Method for preparing fulvestrant derivatives

Abstract

A method for preparing fulvestrant 3-boronic acid and intermediates useful for the preparation of fulvestrant 3-boronic acid by the method are described, which comprises converting a compound of formula (IV) to a compound of formula (III).Fulvestrant 3-boronic acid is obtained in high purity. [Formula 1] JPEG2022522670000012.jpg5488(IV) [chemical 2] JPEG2022522670000013.jpg5688(III)

Description

Technical Field

[0001] The present invention relates to fulvestrant derivatives, specifically, a method for preparing fulvestrant-3 boronic acid, and intermediates useful for its preparation.

Background Art

[0002] Fulvestrant is a selective estrogen receptor degrader (SERD) that can competitively and reversibly bind to the receptor, resulting in its suppression and degradation. Fulvestrant is marketed under the trade name Faslodex (registered trademark) and was first approved in the United States as a drug in 2002 and then in Europe in 2004. Fulvestrant is indicated as a single agent for the treatment of estrogen receptor-positive, locally advanced or metastatic breast cancer in postmenopausal women who have not previously been treated with endocrine therapy or who have had disease recurrence with anti-estrogen therapy, and in combination with palbociclib for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in women who have previously received endocrine therapy. When administered orally, fulvestrant is known to undergo rapid O-glucuronidation and O-sulfation, resulting in phase II polar metabolites that are inactive and water-soluble. Metabolic inactivation and high clearance render fulvestrant inadequate or unavailable to target tissues. Therefore, due to its low oral bioavailability, fulvestrant must be administered by intramuscular injection. Rather, more recently, fulvestrant-3-boronic acid, a fulvestrant derivative in which the hydroxyl group at position 3 is replaced with a boronic acid group, has been developed to prevent initial metabolic inactivation. Such a modification reduces metabolic inactivation of fulvestrant while maintaining the steroid portion that confers its SERD properties, thereby achieving bioavailability even after oral administration (Jiawang Liu et al., "Fulvestrant-3Boronic Acid (ZB716): An Orally Bioavailable Selective Estrogen Receptor Downregulator (SERD)", J.Med.Chem. 2016, 59, 8134-8140). Fulvestrant-3 boronic acid, CAS chemical name ((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)boronic acid, is given by formula (I) [ka] (I) It is a compound and was first described in International Patent Application No. 2016004166. All known methods in the art for the preparation of fulvestrant-3-boronic acid involve the use of intermediates that are difficult to handle and purify, resulting in several drawbacks. In particular, the literature (J.Med.Chem.2016,59,8134-8140) describes a method for preparing fulvestrant-3-boronic acid (Scheme I) which involves esterifying 17-acetyl S-deoxofulvestrant with trifluoromethanesulfonic anhydride to obtain the corresponding triflate (2), and then reacting this with bis(pinacolato)diborone in the presence of palladium(II) acetate and tricyclohexylphosphine to obtain 3-pinacolylboronic acid ester (3). After removing the 17-acetyl group under basic conditions, the deacetylboronic acid ester (4) is oxidized with meta-chloroperbenzoic acid (mCPBA) to obtain the final product as a colorless crystal. Scheme I [ka] However, because boronic acid esters (3 and 4) are oils, their isolation is difficult and requires a complex purification process, which reduces the overall yield and purity of the final product. Furthermore, ester 4 is unstable under chromatographic conditions, leading to the formation of variable amounts of other undesirable products, resulting in a lower yield. Therefore, improved methods for the synthesis of fulvestrant-3 boronic acid that overcome the shortcomings of known methods are still needed. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] International Patent Application No. 2016004166 [Non-patent literature]

[0004] [Non-Patent Document 1] Jiawang Liu et al.,''Fulvestrant-3Boronic Acid(ZB716):An Orally Bioavailable Selective Estrogen Receptor Downregulator(SERD)''J.Med.Chem.2016,59,8134-8140 [Non-Patent Document 2] J.Med.Chem.2016,59,8134-8140 [Overview of the project]

