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Synthesis of estetrol via estrone derived steroids

Inactive Publication Date: 2006-09-21
DONESTA BIOSCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0048] In another aspect of the invention, there is provided the use of the obtained compound as estrogenic substance, preferably for cosmetic and / or therapeutic applications selected from hormone replacement therapy, contraception, therapy of autoimmune diseases, prevention and therapy of breast and colon tumors, enhancement of libido, skin care, and wound healing.

Problems solved by technology

Furthermore, it has also been found that by following the prior art methods mentioned above, estetrol of high purity was obtained only in low yield when using an acetyl group as a protecting group for the 3-hydroxy group of estra-1,3,5(10),15-tetraen-3-ol-17-one, in particular because its sensitivity to hydrolysis and solvolysis.
In particular, the lability of the acetyl group lead not only to an increased formation of byproducts during the reactions, but also during chromatography and crystallisation for purification of intermediate products when protic solvents such as methanol were used.
Therefore, it is difficult to isolate purified estetrol and intermediates thereof in good yield.
Obviously, the formation of such a by-product reduces the yield as well as the purity of the desired product which requires additional purification steps.
The prior art methods also employ stoichiometric amounts of OsO4 in the oxidation step that is known to be a toxic and expensive compound.
Consequently, the use of such a reagent is undesired in view of safety and operational costs.
Indeed, a problem with industrial syntheses are the quantities of chemicals as well as the toxicity and hazardous properties thereof which are involved, thus making the prior art lab-scale methods not transposable to an industrial scale.
The reason behind such impossible replication is that usually the known method either does not provide a sufficient yield, i.e. at least 10% to be considered economically feasible from an industrial point of view and / or produce by-product(s) which necessitates at least a subsequent purification step, thus raising the cost of the method.

Method used

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  • Synthesis of estetrol via estrone derived steroids
  • Synthesis of estetrol via estrone derived steroids
  • Synthesis of estetrol via estrone derived steroids

Examples

Experimental program
Comparison scheme
Effect test

example 1

3-Benzyloxy-estra-1,3,5(10)-trien-17-one (compound 6, A=benzyl)

[0125] To a suspension of estrone (7; 100 g, 0.370 mol) and K2CO3 (160 g, 1.16 mol) in DCM / MeOH (800 mL, 1:1 v / v ratio) at room temperature was added benzyl bromide (132 mL, 1.10 mol) in one portion. The resulting mixture was refluxed for 16 h (50% conversion after 4 h according to TLC). The reaction mixture was cooled to RT and solids were filtered off. The filter-cake was washed with MeOH. The solution was concentrated (to a total volume of ca. 300 mL). The precipitate that had formed was collected by filtration and washed with heptanes to give a white solid. The filtrate was concentrated further (to a total volume of 100 mL) and triturated with heptane. The resulting precipitate was filtered off and combined with the first batch of product. The product (153 g, max 0.370 mol) still contained traces off benzyl bromide but was used without further purification. The product can be purified by recrystallization from DCM / M...

example 2

17,17-Ethylenedioxy-3-benzyloxy estra-1,3,5(10)-trien-17-one (compound 4; A=benzyl, C=ethylene dioxy)

[0126] 3-Benzyl-estrone (compound 6, A=benzyl; 153 g (crude), max. 0.370 mol) was suspended in a mixture of triethyl orthoformate (320 mL) and ethylene glycol (160 mL). p-TsOH monohydrate (5 g, 26.3 mmol) was added and the resulting pinkish suspension was stirred for 3 h at 35° C. (TLC indicated complete conversion after 1.5 h). The mixture was cooled to RT, poured into a mixture of ice-water (2 L) and pyridine (40 mL). The resulting precipitate was collected by filtration and washed with water (150 ml). The remaining white solid was dried azeotropically by stripping with toluene (2×200 mL) to afford the product (153 g, max. 0.370 mmol) as white crystalline material. TLC: Rf=0.3 (heptanes / ethyl acetate=9 / 1); 1H-NMR (200 MHz, CDCl3) δ 7.60-7.24 (m, 5H), 7.29 (d, 1H, J=8.4 Hz), 6.86 (dd, 1H, J1=2.6 Hz, J2=8.4 Hz), 6.80 (d, 1H, J=2.4 Hz), 5.11 (s, 2H), 4.03 (m, 4H), 3.05-2.90 (m, 2H), ...

example 3

17,17-Ethylenedioxy-3-benzyloxy estra-1,3,5(10)-trien-17-one (compound 4; A=benzyl, C=ethylene dioxy)

[0127] A reaction flask equipped with mechanical stirrer, thermometer, nitrogen purge, condenser and dropping funnel was used for the process. The flask was charged with 27 g (100 mmol) of estrone, 50 ml (55 g, 9 equivalents) of glycol and 24 g of triethylorthoformate. The resulting mixture was stirred. 0.5 g of toluenesulfonic acid was added and the reaction temperature was raised to 45° C. At about 35-40° C. an exothermic was observed. The slurry is stirred for 1 hour at 45° C. The conversion is checked with LC. Usually after 1 hour almost complete conversion is observed. To the slurry a solution of sodium methoxide in methanol (30% wt.; 1.1 equivalents) is added from the dropping funnel resulting in a clear yellow solution. The temperature is raised to 65° C. and 15 g of benzyl chloride is added over 5 minutes. Within a few minutes the solution becomes turbid and slowly thickens ...

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Abstract

A process is provided for the making of estetrol starting from a 3-A-oxy-estra 1,3,5(10),15-tetraen-17-one, wherein A is a C1-C5 alkyl group, preferably a methyl group, or a C7-C12 benzylic group, preferably a benzyl group. This process is particularly suitable to industry.

Description

TECHNICAL FIELD OF THE INVENTION [0001] The present invention relates to the synthesis of estetrol [estra-1,3,5(10)-trien-3,15α,16α,17β-tetraol; CAS Nr. 15183-37-6; for convenience, this compound is referred to in this patent application as “estetrol”] via estrone derived steroids, preferably to the synthesis of estetrol which is obtained with high yield and high purity. BACKGROUND OF THE INVENTION [0002] Estrogenic substances are commonly used in methods of Hormone Replacement Therapy (HRT) and methods of female contraception. These estrogenic substances can be divided in natural estrogens and synthetic estrogens. Examples of natural estrogens that have found pharmaceutical application include estradiol, estrone, estriol and conjugated equine estrogens. Examples of synthetic estrogens, which offer the advantage of high oral bioavailability include ethinyl estradiol and mestranol. [0003] Recently, estetrol has been found effective as an estrogenic substance for use in HRT, disclosur...

Claims

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Application Information

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IPC IPC(8): C07J1/00A61K31/56
CPCC07J1/0066Y02P20/55C07J1/0059C07J1/007C07J21/00
Inventor VERHAAR, MARK THEODOORKOCH, THOMASWARMERDAM, ERWIN GERARDUS JACOBUS
Owner DONESTA BIOSCI
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