WO2017053793A1 - Methods of making onapristone intermediates - Google Patents

Methods of making onapristone intermediates Download PDF

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Publication number
WO2017053793A1
WO2017053793A1 PCT/US2016/053435 US2016053435W WO2017053793A1 WO 2017053793 A1 WO2017053793 A1 WO 2017053793A1 US 2016053435 W US2016053435 W US 2016053435W WO 2017053793 A1 WO2017053793 A1 WO 2017053793A1
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Prior art keywords
formula
compound
onapristone
excimer
lamp
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PCT/US2016/053435
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French (fr)
Inventor
Ulf Tilstam
Stefan PRONIUK
Holger Bindernagel
Silvia Werner
Holger Rauter
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Arno Therapeutics, Inc.
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Priority to CA2998924A priority Critical patent/CA2998924A1/en
Priority to JP2018509611A priority patent/JP2018528944A/en
Priority to BR112018005999A priority patent/BR112018005999A2/en
Priority to AU2016326657A priority patent/AU2016326657B2/en
Priority to EP16849747.7A priority patent/EP3353148A4/en
Publication of WO2017053793A1 publication Critical patent/WO2017053793A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J33/00—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J33/005—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton spiro-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0077—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
    • C07J41/0083—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings

Definitions

  • Onapristone is an anti-progestin drug and progesterone receptor antagonist which was originally developed for contraceptive use. However, it has demonstrated substantial activity in advanced breast cancer. It is thought that ONA binds to the progesterone receptor (PR), preventing the PR from binding to DNA, and thereby inhibits or eliminates PR-induced transcription. See, e.g.. Klijn et al., Progesterone antagonists and progesterone receptor modulation in the treatment of breast cancer, Steroids, v. 65, pp. 825-830 (2000); Jonat et al., The clinical efficacy of progesterone antagonists in breast cancer, Endocrine Therapy of Breast Cancer, pp. 117-124.
  • PR progesterone receptor
  • Onapristone is known to be an amorphous compound.
  • (3- Acyloxypropyl)-derivatives of onapristone are crystalline in comparison to the parent compound.
  • Onapristone has previously been isolated as an amorphous solid and as a yellow oil.
  • U. S. Patent Number 4,843, 157 refers to a process for stereoselection of the desired isomer by photochemical conversion.
  • photochemical conversion is performed using a "conventional mercury high-pressure lamp" as the radiation source.
  • the preferred wavelengths are identified as ranging from about 250 to about 350 nm.
  • the process described in U.S. Patent Number 4,843,157 achieved yields in the range of 45 to 60%.
  • Photoconversion of intermediates in the synthesis of progesterone receptor antagonists has also been performed with a mercury lamp at wavelengths of 250-580 nm. See, e.g., Guohua et al., Synthesis of Progesterone Receptor Antagonist ZK98299, Zhongguo Yaoke Daxue Xuebao (1992), 23(4), 209-12.
  • X is selected from the group consisting of OMe, OEt, OPr,
  • the compound of Formula I is:
  • the compound of Formula II is:
  • narrow bandwidth light from a lamp e.g., excimer Dielectric Barrier Discharge Radiation Source (DBD), (Light-Emitting Diode) LED lamp, OLED (Organic Light-Emitting Diode) lamp, or medium pressure mercury lamp (optionally with filters and at a wavelength of about 280 nm to about 330 nm)
  • a lamp e.g., excimer Dielectric Barrier Discharge Radiation Source (DBD), (Light-Emitting Diode) LED lamp, OLED (Organic Light-Emitting Diode) lamp, or medium pressure mercury lamp (optionally with filters and at a wavelength of about 280 nm to about 330 nm)
  • the wavelength is from about 300 nm to about 315 nm.
  • the wavelength is from about 305 nm to about 310 nm.
  • the wavelength is about 308 nm and the light is emitted from an excimer DBD (dielectric barrier discharge) source.