[0005] The object of the present invention is a method for preparing fulvestrant-3-boronic acid, which is produced through the formation of potassium 17-acetyl S-deoxofulvestrant 3-trifluoroborate (abbreviated as potassium fulvestrant 3-trifluoroborate). The compound potassium fulvestrant 3-trifluoroborate is a further object of the present invention. [Brief explanation of the drawing]

[0006] [Figure 1] This is the XRPD spectrum of potassium fulvestrant 3-trifluoroborate. [Figure 2] This is the 1H NMR spectrum of potassium fulvestrant 3-trifluoroborate. [Figure 3] This is the 13C NMR spectrum of potassium fulvestrant 3-trifluoroborate. [Figure 4] This is the LC-MS spectrum of potassium fulvestrant 3-trifluoroborate. [Figure 5] This is a chromatogram of potassium fulvestrant 3-trifluoroborate before recrystallization. [Figure 6] This is a chromatogram of potassium fulvestrant 3-trifluoroborate after recrystallization. [Modes for carrying out the invention]

[0007] After extensive experiments, the inventors of the present invention have now surprisingly found that, starting from, for example, the full vestrant 3-pinacolyl boronate obtained according to the method described in International Publication No. 2016 / 004166, a new intermediate, potassium full vestrant 3-trifluoroborate, can be obtained and can be advantageously used in the synthesis of full vestrant-3 boronic acid. Therefore, an object of the present invention is a method for synthesizing full vestrant-3 boronic acid, comprising converting a compound of formula (IV)

Chemical formula

Chemical formula

[0008] In a particularly preferred embodiment, crystallization of the compound of formula (III) occurs as reported herein by adding a crystallization mixture of heptane:water in a ratio of 16:5 to the reaction mixture, filtering the crude solid precipitate, washing with a heptane:water mixture in a ratio of 1:1, and then drying at a temperature of 30°C to 50°C, preferably about 40°C, for a suitable period of time, for example, 2 to 10 hours, preferably about 5 hours. Drying can be carried out according to methods known in the art, including but not limited to vacuum ovens, Rotavapor®, air drying chambers, static bed dryers, fluidized bed dryers, spray dryers, etc. Preferably, drying is carried out by drying in an oven under vacuum at 40°C ± 5°C. This intermediate (III) is already obtained with very good quality, i.e., >97.0% purity and less than 1.0% single impurity (Figure 5). Furthermore, optional recrystallization yields a product with high yield (recovery rate >90%) and purity >99.8% (Figure 6). The recrystallization can be carried out by hot-cold crystallization, specifically by following methods known in the art, which involve first dissolving potassium fulvestrant 3-trifluoroborate at a warm temperature in a suitable solvent such as acetonitrile, then cooling the resulting solution to obtain a precipitate of the product, and finally separating the precipitate by filtration and drying it. In addition to avoiding the drawbacks of oily intermediates, it is noteworthy that the compound of formula (III) is obtained in crystalline form and remains stable throughout all purification steps. The compound of formula (III) obtained by the present invention has also been characterized by powder X-ray diffraction (XRPD), and the XRPD diffractogram (Figure 1) shows at least three of the following characteristic peaks: 5.09, 8.03, 8.61, 10.20, 15.37, and 17.72 ± 0.2 degrees 2θ. Fulvestrant-3 boronic acid can be obtained from the compound of formula (III) according to conventional methods. However, the inventors have also developed a method for preparing fulvestrant-3 boronic acid through the formation of an intermediate compound of formula (III). According to the present invention, the compound of formula (III), potassium 17-acetyl S-deoxofulborate 3-trifluoroborate, can be converted to fulvestrant 3-boronic acid through oxidation of the sulfur atom and hydrolysis of the acetyl group at position 17 and the potassium trifluoroborate group at position 3, or vice versa. Therefore, a particularly preferred embodiment of the present invention is a method for preparing fulvestrant-3-boronic acid, comprising the following steps: -The oxidation reaction of the compound of formula (III) results in formula (IIa) [ka] (IIa) To obtain the compound, -By hydrolysis of the compound of formula (IIa), fulvestrant 3-boronic acid (I) is obtained, and It also includes. Another particularly preferred embodiment of the present invention is a method for preparing fulvestrant-3-boronic acid, comprising the following steps: -By the hydrolysis reaction of the compound of formula (III), formula (IIb) [ka] (IIb) To obtain the compound, -The oxidation reaction of the compound of formula (IIb) yields fulvestrant 3-boronic acid (I), and It also includes.

