Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
  • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
  • C07J1/0003—Androstane derivatives
  • C07J1/0011—Androstane derivatives substituted in position 17 by a keto group

Definitions

• the specification relates to a process for preparation of 17-substitued steroids, and intermediates useful therein.
• Abiraterone acetate has been commercially marketed as ZytigaTM.
• the structure of abiraterone acetate along with numbering of the carbon atoms is shown below.
• DHEA dehydroepiandrosterone
• the preferred method appears to be a Suzuki- type cross coupling reaction involving a pyridylborane and an appropriately substituted steroid, as shown below.
• the specification discloses a process for preparation of the compound of formula 4, the process containing the steps of:
• M is alkali metal, alkali earth metal or a transition metal of group 11 or 12;
• Ar is an aryl or heteroaryl group
• Ac is an acyl group.
• Ar is an aryl or heteroaryl group
• R is H or an alcohol protecting group
• R 1 is H, an alcohol protecting group or R 1 together with the oxygen to which it is attached forms a leaving group.
• Ar is an aryl or heteroaryl group; and R is a silyl-based protecting group.
• the specification relates to abiraterone acetate having a purity of >95%, >96%, >97%, >98%, >99%, >99.5% or >99.9%, as determined by H PLC.
• the specification relates to abiraterone acetate substantially free of the bis(steroidal) contaminant as determined by HPLC analysis.
• the specification relates to the compound of formula 3 having a purity of >95%, >96%, >97%, >98%, >99%, >99.5% or >99.9%, as determined by HPLC.
• the specification relates to the compound of formula 2 having a purity of >95%, >96%, >97%, >98%, >99%, >99.5% or >99.9%, as determined by HPLC.
• the specification relates to a process for purification of the compound of formula 3 or 4, as disclosed herein, by
• R 1 is H, an alcohol protecting group or R 1 together with the oxygen to which it is attached forms a leaving group
• M is alkali metal, alkali earth metal or a transition metal of group 11 or 12;
• Ar is an aryl or heteroaryl group and Ac is an acyl group.
• the term "alcohol protecting group” as used herein is not particularly limited, and should be known to a skilled worker or can be determined.
• the protecting group forms an ester, ether or is a silyl-based protecting group.
• the ester formed is acetyl (Ac), benzoyl (Bz) or pivaloyl (Piv) .
• the ether protecting group formed is benzyl (Bn), ⁇ -methoxyethoxymethyl ether (M EM), trityl (Tr), dimethoxy trityl (DMT), methoxymethyl ether (MOM), or the like.
• the si lyl- based protecting group formed is tert-butyldimethylsilyl (TBDMS or TBS), tri-iso- propylsilyloxymethyl (TOM), or triisopropylsilyl (TIPS) .
• a "leaving group” as disclosed herein is a molecular fragment or stable species that can be detached from a molecule in a bond-breaking step.
• the process can also involve, for example and without l im itation, a bond-breaking step between the leaving group and molecule, along with formation of a double bond in the molecule.
• the leaving group in accordance with the specification, is not particularly lim ited and should be known to a person of skill in the art or can be determ ined .
• the ability of a leaving group to depart is correlated with the pK a of the conjugate acid, with lower pK a being associated with better leaving group ability.
• Examples of a leaving group include, without lim itation, an acyl ester or a sulfonate.
• Exam ples of su lfonates can include, without limitation, nonaflate, triflate, fluorosulfonate, tosylate, mesylate or besylate.
• the leaving group is mesylate or tosylate.
• alkali metal as used herein is not particularly lim ited, and should be known to a person of skill in the art.
• Alkali metals contain the group 1 elements of the periodic table, excluding hydrogen, and include lithium (Li), sodium (Na), potassium (K), rubidium (Rb) and caesium (Cs) .
• the alkal i metals used in accordance with the specification include lithium (Li), sodium (Na) or potassium (K) .
• the alkali metal used in accordance with the specification include lithium (Li), sodium (Na) or potassium (K) .
• the alkali metal used in accordance with the specification include lithium (Li), sodium (Na) or potassium (K) .
• lithium (Li) lithium (Li) .
• alkali earth metal as used herein is not particularly lim ited, and should be known to a person of skill in the art.
• Alkali earth metals contain group 2 elements of the periodic table, and can include, for example, beryllium (Be), magnesium (Mg), calcium (Ca), Strontium (Sr), Barium (Ba) .
