-17 beta-cyano-17 α-chloromethyl dimethylsilyl bis female steroid-5 (10), 9 (11) diene (III), yield 98%, again in-70 ℃ through Li/4,4 '-di-t-butyl biphenyl (DBB) effect resets by hydrochloric acid hydrolysis, obtains 17 Alpha-hydroxies-19-norpregna-4,9-diene-3,20-diketone (IV), yield 81%, after spent glycol ketal protection carbonyl, under Perfluoroacetone catalysis, introduce epoxidation with hydrogen peroxide again, obtain 3,3,20, two (ethylenedioxy)-17 Alpha-hydroxy-5 α of 20-, 10 α-epoxy-19-norpregna-9 (11)-alkene (V), yield 39.1%, at last under cuprous chloride catalysis, 3,3,20, two (ethylenedioxy)-17 Alpha-hydroxy-5 α of 20-, 10 α-epoxy-19-norpregna-9 (11)-alkene (V) carries out Isosorbide-5-Nitrae-addition with Grignard reagent 4-dimethylin magnesium bromide, obtain target product 3, two (ethylenedioxy)-5 α of 3,20,20-, 17 alpha-dihydroxy-s-11 β-[4-(N, the N-dimethylamino)-phenyl]-19-norpregna-9 (11)-alkene (I), yield is 76% (Steroids, 2000,65,395～400, US5929262A, CN1298409A, CN101466723A).Reaction formula is as follows:
This route is in preparation 17 Alpha-hydroxies-19-norpregna-4,9-diene-3, during 20-diketone (IV), need to use metallic lithium, and metallic lithium is the very high basic metal of a kind of chemical reactivity, meet water or acid and namely violent burning can occur, releasing hydrogen gas and heat, the utmost point are not suitable for using in large-scale industrial production.Secondly, this route in the end uses cuprous chloride catalyst in an Isosorbide-5-Nitrae-conjugate addition reaction that goes on foot, and the yield of reaction is only 76%, and by product is more, causes difficulty for the purifying of the finished product, is unfavorable for the raising of quality product.
Summary of the invention
The object of the present invention is to provide 3,3,20, two (ethylenedioxy)-5 α of 20-, the preparation method of 17 alpha-dihydroxy-s-11 β-[4-(N, N-dimethylamino)-phenyl]-19-norpregna-9 (11)-alkene (I) is intended to overcome the shortcoming in above-mentioned synthetic method.
Be hydrolyzed again after adopting Grignard reagent and nitrile addition, be one of classical way of preparation ketone (March ' s AdvancedOrganic Chemistry, 5
thEd, 2001, p1217.), classical example report (OrganicSyntheses, 1955, CV3,562 are just arranged in Organic Synthesis; Organic Syntheses, 1973, CV5,520).Studies show that, in the conversion reaction of this class functional group, often use cuprous ion to carry out catalysis (J Org Chem, 1987,52,3901.), and be widely used in synthetic in organic synthesis and day hot product.The people such as Matsuda reported application the method synthesize the preparation Jasmonoid compounds (JOrg Chem, 1980,45,237.).The people such as Rinehart have reported that also application the method comes synthesis of natural product Eudistomins (JAm Chem Soc, 1987,109,3378.).
At α, in the Isosorbide-5-Nitrae-conjugate addition reaction of β unsaturated epoxide and Grignard reagent, cuprous chloride is the catalyzer of commonly using.But show in the people's such as Marshall research, this class reaction not only is conducive to the stereoselectivity of reacting as under the existence of cuprous iodide and dimethyl sulphide and in ether solvent, and raising (the J Am Chem Soc that more is conducive to reaction yield, 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 above methodological inspiration, the present invention designs and has implemented following synthetic 3, 3, 20, two (ethylenedioxy)-5 α of 20-, 17 alpha-dihydroxy-s-11 β-[4-(N, the N-dimethylamino)-phenyl]-method route of 19-norpregna-9 (11)-alkene: with 3, 3-ethylenedioxy-17 beta-cyano female steroid-5 (10), 9 (11) diene-17 α-alcohol (II) is raw material, obtain 3 after the CMDMCS chloromethyl dimethyl chlorosilane protection, 3-ethylenedioxy-17 beta-cyano-17 α-chloromethyl (dimethyl) siloxy female steroid-5 (10), 9 (11) diene (III), III and methyl-magnesium-bromide carry out addition reaction, and obtain 17 Alpha-hydroxies-19-norpregna-4 after acid hydrolysis, 9-diene-3, 20-diketone (IV), IV is through 1, after 2-ethylene glycol carries out the ketal protection, oxidizedly under Perfluoroacetone catalysis obtain 3, 3, 20, two (ethylenedioxy)-17 Alpha-hydroxy-5 α of 20-, 10 α-epoxy-19-norpregna-9 (11)-alkene (V), V and equimolar 4-dimethylaminophenyl magnesium bromide are through 1, the 4-addition obtains 3, 3, 20, two (ethylenedioxy)-5 α of 20-, 17 alpha-dihydroxy-s-11 β-[4-(N, the N-dimethylamino)-phenyl]-19-norpregna-9 (11)-alkene (I).Reaction formula is as follows:
Specifically, preparation method provided by the invention comprises following content:
In tetrahydrofuran solvent, under the existence of DMAP and triethylamine, 3,3-ethylenedioxy-17 beta-cyano female steroid-5 (10), 9 (11) diene-17 α-alcohol (II) and CMDMCS chloromethyl dimethyl chlorosilane at room temperature carries out silicon etherification reaction, obtains 3,3-ethylenedioxy-17 beta-cyano-17 α-chloromethyl (dimethyl) siloxy female steroid-5 (10), 9 (11) diene (III).