[0009] More specifically, the hydrolysis reaction can be carried out by reacting the compound of formula (IIa) or (III) with a base in a suitable reaction solvent. A suitable base may be an alkali metal hydroxide selected from lithium hydroxide, potassium hydroxide, and sodium hydroxide, preferably lithium hydroxide. The oxidation reaction can be carried out by reacting the compound of formula (III) or (IIb) with a suitable oxidizing agent in a suitable reaction solvent. Suitable oxidizing agents may include, for example, either sodium periodate or metachloroperbenzoic acid, preferably sodium periodate. Suitable reaction solvents may be protic or aprotic polar solvents selected from, for example, methanol, acetonitrile, acetone, tetrahydrofuran, water, dimethylformamide, dimethylacetamide, and mixtures thereof. Preferably, in oxidation reactions, a suitable solvent is a mixture of water, tetrahydrofuran, and methanol. The above oxidation and hydrolysis reactions are preferably carried out under inert conditions, for example, in the presence of nitrogen, even if not strictly necessary. Furthermore, it is noteworthy that both intermediate compounds of formulas (IIa) and (IIb) are solids. Advantageously, the fulvestrant-3 boronic acid obtained by the present invention has a purity of over 95% without the need for a chromatographic column, and a purity of over 99% can be achieved by using a single chromatograph. While not bound by any theory, the inventors of the present invention believe that this may simply be due to the use of the intermediate compound of formula (III), which makes it possible to avoid the use of oily intermediates that are difficult to purify by conventional methods that do not involve chromatography. Therefore, despite the detailed description of the present invention, the sole essential feature of this method for the preparation of fulvestrant-3 boronic acid is that it occurs via the formation of the intermediate compound of formula (III), fulvestrant-3 potassium trifluoroborate. All terms used in this disclosure should be understood in their general sense as they are known in the art, unless otherwise indicated. The term "approximately" includes the range of experimental error that may occur in a measurement. Specifically, when referring to a value, it means plus or minus 5% of a given value, and when referring to a range, it means plus or minus 5% of the outside value. Even though the present invention has been described in terms of features that define its characteristics, modifications and equivalents that would be obvious to those skilled in the art are included in the appended claims. The present invention will be described below by several embodiments, which are for illustrative purposes only and do not limit the scope of the invention. [Examples]

[0010] X-ray diffraction spectra (XRPDs) of the compound of formula (III) were obtained for the diffraction beam using a Bruker D5005 diffractometer equipped with a CuKα-ray, scintillation detector, and curved graphite monochromator. Samples of the compound of formula (III) after crystallization from acetonitrile were gently ground in an agate mortar to obtain a fine powder, and particle aggregates were broken down. Data were collected at room temperature in a silicon single-crystal low-background sample holder. Detection: 2θ degrees, angle measurement in the range of 3° to 35° (2θ), step of 0.03°, and count time of 4 s / step. HPLC chromatography was performed using an Agilent 1200 series instrument by injecting 10 μL of solution into an RP18 column, 150 x 4.6 mm, 5 μm in diameter. The sample was gradient eluted using a mobile phase consisting of a mixture of acetonitrile with added phosphoric acid and water. The compound was then analyzed by applying a wavelength of 225 nm. 1 H and 13The 13C NMR spectra were obtained at 25°C using a Bruker AVANCE III spectrometer (500 MHz) at 500 MHz and 125.8 MHz, respectively. 1 H and 13 The ¹C was obtained by observation. The chemical shift was expressed in ppm relative to tetramethylsilane, and the spectrum was obtained by dissolving the sample in acetone. LC-mass spectrometry was performed using a Varian 500MS instrument with ESI(-).