• the alkali earth metal used in accordance with the specification is magnesium (Mg) .
• transition metals of group 11 or 12 should be understood by a skilled worker, and includes transition metals of group 11 or 12 of the periodic table.
• the transition metals of group 11 can include copper (Cu) and silver (Ag), while the transition metals of group 12 can include zinc (Zn), cadmium (Cd) and mercury (Hg).
• aryl as used herein is not particularly limited, and should be known to a person of skill in the art.
• aryl refers to any functional group or substituent derived from an aromatic carbocyclic ring .
• the aryl group is a Ce-u aryl.
• aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g ., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
• the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
• aryl include, for example and without limitation, phenyl, naphthyl, anthracenyl, and phenanthrenyl.
• heteroaryl as used herein is not particularly limited, and should be known to a person of skill in the art.
• heteroaryl refers to any functional group or substituent derived from an aromatic ring where one or more of the atoms in the aromatic ring is of an element other than carbon.
• heteroaryl includes 5-, 6-, and 7-membered substituted or unsubstituted single-ring aromatic groups that can have one or more heteroatoms as part of the ring system .
• heteroaryls include, for example and without limitation, pyridinyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, or thiophenyl .
• the heteroaryl group is a pyridinyl .
• acyl group as used herein is not particularly limited and should be known to a skilled worker.
• the acyl group is, for example and without limitation, acetyl (Ac), benzoyl (Bz) or pivaloyl (Piv) .
• the acyl group is, for example and without limitation, acetyl (Ac).
• hydrocarbon refers to a group that contains hydrogen and carbon, linked generally via a carbon backbone, but can optionally include heteroatoms.
• Hydrocarbyl groups include, but are not limited to alkyl, aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.
• groups like methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for the purposes of this
• heteroatom is not particularly limited and should be understood by a skilled worker.
• the term means an atom of any element other than carbon or hydrogen.
• heteroatoms include nitrogen, oxygen, and sulfur.
• alkyl as used herein is not particularly limited and should be known to a person of skill in the art; and refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups, including haloalkyl groups such as trifluoromethyl and 2,2,2- trifluoroethyl, etc.
• the alkyl group is a Ci -5 alkyl.
• Ci -5 alkyl in accordance with the specification is not particularly limited and should be known to a person of skill in the art.
• the Ci-6 alkyl may be, for example, and without limitation, any straight or branched alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n- pentyl, i-pentyl, sec-pentyl, t-pentyl, n-hexyl, i-hexyl, 1,2-dimethylpropyl, 2- methylbutyl, 1,2-dimethylbutyl, l-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1- dimethylbutyl, 2,2-dimethylbutyl, 2-ethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl or 3-methylpentyl.
• nucleophilic addition reaction is not particularly limited and should be known to a skilled worker. Nucleophilic addition reaction can be considered an addition reaction where in a chemical compound a ⁇ -bond is removed by creation of two new ⁇ -bonds by the addition of a nucleophile.
• nucleophile as used herein is not particularly limited and should be known to a skilled worker. Nucleophile can be considered as a species that donate an electron-pair to an electrophile to form a chemical bond in a reaction . All molecules or ions with a free pair of electrons or at least one pi bond can act as nucleophiles.
• electrophile is also not particularly limited and should be known to a skilled worker.
• An electrophile (literally electron -lover) can be considered as a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile.
• Ar in the compound Ar-M can act as the nucleophile, while carbonyl carbon can act as the electrophile.
• various embodiments of the compound Ar-M can be used so long as the nucleophilic addition of Ar to the carbonyl carbon can take place.
• Ar-M can include, for example and without limitation, 3-pyridinyl lithium, phenyl magnesium bromide or 3-pyridinyl magnesium bromide.
• Ar-M can include 3-pyridinyl lithium .
• dehydrating a compound is not particularly limited and should be known to a skilled worker.
• a dehydration reaction can be considered as an elimination reaction that involves the loss of water, or analogue, from the reacting molecule, and which can lead to formation of an additional bond .
• the method of performing the dehydration reaction is not particularly limited. In one embodiment, for example and without limitation, the dehydration reaction is carried out using an acid or a base.
• the term "acid” as used herein is not particularly limited and should be known to a skilled worker.
