DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of earlier Indian Provisional Patent Application Nos. 201741047097 filed on December 28, 2017, and 201841009397 filed on March 14, 2018, which are incorporated by reference herein in their entirety. All literature and patent references cited in this specification are likewise incorporated herein by reference in their entirety.
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of rucaparib and its pharmaceutically acceptable salts.
BACKGROUND OF THE INVENTION
Rucaparib is an inhibitor of the mammalian polyadenosine 5’-diphosphoribose polymerase (PARP) enzyme. Rucaparib is chemically known as 8-fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl]-6H-pyrrolo[4,3,2-ef][2]benzazepin-6-one and its chemical structure is shown below.

Rucaparib is marketed in the United States under the tradename RUBRACA® by Clovis Oncology. RUBRACA® contains the camsylate salt of rucaparib, which has a chemical name of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonate. The chemical formula of rucaparib camsylate is C19H18FN3O•C10H16O4S and the chemical structural shown below.

Rucaparib and process for its preparation are disclosed in U.S. Patent Nos. 6,495,541 and 7,323,562, and in Adam T. Gillmore, et al., “Multkilogram Scale-Up of a Reductive Alkylation Route to a Novel PARP Inhibitor,” Organic Process Research & Development, 16 (12), 1897-1904 (2012). Rucaparib camsylate is disclosed in U.S. Patent No. 9,045,487. There continues to be a need in the art for practical methods for the synthesis of rucaparib and pharmaceutically acceptable salts thereof, particularly on an industrial scale.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of rucaparib. In one embodiment, rucaparib may be prepared by a process that includes the steps of:
a. reacting a compound of Formula-A with a compound of Formula-C in a suitable solvent to give a compound of Formula-B
;
b. deprotecting the compound of Formula-B to yield rucaparib
; and
c. optionally converting rucaparib into its pharmaceutically acceptable salts.
wherein “L” is a leaving group and “P” is an amine protecting group. Each “R” is independently selected from the group consisting of hydrogen (H) and an alkyl moiety, or together the “R” moieties form a cyclic ring, optionally containing one or more of O or N and optionally substituted with an alkyl moiety.
Within the context of this embodiment, the compounds of Formula-A, Formula-B, and/or rucaparib may be complexed with a salt.
Within the context of this embodiment, the leaving group L may be a halogen, for example, F, CI, -Br, or -I. In one embodiment, the leaving group L is -Br and the protecting group P is methyl carbamate.
In one embodiment, “R” is either H in each instance, or together the “R” moieties combine to form a heterocyclic ring.
In another embodiment, rucaparib may be prepared by a process that includes the steps of:
a. reacting a compound of Formula-D with a compound of Formula-E to give a compound of Formula-B
;
b. deprotecting the compound of Formula-B to yield rucaparib
; and
c. converting rucaparib into its pharmaceutically acceptable salts.
wherein “L” is a leaving group and “P” is an amine protecting group. Each “R” is independently selected from the group consisting of hydrogen (H) and an alkyl moiety, or together the “R” moieties form a cyclic ring, optionally containing one or more of O or N and optionally substituted with an alkyl moiety.
Within the context of this embodiment, the compound of Formula-B may be optionally converted to an acid addition salt and the deprotecting step yields the acid addition salt of rucaparib.
In one embodiment, “R” is H.
In another aspect, the present invention provides a process for the preparation of a compound of Formula-E. The compound of Formula-E may be prepared by a process that includes the steps of:
a. subjecting a compound of Formula-F to reductive amination to give a compound of Formula-G
; and
b. protecting the compound of Formula-G to give a compound of Formula-E,
,
wherein “L” is a leaving group and “P” is an amine protecting group. In some embodiments, the protecting group is methyl carbamate. Leaving groups (“L”) are well known to those skilled in the art and may be, for example, a halogen, an alkyl sulfonyloxy group, or an aryl sulfonyloxy group. Suitable halogens include -F, -CI, -Br, and –I. One suitable alkyl sulfonyloxy group includes, but is not limited to a methylsulfonyloxy group. One suitable aryl sulfonyl group includes, but is not limited to, a p-toluene sulfonyloxy group. One of skill in the art would recognize many other suitable leaving groups similar to those named above.