Under the existence of cuprous halide, 3,3-ethylenedioxy-17 beta-cyano-17 α-chloromethyl (dimethyl) siloxy female steroid-5 (10), 9 (11) diene (III) react in suitable organic solvent with methyl-magnesium-bromide, acidic hydrolysis obtains 17 Alpha-hydroxies-19-norpregna-4 again, 9-diene-3,20-diketone (IV).Wherein cuprous halide is selected from cuprous chloride, cuprous bromide or cuprous iodide, organic solvent is selected from one or more mixtures in ether, isopropyl ether, uncle's butyl ether, tetrahydrofuran (THF), benzene,toluene,xylene, temperature of reaction is 10～100 ℃, 3, the mol ratio of 3-ethylenedioxy-17 beta-cyano-17 α-chloromethyl (dimethyl) siloxy female steroid-5 (10), 9 (11) diene and cuprous halide is 1: 0.05～1.
In methylene dichloride, under the existence of triethyl orthoformate and tosic acid, 17 Alpha-hydroxies-19-norpregna-4,9-diene-3,20-diketone (IV) and ethylene glycol are after being dehydrated into ketal, after conventional aftertreatment, then under Perfluoroacetone exists, obtain 3 through hydrogen peroxide oxidation, 3, two (ethylenedioxy)-17 Alpha-hydroxy-5 α of 20,20-, 10 α-epoxy-19-norpregna-9 (11)-alkene (V).
Under the existence of dimethyl sulphide and cuprous halide, 3,3, two (ethylenedioxy)-17 Alpha-hydroxy-5 α of 20,20-, 10 α-epoxy-19-norpregna-9 (11)-alkene (V) is in suitable organic solvent, occur 1 with 4-dimethylaminophenyl magnesium bromide, the 4-addition reaction obtains 3,3,20, two (ethylenedioxy)-5 α of 20-, 17 alpha-dihydroxy-s-11 β-[4-(N, N-dimethylamino)-phenyl]-19-norpregna-9 (11)-alkene; Wherein cuprous halide is selected from cuprous bromide, cuprous iodide, and organic solvent is selected from one or more mixtures in ether, isopropyl ether, uncle's butyl ether, tetrahydrofuran (THF), benzene,toluene,xylene, and temperature of reaction is-10～100 ℃.
The raw material that method provided by the invention is used is more safe and reliable, reacts more easy to control, and yield and the selectivity of reaction are higher, are more suitable for suitability for industrialized production.
Embodiment
Following exemplary embodiments is used for illustrating the present invention, within simple replacement that those skilled in the art do the present invention or improvement etc. all belong to the technical scheme that the present invention protects.
Embodiment 1:3,3-ethylenedioxy-17 beta-cyano-17 α-chloromethyl (dimethyl) siloxy female steroid-5 (10), the preparation of 9 (11) diene (III)
With 3,3-ethylenedioxy-17 beta-cyano female steroid-5 (10), 9 (11) diene-17 α-alcohol (II) 170.5g and 5L tetrahydrofuran (THF) join in reaction flask successively, open and stir, be cooled to 5 ℃, add DMAP 12.2g, triethylamine 96.5mL, drip CMDMCS chloromethyl dimethyl chlorosilane 79.0mL, stirring at room reaction 12h.Be evaporated to driedly under room temperature, add methylene dichloride 1500mL, under stirring, reaction solution is poured in the 800mL saturated sodium bicarbonate aqueous solution.Be concentrated into driedly under separatory, organic phase decompression, add isopropyl ether 500mL, filter, the filter cake forced air drying gets off-white color solid 219.5g, yield 98.0%.