• An acid can be considered as a substance that can act as a proton donor (Bronsted-Lowry acid) or an electron pair acceptor (Lewis acid).
• the acid used in the process disclosed herein is, for example and without limitation, hydrochloric acid (HCI), hydrobromic acid (HBr), acetic acid (CH 3 C0 2 H), sulfuric acid (H 2 S0 4 ) or p-toluenesulfonic acid (p-TSA).
• HCI hydrochloric acid
• HBr hydrobromic acid
• acetic acid CH 3 C0 2 H
• sulfuric acid H 2 S0 4
• p-TSA p-toluenesulfonic acid
• base is not particularly limited and should be known to a skilled worker.
• a base can be considered as a substance that can accept hydrogen ions (protons) or donate an electron pair.
• the base used in the process disclosed herein is, for example and without limitation, triethylamine (TEA), ⁇ , ⁇ -diisopropylethylamine, (DIPEA), l,8-diazabicycloundec-7- ene (DBU), sodium tert-butoxide (t-BuONa), potassium tert- butoxide (t-BuOK), lithium diisopropylamide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS) or lithium tetramethylpiperidide (LiTMP).
• the base used in the process disclosed herein is triethylamine (TEA).
• the step of deprotecting the compound of formula 3 as disclosed herein can be optional depending upon the substituents present. Further, the step of deprotection is not particularly limited and should be known to a skilled worker or can be determined. The method of carrying out the deprotection step can depend upon the substituent. In one embodiment, for example and without limitation, deprotection is carried out using an acid. The acid used for deprotection is not particularly limited and should be known to a skilled worker or can be determined. Examples of an acid include acids as are described herein. [0033] In another embodiment, the step of deprotection is carried out, for example and without limitation, using a fluoride source. The fluoride source is not particularly limited and should be known to a skilled worker or can be determined.
• the fluoride source is sodium fluoride (NaF), tetra-butyl ammonium fluoride or pyridine hydrofluoride (HF-Py) .
• the step of deprotection using a fluoride source can be carried out, for example, when the protecting group is a silyl-based protecting group, as described herein .
• the step of acylating the compound of formula 3 as disclosed herein can be optional depending upon the substituent present. As used herein, acylation can be considered as the process of adding an acyl group to a compound . Further, the step of acylation is not particularly limited and should be known to a skilled worker or can be determined.
• the step of acylation involves acetylating the compound of formula 3, where R is H .
• the process of acetylation is not particularly limited and should be known to a skilled worker or can be determined .
• the step of acetylation is carried out using acetic anhydride (Ac 2 0) or acetyl chloride (AcCI), in the presence of base.
• the base used is not particularly limited and can include one of the bases as noted herein .
• Step 1 involves protecting the hydroxyl group of compound of formula la to form the compound of formula lb.
• the protecting group used is a silyl-based protecting group, and is tert-butyldimethylsilyl (TBS), although other protecting groups, including other silyl-based protecting groups can be used.
• TBS tert-butyldimethylsilyl
• the use of the silyl-based protecting group, such as the tert-butyldimethylsilyl (TBS) can avoid generation of or reduce the amount of the impurity having a double bond at the C3-C4 position .
• the impurity having a double bond between the C3-C4 position can be formed in an elimination reaction, for example in the presence of a base, where, for example, an acetate (leaving group) at the C3 position is removed and a double bond formed.
• the reaction mixture can be quenched using water, which can allow precipitation of the solid product that can be separated by filtration.
• Nucleophilic addition reaction of the compound of formula lb with pyridinyl lithium in step 2 leads to formation of the compound of formula 2b.
• pyridinyl-metal complexes can be used for nucleophilic addition. These include, for example and without limitation, pyridinyl-magnesium, pyridinyl-cuprate or pyridinyl-zinc reagent.
• pyridinyl lithium can help avoid use of more toxic metals and can provide cleaner and safer reaction conditions.
• the reaction conditions such as, for example and without limitation, solvent, temperature and ratio of reagents, for the nucleophilic reaction can vary.
• the solvent used in the nucleophilic reaction in Step 2 of Scheme 1 can include, for example, toluene, tetrahydrofuran (THF), dimethyl ether (DM E) or diethyl ether.
• the solvent used in Step 2, as shown in Scheme 1 is toluene.