Within the context of this embodiment, the compound of Formula-E may be further converted into rucaparib or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a process for the preparation a compound of Formula-C1.
In one embodiment, the compound of Formula-C1 may be prepared by a process that includes the steps of:
a. subjecting a compound of Formula-H to reductive amination to give a compound of Formula-I
; and
b. protecting the compound of Formula-I in a solvent to give a compound of Formula-C1
,
wherein “P” is an amine protecting group.
In one embodiment, the amine protecting group is methyl chloroformate.
Within the context of this embodiment, the solvent may be, for example, 1,4-dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dichloromethane, toluene, acetone, dimethyl formamide, or mixtures thereof. In one embodiment, the solvent is dichloromethane.
Within the context of this embodiment, the compound of Formula-C1 may be further converted into rucaparib or a pharmaceutically acceptable salt thereof.
In another embodiment, the compound of Formula-C1 may be prepared by a process that includes the steps of:
a. reacting a compound of Formula-J with methylamine in a solvent to give a compound of Formula-I
; and
b. protecting the compound of Formula-I in a solvent to give a compound of Formula-C1
,
wherein “L” is a leaving group and “P” is an amine protecting group.
In one embodiment, the amine protecting group is methyl chloroformate.
Within the context of this embodiment, the solvent may be an ether solvent, a polar aprotic solvent, or mixtures thereof.
Examples of suitable ether solvents include, but are not limited to, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, or mixtures thereof.
Examples of polar aprotic solvents include, but are not limited to, acetonitrile, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidine, and mixtures thereof.
Within the context of this embodiment, the compound of Formula-C1 may be further converted into rucaparib or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a process for the preparation of a compound of Formula-M.
In one embodiment, the compound of Formula-M may be prepared by a process that includes the steps of:
a. reacting a compound of Formula-H with diethanolamine in a solvent to give a compound of Formula-K
;
b. subjecting the compound of Formula-K to reductive amination to give a compound of Formula-L
; and
c. protecting the compound of Formula-L to give a compound of Formula-M.
,
wherein “P” is an amine protecting group.
Within the context of this embodiment, examples of suitable solvents include, but are not limited to, methanol, ethanol, propanol, butanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, toluene, diisopropyl ether, methyl t-butyl ether, isopropyl ether, isopropanol, dichloromethane, chloroform, or mixtures thereof.
In another aspect, the present invention provides a process of preparing a compound of Formula-D. In one embodiment, the compound of Formula-D may be prepared by a process that includes the step of treating a compound of Formula-A with a suitable reagent in the presence of a base and a solvent
,
wherein “L” is a leaving group and each “R” is independently selected from the group consisting of hydrogen (H) and an alkyl moiety, or together the “R” moieties form a cyclic ring, optionally containing one or more of O or N and optionally substituted with an alkyl moiety.
Examples of suitable reagents include, but are not limited to, trimethyl borane, sequential trimethyl borane and diethanolamine, bis(pinacolato)diborane, and trialkylborates. Examples of suitable trialkylborates include, but are not limited to, triisopropyl borate, trimethyl borate, or triethyl borate.
Within the context of the invention, the compound of Formula-D may be converted to rucaparib or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides novel compounds of Formula-C1, Formula-C2, Formula-C3, Formula-D1, Formula-D2, Formula-D3, and Formula-L. Each of these compounds may be useful in the preparation of rucaparib.
DETAILED DESCRIPTION OF THE INVENTION
The present invention now will be described more fully hereinafter with reference to the accompanying examples and experiments in which illustrative embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
The present invention provides processes for the preparation of rucaparib, intermediates thereof, and pharmaceutically acceptable salts of rucaparib.
The intermediates utilized in the reaction schemes disclosed herein contain moieties that are interchangeable in different embodiments, for example, leaving groups, protecting groups, and moieties designated (and well understood in the art) as “R”.