  • the resulting mixture can be further purified to increase the percentage of the compound of Formula II (e.g., via functionalization and column chromatography) and used in methods of synthesizing steroids, including onapristone.
  • Figure 1 shows an exemplary scheme for photoconversion of the CI 3 methyl group of the compound of Formula I to the compound of Formula II.
  • the methods and systems provide a higher yield of the compound of Formula II which increases efficiency and reduces the cost of synthesizing compounds derived from the compound of Formula II, for example, in the synthesis of onapri stone.
  • the compound of Formula I is photo converted into the compound of Formula II through use of narrow band frequency (e.g., about 295 nm to about 320 nm) light generated by, for example, an excimer DBD light source at 308 nm.
  • narrow band frequency e.g., about 295 nm to about 320 nm
  • photoconversion refers to the use of light to alter, change, or transform the structure of a chemical compound from one conformation to another conformation (e.g., the position of a substituent on a molecule).
  • the compound of Formula I is placed in a glass cell which is placed in a photo reactor apparatus.
  • Suitable photo reactors include, but are not limited to, those described in Kappe, O, et al J.Org. Chem, 2014,79,8486; Schlogl S. et al J. App. Polymer Science, 2012, 124, 3478; and Puma, G. L., Cat. Today, 2007, 124.
  • the photoreactor can be run in batch or continuous mode. Running the photoreactor in continuous mode could, for example, avoid back mixing or an over reaction.
  • the photo reactor comprises a glass cell which can contain a solvent and a compound, and a monochromatic light source.
  • photo reactor comprises a quartz glass cell with an 80 um layer gap, one excimer DBD light source (308 nm; power 1 * 100W) and optionally a middle pressure mercury lamp with a band filter open between 350 and 410 nm.
  • the glass cell can be made of quartz, for example.
  • the compound of Formula I can be mixed with a solvent (e.g., TUF (tetrahydrofuran), dioxane, MTBE (methyl tertiary butyl ether), diisopropyl ether, diethylether) at a concentration ranging from about 1 : 10 volumes to about 1 :500 volumes.
  • a solvent e.g., TUF (tetrahydrofuran), dioxane, MTBE (methyl tertiary butyl ether), diisopropyl ether, diethylether
  • the photo reactor comprises a plastic tube of suitable diameter wrapped around a (quartz) glass cylinder.
  • irradiation can occur from a light source inserted into the glass cylinder or several light sources placed at suitable distance and angles around the glass cylinder.
  • Suitable lamps include, for example, an excimer radiation source (e.g., emission line 308 nm) available from Heraeus
  • Suitable lamps include excimer DBD, LED, and others.
  • the lamp emits monochromatic light at a wavelength of about 250 nm to about 350 nm.
  • X can be selected from the group consisting of OMe, OEt, OPr, OCH2CH2O and [0033]
  • the wavelength of monochromatic light is about 308 nm.
  • the lamp is an excimer DBD light source.
  • X is
  • a solution of starting material (e.g., 3.5 L containing 200 G starting material 1) is dissolved in 6.5 L THF (tetrahydrofuran) and the solution is transferred into the starting material flask.
  • a cleaned falling film reactor is prepared and the whole system is filled with argon gas.
  • a first cryostat (Cryostat 1) is started at -30 °C.
  • a second cryostat Cryostat 2) is started, and the pump set to allow the starting material solution to flow through the falling film reactor to form a steady thin film.
  • an excimer DBD light source set to 308 nm is started, and samples are taken every hour to monitor the reaction progress.
  • the reaction is stopped when little or no starting material can be detected (i.e., when less than 10% of the starting material is detected).
  • the lamp is turned off, the remaining liquid phase is pumped into the collector flask.
  • the system is washed with THF, and the solution added to the collector flask.

Abstract

Methods and systems for making intermediates in the synthesis of onapristone are provided. Aspects include the photoconversion of onapristone synthesis intermediates using a narrow band frequency light source.