• the temperature for carrying out the nucleophilic coupling reaction can also vary. Temperatures for the nucleophilic coupling reaction can range from low temperatures, such as, for example and without limitation, -80°C to higher temperatures, such as, for example and without limitation, 50°C. In one
• the temperature for carrying out the nucleophilic addition reaction is from -80°C to 25°C, and values in between .
• the temperature can range from -80°C to 0°C, -75°C to - 10°C, -70°C to -20°C, -70°C to -40°C or -70°C to -60°C.
• the reaction can be quenched using an aqueous solution, which can include, for example and without limitation, brine. Extraction and evaporation of the organic layer can provide crude compound 2b.
• Crude compound 2b can be triturated with an organic solvent to provide compound 2b that can be used in subsequent process steps without further purification .
• the solvent used for trituration can vary.
• trituration was performed using acetonitrile.
• the hydroxyl group formed in step 2 can be converted into a leaving group in step 3, by reaction with mesyl chloride to form a mesylate, which can then undergo a dehydration reaction in the presence of a base to form compound 3b.
• the leaving group formed can vary and different leaving groups can be used for the elimination reaction to form the double bond.
• the hydroxyl group is converted into a sulfonate-based leaving group, which can include, for example and without limitation, nonaflate, triflate, fluorosulfonate, tosylate, mesylate or besylate, as noted above.
• a sulfonate-based leaving group can include, for example and without limitation, nonaflate, triflate, fluorosulfonate, tosylate, mesylate or besylate, as noted above.
• dehydration of the alcohol is performed in the presence of an acid, where H 2 0 forms the leaving group.
• the sulfonate-based leaving groups can form good leaving groups and can help in improving the overall elimination reaction to form the double bond .
• the sulfonate-based leaving group is a mesylate.
• the reaction conditions such as, for example and without limitation, solvent, temperature and ratio of reagents, for the dehydration reaction can vary.
• the solvent used in the nucleophilic reaction in Step 3 of Scheme 1 can include, for example, dichloromethane (DCM), toluene, tetrahydrofuran (THF), dimethyl ether (DME) or diethyl ether.
• the solvent used in Step 3, as shown in Scheme 1, is dichloromethane (DCM) .
• the temperature for carrying out the dehydration reaction can also vary.
• Temperatures for the dehydration reaction can range from temperatures as low as, for example and without limitation, -40°C to higher temperatures, such as, for example and without limitation, 200°C, and can depend upon the leaving group.
• the temperature for carrying out the dehydration reaction, as shown in Step 3 of Scheme 1 is from -40°C to 50°C, and values in between .
• the temperature can range from -20°C to 40°C, - 15°C to 30°C, -10°C to 25°C, 0°C to 25°C or 5°C to 25°C.
• the reaction is initially performed at about 5°C and then allowed to continue at about 25°C.
• Step 4 Deprotection of compound 3b using an acid leads to compound 3c (Step 4).
• Step 5 involves acylation of the compound 3c using acetic anhydride to form compound 4.
• the reaction mixture can be quenched with an aqueous solution, for example water, to precipitate compound 4, which can be separated by filtration.
• compound 4 having purities of about 95% or greater can be achieved.
• the process can avoid formation of the bis(steroidal) impurity that can be difficult to separate by purification.
• the solvent system used for recrystallization is methanol, ethanol, isopropanol, isopropanol/water, toluene/heptanes or
• acetonitrile/water different ratios of the solvent system have been determined for recrstallization.
• methanol or ethanol was used for recrystallization from about 3 to 10 parts v/w and values in between like about 4 to 6 parts v/w or about 5 parts v/w.
• the ratio of the solvents can vary.
• toluene/heptanes mixtures of about 0.5/3 v/v or about 1/2 v/v parts can be used; and for acetonitrile/water, mixtures of about 8/1 v/v, about 7/1, about 6/1 or about 5/1 parts can be used.
• the compound of formula 4 can be recrystallized using ethanol (5 v/w part) to provide a product having 98% purity or more, as disclosed herein, and lacking any bis(steroidal) contaminant. Further optimization using solvent and scale can improve purity.
• recrystallization as used herein is not particularly limited and should be known to a skilled worker.
• recrystallization refers to a technique used to purify chemical compounds. The process can be carried out by dissolving both impurities and a compound in an appropriate solvent, either the desired compound or impurities can be coaxed out of solution, leaving the other behind.