Within the context of the reaction schemes depicted and disclosed herein, “L” is a leaving group and “P” is an amine protecting group. Each “R” may be, independently, a hydrogen (H) or an alkyl moiety, or together the “R” moieties form a cyclic ring, optionally containing one or more of O or N and optionally substituted with an alkyl moiety.
Leaving groups (“L”) are well known to those skilled in the art and may be, for example, a halogen, an alkyl sulfonyloxy group, or an aryl sulfonyloxy group. Suitable halogens include -F, -CI, -Br, and –I. One suitable alkyl sulfonyloxy group includes, but is not limited to a methylsulfonyloxy group. One suitable aryl sulfonyl group includes, but is not limited to, a p-toluene sulfonyloxy group. One of skill in the art would recognize many other suitable leaving groups similar to those named above.
Amine protecting groups (“P”) are well known to those skilled in the art. Examples of suitable amine protecting groups, as well as suitable conditions for protecting and deprotecting can be found in prior art, such as J.F.W. McOmie (Ed.), Protective Groups in Organic Chemistry, Plenum Press, London (1973) and Greene's Protective Groups in Organic Synthesis, 5th Edition, Peter G. M. Wuts, John Wiley & Sons, Inc., Hoboken, New Jersey (2014), which are incorporated herein by reference in their entirety. For example, suitable protecting groups include, but are not limited to, carbonyls (e.g., methyl carbamate, 9- fluorenylmethyoxycarbonyl (Fmoc), trichloroethoxycarbonyl (Troc), tert-butyloxycarbonyl (BOC), 2-trimethylsilylethyloxycarbonyl (Teoc), allyloxycarbonyl (Alloc), p-methoxybenzyl carbonyl (Moz), and carboxybenzyl (Cbz)), sulfonyls (e.g., p-toluenesufonyl (Ts), trimethylsilylethanesulfoyl (Ses), tert-butylsulfonyl (Bus), 4-methoxyphenylsulfonyl, 4- nitrobenzenesulfonyl (nosyl)), trityl (trt), benzyl (Bn), 3,4-dimethyoxybenzyl (Dmpm), p- methoxybenzyl (PMB), p-methoxyphenyl (PMP), acetyl (Ac), formyl, trifluoroacetyl (Tfa), benzoyl (Bz), or 2-nitrophenylsulfenyl (Nps) groups. In some embodiments, the protecting group is methyl carbamate.
As used herein, “rucaparib”, unless otherwise indicated, includes any polymorphic or amorphous form. It further includes any salt, solvate, or combination thereof.
In one embodiment, rucaparib may be prepared by a process that includes the steps of:
a) reacting a compound of Formula-A with a compound of Formula-C to give a compound of Formula-B
;
b) removing the protecting group (“P”) of the compound of Formula-B to yield rucaparib
; and
c) optionally converting rucaparib into its pharmaceutically acceptable salts.
Contemplated as within the scope of this embodiment is the use of pharmaceutically acceptable salts of Formula-A. In such instances, the salt complex would be carried through the reaction, creating the salt of Formula-B and the salt of rucaparib. The salt may be, but is not limited to, hydrochloride, sulfuric, phosphorous, hydrobromide, oxalate, maleate, fumarate, malate, tartrate, citrate, benzoate, sulfonate, or camsylate.
As depicted above, a compound of Formula-A (or its salt) may be reacted with a compound of formula-C to yield a compound of Formula-B (or its salt). This conversion may be carried out in the presence of a catalyst and a suitable solvent. The catalyst may be, for example, 1,1-bis(diphenylphosphino)ferrocene palladium (II) chloride, bis(dibenzylideneacetone)palladium(0) (“Pd(dba)2”), tris(dibenzylidenacetone)palladium(0) (“Pd(dba)3”), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (“Pd(dppp)2Cl2”), tetrakis(triphenylphosphine)palladium(0) (“Pd(PPh3)4”), Palladium(II) acetate (“Pd(OAc)2”), or bis(triphenylphosphine)palladium(II) dichloride (“Pd(PPh3)2Cl2”). The solvent may be, for example, dimethyl formamide, dimethyl acetamide, 1,4-dioxane, toluene, ethyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, monoglyme, diglyme, water, or mixtures thereof.
The compound of Formula-B may be optionally purified by forming an acid addition salt. Suitable acid addition salts include, but are not limited to, hydrochloride, sulfuric, phosphorous, hydrobromide, oxalate, maleate, fumarate, malate, tartrate, citrate, benzoate, and sulfonate salts.
The compound of Formula-B may be converted into rucaparib by methods known in the art, for example, by the processes disclosed in U.S. Patent No. 7,323,562, which is hereby incorporated by reference. Rucaparib may further converted into a pharmaceutically acceptable salts by methods well known in the art, for example, per the processes disclosed in U.S. Patent No. 9,045,487, which is hereby incorporated by reference.
In Formula-C, both “R” moieties may be H. This embodiment is shown below as Formula-C1.