[0011] Example 1: Synthesis of potassium ((7R,8R,9S,13S,14S,17S)-17-acetoxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)thio)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl)trifluoroborate(III). 32 g of the crude residue obtained as described in the literature (International Publication No. 2016004166 - Example 2, Step 2) containing (7R,8R,9S,13S,14S,17S)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)thio)nonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-17-yl acetate) was dissolved in acetone (85.5 ml), and under stirring, desalinated water (38.5 ml) and 4.5 M potassium difluoride aqueous solution (57 ml) were added. The reaction mixture was maintained at room temperature for 90 minutes. At the end of the reaction, water (160 ml) and heptane (512 ml) were added. The solid was filtered and washed with a mixture of heptane (70 ml) and water (70 ml). The solid was dried in an oven at 40°C under vacuum for 5 hours. 24 g of potassium ((7R,8R,9S,13S,14S,17S)-17-acetoxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)-thio)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)trifluoroborate(III) was obtained with HPLC purity of 97.2%. Furthermore, the compound of formula (III) can be recrystallized. 24 g of compound (III) was dissolved in 60 ml of acetonitrile at reflux temperature and then cooled to 0-10°C. The product was filtered and washed with 24 ml of acetonitrile at 0-10°C. The product was dried at 40°C under vacuum for 5 hours. 22 g of compound (III) with HPLC purity >99.8% was obtained. 1 H NMR:7.24(1H,d,H-1), 7.18(1H,s,H-4), 7.04(3H,d,H-4), 4.69(1H,t,H-17), 2 .65(2H,t,-CH2-S), 2.53(2H,t,-CH2-S), 2.00(3H,s,-CH3), 0.86(3H,s,-CH3). 13 C NMR:12.5(CH3), 21.0(CH3), 21.4(tCH2), 29.9(tCH2), 32.2-23.5(nCH2), 34.5(CH), 35.5(CH2), 38.1(CH2), 39.6(CH), 43.0(CH), 43.9(C), 47.2, 83.3, 124.5, 130.2(CH), 133.0(C), 134.4(CH), 136.5, 171.0, 206.3(C).

[0012] Example 2: Synthesis of potassium ((7R,8R,9S,13S,14S,17S)-17-acetoxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl)trifluoroborate (IIa). In a round-bottom flask and under nitrogen, the compound of formula (III) (5.0 g, 6.9 mmol) was dissolved in THF (50 ml) and methanol (10 ml) with stirring, and the solution was brought to 0-5°C. In a separate round-bottom flask, a solution of sodium periodate (2.95 g, 13.8 mmol) in water (12 ml) was prepared at 30-35°C. The sodium periodate solution was added to the reaction mixture at 0-5°C. The temperature was then increased to 20-25°C, and the reaction mixture was stirred for 24-48 hours until the reaction was complete. The resulting solid was filtered, washed with THF, and the oxidation intensity was eliminated with 10% w / w sodium thiosulfate aqueous solution (10 ml). The organic solvent was removed under vacuum, and the mixture was dissolved in ethyl acetate (50 ml). The phases were separated, and the aqueous phase was extracted again with ethyl acetate (25 ml). The recovered organic phase was washed once with water (25 ml) and once with saturated sodium chloride solution (25 ml). The solvent was evaporated to obtain the residue, and 4,5-potassium ((7R,8R,9S,13S,14S,17S)-17-acetoxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)trifluoroborate (IIa) was obtained with HPLC purity of 96.5%.

[0013] Example 3: Synthesis of ((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl)boronic acid (I). In a round-bottom flask under nitrogen, 3.0 g, 4.0 mmol of the compound of formula (IIa) was dissolved in 30 ml of acetonitrile and 10 ml of water. Separately, a solution of lithium hydroxide (1.2 g, 28.0 mmol) in 10 ml of water was prepared and added to the reaction mixture with stirring at 0-5°C. The temperature was increased to 20-25°C and the mixture was reacted for 24-48 hours. After the reaction was complete, a solution of ammonium chloride and hydrochloric acid with a maximum pH of 5-6 and ethyl acetate (30 ml) were added. The phases were separated, and the aqueous phase was extracted again with ethyl acetate (15 ml). The recovered organic phase was washed once with water (15 ml) and once with saturated sodium chloride solution (15 ml). The solvent was evaporated to obtain the residue, and 2.0 g of ((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)-sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)boronic acid (I) was obtained with HPLC purity of 95.0%.