Description

METHODS OF MAKING ONAPRISTONE INTERMEDIATES
PRIORITY CLAIM
[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 62/233, 166 filed on September 25, 2015. The above referenced provisional patent application is incorporated herein by reference as if restated in full. All references cited herein, including, but not limited to patents and patent applications, are incorporated by reference in their entirety.
[0002] All references cited herein, including but not limited to patents and patent applications, are incorporated by reference in their entirety.
BACKGROUND
[0003] Onapristone (ONA) is an anti-progestin drug and progesterone receptor antagonist which was originally developed for contraceptive use. However, it has demonstrated substantial activity in advanced breast cancer. It is thought that ONA binds to the progesterone receptor (PR), preventing the PR from binding to DNA, and thereby inhibits or eliminates PR-induced transcription. See, e.g.. Klijn et al., Progesterone antagonists and progesterone receptor modulation in the treatment of breast cancer, Steroids, v. 65, pp. 825-830 (2000); Jonat et al., The clinical efficacy of progesterone antagonists in breast cancer, Endocrine Therapy of Breast Cancer, pp. 117-124.
[0004] Onapristone is known to be an amorphous compound. For example, (3- Acyloxypropyl)-derivatives of onapristone are crystalline in comparison to the parent compound. Neef, G; Wiechert, R.; Beier, S.; Elger, W.; Henderson, D. UP 4,780461, 1988. Onapristone has previously been isolated as an amorphous solid and as a yellow oil. Neef, G; Wiechert, R.; Beier, S.; Elger, W.; Henderson, D. Steroids, 1984, 44, 349; Neef, G Sauer, G.; Wiechert, R.; Beier, S.; Elger, W.; Henderson, D.; Rohde, R.
DE3321826, 1984. [0005] U. S. Patent Number 4,843, 157 refers to a process for stereoselection of the desired isomer by photochemical conversion. In this process, photochemical conversion is performed using a "conventional mercury high-pressure lamp" as the radiation source. The preferred wavelengths are identified as ranging from about 250 to about 350 nm. However, the process described in U.S. Patent Number 4,843,157 (incorporated by reference herein in its entirety) achieved yields in the range of 45 to 60%.
Photoconversion of intermediates in the synthesis of progesterone receptor antagonists has also been performed with a mercury lamp at wavelengths of 250-580 nm. See, e.g., Guohua et al., Synthesis of Progesterone Receptor Antagonist ZK98299, Zhongguo Yaoke Daxue Xuebao (1992), 23(4), 209-12.
[0006] What is needed is an improved, less costly method for making, forming, or synthesizing onapristone and related compounds with fewer impurities, and fewer and simpler steps.
SUMMARY
[0007] In one aspect, methods are described herein for photoconversion of the compound of Formula I:
Figure imgf000003_0001
[0008] X OH Formula I
[0009] to the compound of Formula II:
Figure imgf000004_0001
[0011] wherein X is selected from the group consisting of OMe, OEt, OPr,
OCH2CH20 and OCH2C(Me)2CH20.
[0012] In one aspect, the compound of Formula I is:
Figure imgf000004_0002
[0014] This compound, (5R, 11R, 13S)-1 l-(Dimethylamino)phenyl-5-hydroxy-13- methyl- 1,2,5,6,7,8, 11, 12, 13, 14,15.16-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2' [l,3]dioxolan]-17(4H)-one, is also referred to herein as Steroid 1.
[0015] In another aspect, the compound of Formula II is:
Figure imgf000004_0003
[0017] This compound, (5-R, l 1R,13R)-1 l-(Dimethylamino)phenyl-5-hydroxy-13- methyl- 1,2,5,6,7,8, 11, 12, 13, 14,15.16-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2' [l,3]dioxolan]-17(4H)-one), is also referred to herein as Steroid 2. [0018] In one aspect, narrow bandwidth light from a lamp (e.g., excimer Dielectric Barrier Discharge Radiation Source (DBD), (Light-Emitting Diode) LED lamp, OLED (Organic Light-Emitting Diode) lamp, or medium pressure mercury lamp (optionally with filters and at a wavelength of about 280 nm to about 330 nm)) is used to irradiate the compound of Formula I to convert the compound of Formula I to the compound of Formula II (e.g., shifting the C13 methyl group from S to R configuration) resulting in a mixture of Formula I and Formula II with a ratio of about 5-10%:90-95%.. In another aspect, the wavelength is from about 300 nm to about 315 nm. In yet another aspect, the wavelength is from about 305 nm to about 310 nm. In another aspect, the wavelength is about 308 nm and the light is emitted from an excimer DBD (dielectric barrier discharge) source.
[0019] The resulting mixture can be further purified to increase the percentage of the compound of Formula II (e.g., via functionalization and column chromatography) and used in methods of synthesizing steroids, including onapristone.
FIGURE
[0020] Figure 1 shows an exemplary scheme for photoconversion of the CI 3 methyl group of the compound of Formula I to the compound of Formula II.
DETAILED DESCRIPTION
[0021] Before describing several exemplary aspects described herein, it is to be understood that the invention is not limited to the details of construction or process steps set forth in the following description. The aspects described herein are capable of being practiced or being carried out in various ways.
[0022] Aspects described herein provide methods and systems for synthesis of the compound of Formula II through, for example, photoconversion to shift the CI 3 methyl group from the S to the R position (Figure 1).