In Formula-C, both “R” moieties may be H and the protecting group may be methyl carbamate. This embodiment is shown below as Formula-C2.

In Formula-A, the leaving group may be bromine. This embodiment is shown below as Formula-A1.

The compound of Formula-B1 may be formed by reacting a compound of Formula-A1 with a compound of Formula-C2, shown below. An example of the preparation of the compound of Formula-B1 by this route is shown in Example 8.

Formula-A1 may be prepared by methods known in the art, for example, by processes disclosed in U.S. Patent No. 6,495,541 and Chinese Patent No. 106008530, both which are hereby incorporated by reference.
In Formula-C, the protecting group may be methyl carbamate and the “R” moieties may form a heterocyclic ring, shown below as Formula-C3.

Formula-B1 may be formed by reacting a compound of Formula-A1 with a compound of Formula-C3, shown below. An example of the preparation of the compound of Formula-B1 by this route is shown in Example 9.

In another embodiment, rucaparib may be prepared by a process that includes the steps of:
a) reacting a compound of Formula-D with a compound of Formula-E to give a compound of Formula-B; and

b) deprotecting the compound of Formula-B to yield rucaparib
.
Within the context of the reaction schemes depicted above, “L” and “P” are as defined above.
According to this embodiment, a compound of Formula-D may be reacted with a compound of Formula-E to result in a compound of Formula-B. This may be carried out in the presence of a catalyst in a suitable solvent. Examples of suitable solvents include, but are not limited to, dimethyl formamide, dimethyl acetamide, 1,4-dioxane, toluene, ethyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, monoglyme, diglyme, water, or mixtures thereof. Examples of suitable catalyst include 1,1-bis(diphenylphosphino)ferrocene palladium (II) chloride, bis(dibenzylideneacetone)palladium(0) (“Pd(dba)2”), tris(dibenzylidenacetone)palladium(0) (“Pd(dba)3”), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (“Pd(dppp)2Cl2”), tetrakis(triphenylphosphine)palladium(0) (“Pd(PPh3)4”), Palladium(II) acetate (“Pd(OAc)2”), or bis(triphenylphosphine)palladium(II) dichloride (“Pd(PPh3)2Cl2”).
Optionally, the compound of Formula-B may purified, for example, by forming an acid addition salt. Suitable salts include hydrochloride, sulfuric, phosphorous, hydrobromide, oxalate, maleate, fumarate, malate, tartarate, citrate, benzoate, sulfonate, and camsylate salts. In such instances, deprotecting of the salt of Formula-B will result in a salt of rucaparib.
Formula-B may be deprotected into rucaparib by methods known in the art, for example, by the processes disclosed in U.S. Patent No. 7,323,562, which is hereby incorporated by reference, or by any common methods well-known in the art.
Rucaparib may further converted into a pharmaceutically acceptable salts by methods well known in the art, for example, per the processes disclosed in U.S. Patent No. 9,045,487, which is hereby incorporated by reference
In Formula-D; each “R” moiety may be H. This embodiment is shown below as Formula-D1.