Embodiment 2:17 Alpha-hydroxy-19-norpregna-4,9-diene-3, the preparation of 20-diketone (IV)
With 3,3-ethylenedioxy-17 beta-cyano-17 α-chloromethyl (dimethyl) siloxy female steroid-5 (10), 9 (11) diene (III) 219.5g join in the mixed solvent of 500mL toluene and 500mL tetrahydrofuran (THF), after stirring 15min under room temperature, add cuprous bromide 7.0g, drip under room temperature.Dropwise rear continuation stirring reaction 23h, remove solvent under reduced pressure, the dilute hydrochloric acid that slowly adds 300mL 5%, after continuing at room temperature to stir 30min, with dichloromethane extraction secondary (500mL * 2), organic phase is respectively washed once with 300mL saturated aqueous common salt, water successively, filter after anhydrous magnesium sulfate drying, filtrate is concentrated into dried, obtains product 142.2g, yield 92.3%.
Embodiment 3:3, two (ethylenedioxy)-17 Alpha-hydroxy-5 α of 3,20,20-, the preparation (V) of 10 α-epoxy-19-norpregna-9 (11)-alkene
With 17 Alpha-hydroxies-19-norpregna-4,9-diene-3, open after 20-diketone 138.7g (IV), 122.9mL ethylene glycol and 1500mL methylene dichloride mix and stir, drip the 200mL dichloromethane solution of triethyl orthoformate (220.4mL) under room temperature.Drip and finish, add the 5.1g tosic acid, continue under room temperature to stir after 18 hours, slowly drip the 700mL saturated sodium bicarbonate solution.Drip and finish, separatory, organic phase is respectively washed once with saturated aqueous common salt, water 700mL successively.Organic phase is after anhydrous magnesium sulfate drying, filter, add the 71.2g Perfluoroacetone in gained methylene dichloride filtrate, open to stir and be cooled to 4 ℃, drip Sodium phosphate dibasic (25g) mixing solutions of 30% hydrogen peroxide (125mL), drip and finish, continue to stir 25min, drip the 10% sodium sulfide solution 1000mL of 4 ℃.Separatory, organic phase dichloromethane extraction (1000mL * 2).Merging organic interdependent time respectively washes once with saturated aqueous common salt, water 800mL.Organic phase is filtered after anhydrous magnesium sulfate drying, and filtrate is concentrated into dried, adds the 400mL methyl tertiary butyl ether in resistates, and 4 ℃ are stirred 1h, and filtration drying obtains product 198.8g, yield 56%.
Embodiment 4:3, two (ethylenedioxy)-5 α of 3,20,20-, the preparation (I) of 17 alpha-dihydroxy-s-11 β-[4-(N, N-dimethylamino)-phenyl]-19-norpregna-9 (11)-alkene
With two (ethylenedioxy)-17 Alpha-hydroxy-5 α of 3,3,20,20-, 10 α-epoxy-19-norpregna-9 (11)-alkene (V) 138.5g, cuprous iodide 6.3g, dimethyl sulphide 25mL join the 1500mL tetrahydrofuran (THF).Open and stir, drip the tetrahydrofuran solution (500mL) of the 4-dimethylaminophenyl magnesium bromide of 73.6g under room temperature, continue to stir 1～2h, TLC detects until react completely.Drip 20% ammonium chloride solution 2000mL, vigorous stirring 10min.Tell the tetrahydrofuran (THF) phase, add the 1000mL dichloromethane extraction, separatory, organic phase is successively with 20% ammonium chloride solution, each 1000mL washing of 2N sodium hydroxide solution once.Organic phase is filtered after anhydrous magnesium sulfate drying, and filtrate is concentrated into dried off-white color solid 166.1g, the yield 93% of obtaining.