[0023] In one aspect, the methods and systems provide a higher yield of the compound of Formula II which increases efficiency and reduces the cost of synthesizing compounds derived from the compound of Formula II, for example, in the synthesis of onapri stone.
[0024] In another aspect, the compound of Formula I is photo converted into the compound of Formula II through use of narrow band frequency (e.g., about 295 nm to about 320 nm) light generated by, for example, an excimer DBD light source at 308 nm.
[0025] In another aspect, the term "photoconversion" refers to the use of light to alter, change, or transform the structure of a chemical compound from one conformation to another conformation (e.g., the position of a substituent on a molecule).
[0026] In this aspect, the compound of Formula I is placed in a glass cell which is placed in a photo reactor apparatus. Suitable photo reactors include, but are not limited to, those described in Kappe, O, et al J.Org. Chem, 2014,79,8486; Schlogl S. et al J. App. Polymer Science, 2012, 124, 3478; and Puma, G. L., Cat. Today, 2007, 124.
[0027] In another aspect, the photoreactor can be run in batch or continuous mode. Running the photoreactor in continuous mode could, for example, avoid back mixing or an over reaction.
[0028] In another aspect, the photo reactor comprises a glass cell which can contain a solvent and a compound, and a monochromatic light source. In another aspect, photo reactor comprises a quartz glass cell with an 80 um layer gap, one excimer DBD light source (308 nm; power 1 * 100W) and optionally a middle pressure mercury lamp with a band filter open between 350 and 410 nm.
[0029] In one aspect, the glass cell can be made of quartz, for example. The compound of Formula I can be mixed with a solvent (e.g., TUF (tetrahydrofuran), dioxane, MTBE (methyl tertiary butyl ether), diisopropyl ether, diethylether) at a concentration ranging from about 1 : 10 volumes to about 1 :500 volumes.
[0030] Alternatively, the photo reactor comprises a plastic tube of suitable diameter wrapped around a (quartz) glass cylinder. In this aspect, irradiation can occur from a light source inserted into the glass cylinder or several light sources placed at suitable distance and angles around the glass cylinder.
[0031] In this aspect, exposure of the compound of Formula I to monochromatic light from any suitable lamp converts the C13(R) methyl or alkyl group for a C13(S) methyl or alkyl group forming the compound of Formula II. Suitable lamps include, for example, an excimer radiation source (e.g., emission line 308 nm) available from Heraeus
Noblelight. Other suitable lamps include excimer DBD, LED, and others. In another aspect, the lamp emits monochromatic light at a wavelength of about 250 nm to about 350 nm.
Aspects described herein provide methods of making the compound of
Figure imgf000007_0001
with monochromatic light from a lamp selected from the group consisting of excimer DBD, LED at a wavelength from about 295 nm to about 320 nm. In this aspect, X can be selected from the group consisting of OMe, OEt, OPr, OCH2CH2O and
Figure imgf000007_0002
[0033] In another aspect, the wavelength of monochromatic light is about 308 nm. In yet another aspect, the lamp is an excimer DBD light source. In another aspect, X is
EXAMPLES
[0034] The following non-limiting examples illustrate aspects described herein. Not every element described herein is required. Indeed, a person of skill in the art will find numerous additional uses of and variations to the methods described herein, which the inventors intend to be limited only by the claims. All references cited herein are incorporated by reference in their entirety.
[0035] Example 1 - Photoconversion
[0036] (5R,11R,13S)-1 l-(Dimethylamino)phenyl-5-hydroxy-13-methyl- 1,2,5,6,7,8, 11, 12, 13, 14,15.16-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'- [l,3]dioxolan]-17(4H)-one (Steroid 1).
[0037] A solution of starting material (Formula I) (e.g., 3.5 L containing 200 G starting material 1) is dissolved in 6.5 L THF (tetrahydrofuran) and the solution is transferred into the starting material flask. A cleaned falling film reactor is prepared and the whole system is filled with argon gas. A first cryostat (Cryostat 1) is started at -30 °C. A second cryostat Cryostat 2) is started, and the pump set to allow the starting material solution to flow through the falling film reactor to form a steady thin film. Next, an excimer DBD light source set to 308 nm is started, and samples are taken every hour to monitor the reaction progress. The reaction is stopped when little or no starting material can be detected (i.e., when less than 10% of the starting material is detected). After the lamp is turned off, the remaining liquid phase is pumped into the collector flask. The system is washed with THF, and the solution added to the collector flask.
[0038] In this aspect, the process of separating the compounds of Formula I and Formula II is simpler than previous methods. Without being bound by theory, it is believed that use of a narrow band light source generates fewer and more polar impurities, which simplifies and reduces the time and cost associated with separating the compounds of Formula I and Formula II.
[0039] Although the above description refers to particular aspects, it is to be understood that these aspects are merely illustrative. It will be apparent to those skilled in the art that various modifications and variations can be made to the polymorphic forms and methods described herein. Thus, it is intended that the present description include modifications and variations that are within the scope of the appended claims and their equivalents.