In Formula-E, the leaving group may be bromine (-Br) and the protecting group may be a methyl carbamate group. This embodiment is shown below as Formula-E1.

A compound of Formula-D1 may be reacted with a compound of Formula-E1 to result in the compound of Formula-B1 as shown below. An example of this reaction can be found in Example 10.

In Formula-D, the “R” moieties may form a heterocyclic ring as shown below as Formula-D2.
.
A compound of Formula-D2 may be reacted with a compound of Formula-E1 to result in the compound of Formula-B1. An example of this reaction is disclosed in Example 11.
In Formula-D, the “R” moieties may form a heterocyclic ring substituted with methyl groups, shown below as Formula-D3.

A compound of Formula-D3 may be reacted with a compound of Formula-E1 to result in the compound of Formula-B1. An example of this reaction is disclosed in Example 12.
In another aspect, the present invention provides a method for preparing a compound of Formula-D.
In one embodiment, a compound of Formula-D may prepared by reacting a compound of Formula-A or an acid addition salt thereof with suitable reagent in the presence of a base and a solvent to give a compound of Formula-D.

Within the context of the reaction schemes depicted above, “L” and “R” are as previously defined.
According to this embodiment, a compound of Formula-A or an acid addition salt thereof, may be converted to a compound of Formula-D. This may be carried out with suitable reagent in the presence of a base in a suitable solvent. The suitable base includes, but is not limited to, n-butyl lithium. Suitable solvents include, but are not limited to, tetrahydrofuran, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, 1,4-dioxane, dimethyl formamide, dimethyl acetamide, toluene, ethyl acetate, 2-methyl tetrahydrofuran, monoglyme, diglyme, water, or mixtures thereof. In particularly useful embodiments, tetrahydrofuran is used.
Suitable acid addition salts of Formula-A include, but are not limited to, hydrochloride, sulfuric, phosphorous, hydrobromide, oxalate, maleate, fumarate, malate, tartarate, citrate, benzoate, sulfonate, or camsylate salts.
Suitable reagents may be chosen based on the desired identity of the “R” moieties. For example, as disclosed above, the reagent may be trimethyl borane, sequential trimethyl borane and diethanolamine, bis(pinacolato)diborane, and trialkylborates. Examples of suitable trialkyl borates include, but are not limited to, triisopropyl borate, trimethyl borate, or trimethyl borate.
In one embodiment, the suitable reagent is trimethyl borane and the reaction results in the formation of a compound of Formula-D1, shown below. An example of the preparation of a compound of Formula-D1 is shown in Example 6.

In another embodiment, a compound of Formula-D1 may be further reacted with diethanolamine to result in the formation of a compound of Formula-D2, shown below. An example of the preparation of a compound of Formula-D2 is shown in Example 7.

In another embodiment, the suitable reagent is bis(pinacolato)diborane and results in the formation of a compound of Formula-D3, shown below. An example of preparation of a compound of Formula-D3 is shown in Example 5.

In another aspect, the present invention provides a method for preparing a compound of Formula-E.
In one embodiment, a compound of Formula-E may be prepared by a process that includes the steps of:
a) subjecting a compound of Formula-F to reductive amination to give a compound of Formula-G; and

a) protecting the compound of Formula-G to give a compound of Formula-E
.

