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Industrial process for preparation of high purity estetrol

A technology for the use of estetrol, which is applied in the field of preparation of pharmaceutical compositions, general formulas and intermediates, and can solve problems such as low economy, unfavorable yield, and unresolved estetrol

Active Publication Date: 2022-04-08
RICHTER GEDEON NYRT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the instructions do not contain any information on how to prepare estetrol in the purity of the active substance from the intermediates obtained
[0033] From all this, it can be concluded that either there is no solution for the preparation of estetrol of pharmaceutical grade purity or the preparation of pure active substance can be solved with unfavorable yields and low economy

Method used

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  • Industrial process for preparation of high purity estetrol
  • Industrial process for preparation of high purity estetrol
  • Industrial process for preparation of high purity estetrol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] (15α,16α,17β)-3-(Benzyloxy)estra-1,3,5(10)-triene-15,16,17-triyltriacetate Method A (isolated)

[0100] a.) cis hydroxylation

[0101] (15α,16α,17β)-, and (15β,16β,17β)-3-(benzyloxy)estra-1,3,5(10)-triene-15,16,17- triol

[0102] At 20-25°C, in N 2 Under the atmosphere, 40 mg of potassium osmate dihydrate (K 2 OSo 4 2H 2 O) Suspended in 100 mL of 2-butanone (methyl ethyl ketone), 7.7 mL of purified water and 1.1 g of trimethylamine N-oxide dihydrate were added. 2.0 g (5.5 mmol) of 3-benzyloxy-estra-1,3,5(10),15-tetraen-17-ol (WO2004 / 041839 (Pantarhei), Example 7) was dissolved in 40 mL of 2 -butanone and added dropwise to the reaction mixture. Then, at N 2 The reaction mixture was stirred at 20-25°C for 28 hours under atmosphere. The reaction was monitored by TPLC (n-heptane:acetone 1:1).

[0103] Post-processing: 25 mL of 10% Na 2 S 2 o 5 The solution was added to the mixture, followed by the addition of 100 mg of activated carbon, followed by stirr...

Embodiment 2

[0128] (15α,16α,17β)-3-Hydroxyestro-1,3,5(10)-triene-15,16,17-triyltriacetate

[0129] Method A

[0130] At 20-25°C, in N 2 Under atmosphere, 25.7g (49.36mmol) of (15α,16α,17β)-3-(benzyloxy)estra-1,3,5(10)-triene-15,16,17-triyltriethyl The acid ester (Example 1) was dissolved in 315 mL of ethyl acetate. 770 mg of 10% palladium on carbon catalyst was suspended in 19 mL of cryogenic ethyl acetate and then added to the solution. Will N 2 Atmosphere changed to H 2 atmosphere, and the reaction mixture was stirred at 20-25 °C for 3 hours at atmospheric pressure.

[0131] Post-processing : The catalyst was filtered off, washed with ethyl acetate, and concentrated to a final volume under reduced pressure, then n-heptane was added, and the suspension was kept at 0-5 °C for 1 hour, then filtered, and used on the filter with The crystalline product was washed with n-heptane and dried in vacuum at 40 °C to constant weight. Thus, 19.88 g (93.55%) of white crystalline product were ...

Embodiment 3

[0142] (15α,16α,17β)-3-(Benzyloxy)estra-1,3,5(10)-triene-15,16,17-triyltricarboxylate

[0143] 5.00 g of (15α,16α,17β)-3-(benzyloxy)estra-1,3,5(10)-triene-15,16,17-triol (Example 1, method "A" , step a)) was dissolved in 73 mL of pyridine and cooled to 0° C., then between about 0-10° C., in about 25 minutes, 49 mL of formic acid cooled to 0° C. and 18.3 mL of A mixture of mixed anhydrides made from the anhydride of acetic acid. After stirring for 1 hour, 305 mL of water was added to the reaction mixture, and the resulting white precipitate was filtered off and washed with water. The dried crude product weighed 5.65 g (93.23%).

[0144] The crude product - according to method B step c) of example 1 - was recrystallized from methanol to afford 3.92 g (69.4%) of the pure title product as white crystals.

[0145] Purity (HPLC): 99.2% ααβ-isomer, 0.05% βββ-isomer (area).

[0146] Mp.:153.5-154.3℃

[0147] EI HRMS: M=478.19866; δ=0.06ppm; C 28 h 30 o 7

[0148] 1 H NMR (49...

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Abstract

The invention relates to the preparation of estetrol of formula (I), its derivatives of general formula (III) protected at the 3, 15 alpha, 16 alpha, 17 beta-position, its 3-hydroxy derivatives of general formula (IV) protected at the 15 alpha, 16 alpha, 17 beta-position, and intermediates of general formulas (III) and (IV) for use in said preparation methods. A further aspect of the invention is the use of estetrol of formula (I) obtained by the process of the invention in the preparation of a pharmaceutical composition.

Description

[0001] field of invention [0002] The present invention relates to estetrol (estra-1,3,5(10)-triene-3,15α,16α,17β-tetraol) of formula (I), estetrol of general formula (III) at 3,15α,16α , the preparation of its derivatives whose 17β-position is protected, its 3-hydroxyl derivatives which are protected at 15α, 16α, and 17β-positions of general formula (IV), and the general formula (III) used in the preparation method and intermediates of (IV). Another aspect of the present invention is the use of estetrol of formula (I) obtained by the process of the present invention in the preparation of pharmaceutical compositions. [0003] Background of the invention [0004] Estrol (estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol) of formula (I) is endogenously produced by the fetal liver during human pregnancy with weak estrogen active compound. [0005] [0006] Discovery of estetrol in hormone replacement therapy, methods of treating vaginal dryness, methods of treating perimenopausal...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J1/00A61P15/02A61P15/00A61P15/18A61P17/00A61P17/02A61P35/00A61P37/02
CPCA61K31/565A61K31/585A61P5/30A61P15/00A61P15/02A61P15/18A61P17/00A61P17/02A61P25/00A61P35/00A61P37/06C07J1/007C07J1/0074Y02P20/55A61K2300/00A61P15/12C07J1/00C07J75/00A61K31/566A61P37/00C07J1/0066
Inventor R·罗瓦斯S·玛浩I·巴克萨B·马耶尔
Owner RICHTER GEDEON NYRT
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