Claims

CLAIMS What is claimed is:
1. A method of making the compound of Formula II
Figure imgf000010_0001
with narrow band frequency light from a lamp selected from the group consisting of an excimer DBD light source and an LED at a wavelength from about 295 nm to about 320 nm;
wherein X is selected from the group consisting of OMe, OEt, OPr, OCH2CH2O and OCH2C(Me)2CH20.
2. The method of claim 1, wherein the wavelength of narrow band frequency light is about 308 nm from the excimer DBD light source.
3. The method of claim 1, wherein the lamp is the excimer DBD light source.
4. The method of claim 1, wherein X is OCH2CH2O.
5. The method of claim 1, wherein the ratio of Formula I to Formula II is about 20:80.
6. A method of making Steroid 2:
Figure imgf000011_0001
Figure imgf000011_0002
with narrow band frequency light from a lamp selected from the group consisting of an excimer DBD light source and an LED, at a wavelength from about 295 nm to about 320 nm;
7. The method of claim 6, wherein the wavelength of narrow band frequency light is about 308 nm.
8. The method of claim 6, wherein the lamp is an excimer DBD light source.
9. The method of claim 6, wherein the ratio of Formula I to Formula II is about 5- 10:90-95%.
PCT/US2016/053435 2015-09-25 2016-09-23 Methods of making onapristone intermediates WO2017053793A1 (en)

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JP2018509611A JP2018528944A (en) 2015-09-25 2016-09-23 Method for producing onapristone intermediate
BR112018005999A BR112018005999A2 (en) 2015-09-25 2016-09-23 methods for the production of onapristone intermediates
AU2016326657A AU2016326657B2 (en) 2015-09-25 2016-09-23 Methods of making onapristone intermediates
EP16849747.7A EP3353148A4 (en) 2015-09-25 2016-09-23 Methods of making onapristone intermediates

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WO2018102369A1 (en) 2016-11-30 2018-06-07 Arno Therapeutics, Inc. Methods for onapristone synthesis dehydration and deprotection

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