Within the context of the reaction schemes depicted above, “L” and “P” are as previously defined.
According to the present embodiment, a compound of Formula-F may be subjected to reductive amination to give a compound of Formula-G. This may be carried out, for example, by reacting a compound of Formula-E with methylamine followed by addition of suitable reducing agent. Examples of suitable reducing agents include, but are not limited to, sodium cyanoborohydride, potassium cyanoborohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride, Raney-Ni, Pd/C, or trichlorosilane.
The compound of Formula-G may then be protected with a suitable amine protecting group to give a compound of Formula-E. Any suitable conditions for the protecting step may be used, e.g., J.F.W. McOmie (Ed.), Protective Groups in Organic Chemistry, Plenum Press, London (1973); Greene's Protective Groups in Organic Synthesis, 5th Edition, Peter G. M. Wuts, John Wiley & Sons, Inc., Hoboken, New Jersey (2014), which are incorporated herein by reference in their entirety.
In particular, a compound of Formula-E wherein “P” is an alkoxy carbonyl group may be formed by reacting the compound of Formula-G with an alkyl halo formate in the presence of a suitable base and solvent. The alkyl halo formate may be, for example, methyl chloroformate. Suitable bases include, but are not limited to, inorganic bases such as alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali amines, alkali alkoxides, and organic bases such as pyridine, triethylamine, and N,N-diisopropylethylamine, morpholine, and N-methyl morpholine. In particularly useful embodiments, triethylamine is used. Examples of suitable solvents include 1,4-dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dichloromethane, toluene, acetone, dimethyl formamide, or mixtures thereof. In particularly useful embodiments, the solvent is dichloromethane.
In another aspect, the present invention provides a method for the preparation of a compound of Formula-C.
In one embodiment, a compound of Formula-C may be prepared by a process that includes the steps of:
a) subjecting a compound of Formula-H to reductive amination to give a compound of Formula-I; and

b) protecting the compound of Formula-I with a suitable protecting group to give a compound of Formula-C1.

According to the present embodiment, a compound of Formula-H may be subjected to reductive amination to yield a compound of Formula-I. This may be carried out, for example, by reacting a compound of Formula-H with methylamine and adding a suitable reducing agent. Examples of suitable reducing agents include, but are not limited to sodium cyanoborohydride, potassium cyanoborohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride, Raney-nickel, palladium on carbon (Pd/C), or trichlorosilane.
The compound of Formula-I may then be protected with a suitable amine protecting group to yield a compound of Formula-C1.
Amine protecting groups (“P”) are as defined above. For example, the “P” in Formula-C1 may be an alkoxy carbonyl group and may be formed by reacting a compound of Formula-I with an alkyl halo formate in the presence of a suitable base and solvent. Suitable bases include, but are not limited to, inorganic bases such as alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali amines, alkali alkoxides, and organic bases such as pyridine, triethylamine, and N,N-diisopropylethylamine, morpholine, and N-methyl morpholine. In particularly useful embodiments, triethylamine is used. Examples of suitable solvents include 1,4-dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dichloromethane, toluene, acetone, dimethyl formamide, or mixtures thereof. In particularly useful embodiments, the solvent is dichloromethane.
The alkyl halo formate may be methyl chloroformate and the compound of Formula-I may be converted to a compound of Formula-C2.

In another embodiment, a compound of Formula-C1 may be prepared a process that includes the steps of:
a) reacting a compound of Formula-J with methylamine in the presence of a suitable solvent to give a compound of Formula-I; and

b) protecting the compound of Formula-I to give a compound of Formula-C1.

