Process for the preparation of estetrol

Inactive Publication Date: 2014-08-21
ESTETRA S P R L
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0047](2) conversion of 17-B-oxy-3-A-oxy-estra-1,3,5(10),16-tetraene III into 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one IV, wherein A is a protecting group, wherein said conversion o

Problems solved by technology

Due to the high cost of palladium, application of this method is therefore not desirable for a process that is executed on an industrial scale.
Although the process disclosed in WO 2004/041839 is suitable for an industrial scale preparation of estetrol 1, and although estetrol is obtained with a reasonable overall yield, the process still suffers from several disadvantages.
Isolation and purification of each in

Method used

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  • Process for the preparation of estetrol

Examples

Experimental program
Comparison scheme
Effect test

example 1

3-Benzyloxy-estra-1,3,5(10)-trien-17-one (3-protected estrone, A is benzyl)

[0139]To a suspension of estrone (II; 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 (RT) 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 recrystalliz...

example 2

3-Benzyloxy-17-trimethylsilyloxy-estra-1,3,5 (10), 16-tetraene (compound III, A is benzyl, B is trimethylsilyl)

[0141]3-Benzyloxy-estra-1,3,5(10)-trien-17-one (3-protected estrone, A is benzyl; 238 mg, 0.660 mmol) was dissolved in DCM (10 ml). Et3N (0.166 ml, 1.188 mmol) and TMS-OTf (0.143 ml, 0.792 mmol) were added and the solution was stirred at ambient temperature for 1 h. According to TLC (alumina, heptane / ethyl acetate 4 / 1 plus Et3N). The entire content of the flask was transferred onto a small column of basic alumina (type II) and eluted with heptane / ethyl acetate 4 / 1 plus Et3N. The product was obtained as a white solid (248 mg, 87%).

example 3

3-Benzyloxy-estra-1,3,5(10),15-tetraen-17-one (compound IV, A is benzyl)

[0142]Unstabilised IBX (1.0 g; 3.6 mmol), a catalytic amount of trimethylamine-N-oxide (40 mg, 10 mol %) and 3 Å molecular sieves (100 mg) were added to 10 ml dry DMSO.

[0143]A fluorobenzene solution containing about 2.8 mmol crude (94% GC) benzylestrone-trimethylsilyl enol ether III (4.5 ml; corresponding to 1.0 g ketone) was added, giving a sudden solidification of the reaction mixture due to precipitated substrate. Mild heating to 40-45° C. was needed for dissolution. After 1 h HPLC showed a clean conversion of the enol ether to the enone with some ketone present due to advantageous hydrolysis.

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Abstract

The present invention relates to a process for the preparation of estra-1,3,5(10)-trien-3,15α,16α,17β-tetraol (estetrol), via a silyl enol ether derivative 17-B-oxy-3-A-oxy-estra-1,3,5(10),16-tetraene, wherein A is a protecting group and B is —Si(R2)3. The invention further relates to a process for the synthesis of 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one, wherein A is a protecting group, via said silyl enol ether derivative.

Description

TECHNICAL FIELD OF THE INVENTION[0001]The present invention relates to a process for the preparation of estra-1,3,5(10)-trien-3,15α,16α,17β-tetraol (estetrol), starting from estrone. The invention further relates to a process for the preparation of 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one, starting from estrone, via the corresponding silyl enol ether 17-B-oxy-3-A-oxy-estra-1,3,5(10),16-tetraene, wherein A is a protecting group and B is —Si(R2)3.BACKGROUND OF THE INVENTION[0002]Estrogenic substances are commonly used in methods of Hormone Replacement Therapy (HRT) and in 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]Estetrol has been fo...

Claims

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Application Information

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IPC IPC(8): C07J1/00
CPCC07J1/0059C07J1/007C07J13/005C07J75/00Y02P20/55
Inventor PLATTEEUW, JOHANNES JANCOELINGH BENNINK, HERMAN JAN TIJMENDAMEN, FRANCISCUS WILHELMUS PETRUSVAN VLIET, MICHIEL CHRISTINE ALEXANDER
Owner ESTETRA S P R L
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