• the compound of formula 3 or 4 along with impurities, is dissolved in the relevant solvent. Dissolution can take place at elevated temperatures, including at the boiling point of the solvent used. This solvent is allowed to cool and crystallization of the compound of formula 3 or 4 to take place, followed by collection of the crystals.
• Scheme 2 discloses alternate embodiments of carrying out the process for preparation of the compound of formula 4 in accordance with the specification, and where different R groups can be present and the reaction can be carried out in the presence or absence of a protecting group.
• Scheme 2 also discloses alternative methods for carrying out the elimination reaction.
• compound of formula 2c can be converted to the compound of formula 3c by use of an acid.
• the acid used in not particularly limited, and can include, for example and without limitation, hydrochloric acid, para-toluenesulfonic acid (PTSA) or acetic acid (AcOH).
• PTSA para-toluenesulfonic acid
• AcOH acetic acid
• the acetylation and elimination reaction can be carried out concurrently by reaction of the compound of formula 2c with acetic anhydride to form compound of formula 4.
• the organic solvent used in the reactions described herein is not particularly limited and should be known to a person of skill in the art or can be determined. The particular solvent used would depend upon the reactants and the reaction being carried out, to allow the reaction to proceed.
• the reaction temperature used in the process steps disclosed herein is not particularly limited and should be known to a skilled worker or can be determined . The reaction temperature can depend upon a number of factors including reagents, solvent and presence of catalyst.
• the specification relates to the compound of formula 3, where Ar is an aryl group; and R is a silyl-based protecting group.
• the specification relates to abiraterone acetate having a purity of >95%, >96%, >97%, >98%, >99%, >99.5% or >99.9%, as determined by H PLC. Further, the specification discloses abiraterone acetate being substantially free of the bis(steroidal) contaminant. [0053] In still another aspect, the specification relates to the compound of formula 3 having a purity of >95%, >96%, >97%, >98%, >99%, >99.5% or >99.9%, as determined by HPLC.
• the specification relates to compound of formula 2 having a purity of >95%, >96%, >97%, >98%, >99%, >99.5% or >99.9%, as determined by HPLC.
• a 2L three neck round bottom flask equipped with a overhead stirrer, thermometer, dropping funnel and nitrogen inlet was charged with toluene (500 ml) and cooled to -65°C. With agitation, 2.5M n-butyl lithium (nBuLi) in hexanes (225ml, 550mmol) was charged while maintaining a temperature of reaction less than -60°C. Addition took 50 min. Then 3-bromopyridine (59g 373mmol) in toluene (100 ml) was charged over 2 hr. The solution was agitated at -65°C for 0.5 hr.
• the reaction mixture was then stirred at 5°C for 1.5 - 2 h.
• the ice-bath was removed and the reaction mixture was stirred to room temperature for 12 h.
• DI water 600 mL 3 parts was added to the reaction mixture and stirred for 30 minutes, separated out the DCM layer.
• the DCM layer is then washed with DI water (600 mL, 3 parts) and was concentrated on a rotovap (bath @35°C) down to 1000 mL (5 parts).
• solvent exchanged to tetrahydrofuran (THF) by charging THF (2x2000 mL, 10 parts each) and concentrated to 1000 mL (5 parts).
• THF tetrahydrofuran
• R is H or an alcohol protecting group
• R 1 is H, an alcohol protecting group or R 1 together with the oxygen to which it is attached forms a leaving group
• M is alkali metal, alkali earth metal or a transition metal of group 11 or 12;
• Ar is an aryl group
• Ac is an acyl group.
• step of acylating comprises acetylating the compound of formula 3.
• Ar is an aryl group
• R is H or an alcohol protecting group
• R 1 is H, an alcohol protecting group or R 1 together with the oxygen to which it is attached forms a leaving group.
• R is a silyl-based protecting group.
• R is H or an alcohol protecting group
• Ar is an aryl or heteroaryl group and Ac is an acyl group
• the process containing the step of recrstallizing the compound of formula 3 or 4 with a solvent selected from the group consisting of methanol, ethanol, isopropanol, isopropanol/water, toluene/heptanes and acetonitrile/water.
• a solvent selected from the group consisting of methanol, ethanol, isopropanol, isopropanol/water, toluene/heptanes and acetonitrile/water.

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• 2013
  • 2013-04-22 CA CA2871314A patent/CA2871314A1/en not_active Abandoned
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