Claims (5)
1. one kind prepares 3,3,20, two (ethylenedioxy)-5 α of 20-, the novel method of 17 alpha-dihydroxy-s-11 β-[4-(N, N-dimethylamino)-phenyl]-19-norpregna-9 (11)-alkene is characterized in that described preparation method comprises the following steps:
(a) in tetrahydrofuran solvent, under the existence of DMAP and triethylamine, (17 α)-3,3-[1,2-second two base is two-and (oxygen)]-17-hydroxy-estra-5 (1), 9 (11)-diene-17-cyano group and CMDMCS chloromethyl dimethyl chlorosilane carry out silicon etherification reaction, obtain 3,3-ethylenedioxy-17 beta-cyano-17 α-chloromethyl (dimethyl) siloxy female steroid-5 (10), 9 (11) diene;
(b) under the existence of cuprous halide, 3,3-ethylenedioxy-17 beta-cyano-17 α-chloromethyl (dimethyl) siloxy female steroid-5 (10), 9 (11) diene and methyl-magnesium-bromide react in suitable organic solvent, acidic hydrolysis obtains 17 Alpha-hydroxies-19-norpregna-4 again, 9-diene-3, the 20-diketone; Wherein cuprous halide is selected from cuprous chloride, cuprous bromide or cuprous iodide, organic solvent is selected from one or more mixtures in ether, isopropyl ether, uncle's butyl ether, tetrahydrofuran (THF), benzene,toluene,xylene, temperature of reaction is 10～100 ℃, 3, the mol ratio of 3-ethylenedioxy-17 beta-cyano-17 α-chloromethyl (dimethyl) siloxy female steroid-5 (10), 9 (11) diene and cuprous halide is 1: 0.05～1;
(c) in methylene dichloride, under the existence of triethyl orthoformate and tosic acid, 17 Alpha-hydroxies-19-norpregna-4,9-diene-3,20-diketone and ethylene glycol are after being dehydrated into ketal, after conventional aftertreatment, then under Perfluoroacetone exists, obtain 3 through hydrogen peroxide oxidation, 3, two (ethylenedioxy)-17 Alpha-hydroxy-5 α of 20,20-, 10 α-epoxy-19-norpregna-9 (11)-alkene;
(d) under the existence of dimethyl sulphide and cuprous halide, 3,3, two (ethylenedioxy)-17 Alpha-hydroxy-5 α of 20,20-, 10 α-epoxy-19-norpregna-9 (11)-alkene is in suitable organic solvent, occur 1 with 4-dimethylaminophenyl magnesium bromide, the 4-addition reaction obtains 3,3,20, two (ethylenedioxy)-5 α of 20-, 17 alpha-dihydroxy-s-11 β-[4-(N, N-dimethylamino)-phenyl]-19-norpregna-9 (11)-alkene; Wherein cuprous halide is selected from cuprous bromide, cuprous iodide, and organic solvent is selected from one or more mixtures in ether, isopropyl ether, uncle's butyl ether, tetrahydrofuran (THF), benzene,toluene,xylene, and temperature of reaction is-10～100 ℃.
2. method according to claim 1 is characterized in that in step (b) organic solvent is selected from one or more mixtures in ether, isopropyl ether, uncle's butyl ether, tetrahydrofuran (THF), benzene,toluene,xylene, wherein preferred ether or tetrahydrofuran (THF).
3. method according to claim 1, it is characterized in that in step (b) 3,3-ethylenedioxy-17 beta-cyano-17 α-chloromethyl (dimethyl) siloxy female steroid-5 (10), the mol ratio of 9 (11) diene and cuprous halide is 1: 0.05～1, wherein preferred 1: 0.05～0.3.
4. method according to claim 1, is characterized in that having used catalysis Isosorbide-5-Nitrae-addition reaction under dimethyl sulphide and the cuprous common existence of halo in step (d).
5. method according to claim 1 is characterized in that in step (d) organic solvent is selected from one or more mixtures in ether, isopropyl ether, uncle's butyl ether, tetrahydrofuran (THF), benzene,toluene,xylene, wherein preferred ether or tetrahydrofuran (THF).
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103641881A (en) * | 2013-11-22 | 2014-03-19 | 湖南新合新生物医药有限公司 | Preparation method for Ulipristal intermediate |
| CN107200770A (en) * | 2016-03-18 | 2017-09-26 | 华东师范大学 | Eposide isomers efficiently separates and circulation utilization method in special plast ketone synthesis |
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| US6020328A (en) * | 1998-03-06 | 2000-02-01 | Research Triangle Institute | 20-keto-11β-arylsteroids and their derivatives having agonist or antagonist hormonal properties |
| HU227112B1 (en) * | 2006-06-14 | 2010-07-28 | Richter Gedeon Nyrt | Industrial process for the synthesis of 17alpha-acetoxy-11betha-[4-(n,n-dimethyl-amino)-phenyl]-19-norpregna-4,9-diene-3,20-dione and the new intermediates of the process |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103641881A (en) * | 2013-11-22 | 2014-03-19 | 湖南新合新生物医药有限公司 | Preparation method for Ulipristal intermediate |
| CN107200770A (en) * | 2016-03-18 | 2017-09-26 | 华东师范大学 | Eposide isomers efficiently separates and circulation utilization method in special plast ketone synthesis |
| 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 |
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