[0014] Example 4: Synthesis of ((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)thio)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)boronic acid (IIb). In a round-bottom flask under nitrogen, the compound of formula (III) (1.0 g, 1.38 mmol) was dissolved in THF (5 ml) and MeOH (5 ml). Separately, a solution of potassium hydroxide (0.78 g, 13.8 mmol) in methanol (5 ml) was prepared and added to the reaction mixture with stirring at 0-5°C. The temperature was increased to 20-25°C and the mixture was reacted for 18 hours. After the reaction was complete, acetic acid was added to bring the pH to 5-6. The organic solvent was removed under vacuum and ethyl acetate (10 ml) was added. The phases were separated, and the aqueous phase was extracted again with ethyl acetate (5 ml). The recovered organic phase was washed once with water (5 ml) and once with saturated sodium chloride solution (5 ml). The solvent was evaporated to obtain the residue, and 0.85 g of ((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)-thio)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)boronic acid (IIb) was obtained with HPLC purity of 94.2%.

[0015] Example 5: Synthesis of ((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl)boronic acid (I). In a round-bottom flask under nitrogen, the compound of formula (IIb) (0.66 g, 1.07 mmol) was dissolved in THF (7 ml) and methanol (1.2 ml) with stirring. In a separate round-bottom flask, a solution of sodium periodate (0.39 g, 1.7 mmol) in water (2 ml) was prepared at 30-35°C. The sodium periodate solution was added to the reaction mixture at 0-5°C. The temperature was then increased to 20-25°C, and the reaction mixture was stirred for 24-48 hours until the reaction was complete. The resulting solid was filtered, washed with THF, and the oxidation intensity was eliminated with 10% w / w sodium thiosulfate aqueous solution (5 ml). The organic solvent was removed under vacuum, and the mixture was dissolved in ethyl acetate (10 ml). The phases were separated, and the aqueous phase was extracted again with ethyl acetate (5 ml). The recovered organic phase was washed once with water (5 ml) and once with saturated sodium chloride solution (25 ml). The solvent was evaporated to obtain the residue, yielding 0.6 g of ((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)-sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)boronic acid (I). HPLC purity 92%.

Claims

1. Formula (IV) 【Chemistry 1】 (IV) The compound Formula (III) 【Chemistry 2】 (III) 2. A process for preparing fulvestrant 3-boronic acid (I), comprising converting fulvestrant 3-boronic acid (I) into a compound of formula (I):

2. 2. The method of claim 1, wherein the conversion occurs by reaction of the compound of formula (IV) with potassium hydrogen difluoride in a suitable reaction solvent.

3. 3. The method according to claim 2, wherein the solvent is a water-miscible solvent, preferably selected among acetonitrile, tetrahydrofuran, methanol, acetone, water and mixtures thereof.

4. 4. The method of claim 3, wherein the solvent is a mixture of water and acetone.

5. The following process: - by oxidation of the compound of formula (III), a compound of formula (IIa) 【Transformation 3】 (IIa) and obtaining a compound of formula - hydrolysis of the compound of formula (IIa) to obtain fulvestrant 3-boronic acid (I); The method of claim 1 further comprising:

6. The following process: - by hydrolysis of the compound of formula (III), a compound of formula (IIb) 【Chemistry 4】 (IIb) and obtaining a compound of formula - oxidation of the compound of formula (IIb) to obtain fulvestrant 3-boronic acid (I); The method of claim 1 further comprising:

7. A compound of formula (III).

8. 8. The compound of claim 7, having at least three of the following characteristic peaks in an XRPD diffractogram: 5.09, 8.03, 8.61, 10.20, 15.37, 17.72±0.2 degrees 2θ.

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