Within the context of the reaction schemes depicted above, “L” and “P” are as previously defined. In particularly useful embodiments, the leaving group is bromine (-Br).
According to the present embodiment, a compound of Formula-J may be reacted with methylamine in the presence of a suitable solvent. Examples of suitable solvents include, but are not limited to, ethers, polar aprotic solvents, and mixtures thereof. Examples of suitable ethers include, but are not limited to, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, or mixtures thereof. Examples of suitable polar aprotic solvents include, but are not limited to, acetonitrile, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, N methylpyrrolidine, or mixtures thereof.
A compound of Formula-I wherein “P” is an alkoxy carbonyl group may be formed by reacting the compound of Formula-I with an alkyl halo formate in the presence of a suitable base and solvent. The alkyl halo formate may be, for example, methyl chloroformate, in which case, a compound of Formula-C2 would be formed. Suitable bases include, but are not limited to, inorganic bases such as alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali amines, alkali alkoxides, and organic bases such as pyridine, triethylamine, and N,N-diisopropylethylamine, morpholine, and N-methyl morpholine. In particularly useful embodiments, triethylamine is used. Examples of suitable solvents include 1,4-dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dichloromethane, toluene, acetone, dimethyl formamide, or mixtures thereof. In particularly useful embodiments, the solvent is dichloromethane.
In another aspect, the present invention provides a process for the preparation of a compound of Formula-M.
In one embodiment, a compound of Formula-M may be prepared by a process that includes the steps of:
a) reacting a compound of Formula-H with diethanolamine to give a compound of Formula-K;

b) subjecting the compound of Formula-K to reductive amination to give a compound of Formula-L; and

c) protecting the compound of Formula-L to give a compound of Formula-M
.
According to the present embodiment, a compound of Formula-H may be reacted with diethanolamine to yield a compound of Formula-K. This may be carried out in a solvent, for example, methanol, ethanol, propanol, butanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, toluene, diisopropyl ether, methyl t-butyl ether, isopropyl ether, isopropanol, dichloromethane, chloroform, or mixtures thereof.
The compound of Formula-K may then be reacted with methylamine followed by addition of a suitable reducing agent to give a compound of Formula-L. Examples of suitable reducing agents include, but are not limited to sodium cyanoborohydride, potassium cyanoborohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride, Raney-Ni, Pd/C, or trichlorosilane.
Amine protecting groups (“P”) are well known to those skilled in the art and as defined above.
For example, in some embodiments, “P” may be an alkoxy carbonyl group in the compound of Formula-M and may be formed by reacting the compound of Formula-L with an alkyl halo formate in the presence of a suitable base and solvent. Suitable bases include, but are not limited to, inorganic bases such as alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali amines, alkali alkoxides, and organic bases such as pyridine, triethylamine, and N,N-diisopropylethylamine, morpholine, and N-methyl morpholine. Examples of suitable solvents include 1,4-dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dichloromethane, toluene, acetone, dimethyl formamide, 2-methyl tetrahydrofuran, monoglyme, diglyme, or mixtures thereof. In particularly useful embodiments, the solvent is dichloromethane.
When the alkyl halo formate is methyl chloroformate, the compound of Formula-L may be converted to a compound of Formula-C3, as shown below:

In another aspect, the present invention provides novel intermediates of Formula-C1, Formula-C2, Formula-C3, Formula-D1, Formula-D2, Formula-D3, and Formula-L.

As disclosed herein, each intermediate shown above (Formula-C1, Formula-C2, Formula-C3, Formula-D, Formula-D1, Formula-D2, Formula-D3, and Formula-L) may be converted into rucaparib or a pharmaceutically acceptable salt thereof.
By using the methods disclosed herein, formation of dimer impurity structured below is reduced or avoided. Thus, rucaparib (or pharmaceutically acceptable salts thereof) with a high purity may be prepared.

Rucaparib, including pharmaceutically acceptable salts thereof, prepared by methods disclosed herein, may be useful for incorporating into pharmaceutical dosage forms. For example, the dosage forms may be oral dosage forms such as capsules or tablets. Dosage forms may include pharmaceutically acceptable excipients such as microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol, talc, and any combination thereof. Artificial coloring and flavoring may also be incorporated.
Tablets or capsules may contain an effective dose of about 200 mg to about 300 mg of rucaparib, including 200 mg, 250 mg, and 300 mg. In particularly useful embodiments, rucaparib is incorporated into a dosage form as the camsylate salt.
Tablets or capsules may be useful in the treatment of recurrent epithelial ovarian, fallopian tube, prostate, bladder, or primary peritoneal cancer in patients who are in a complete or partial response to platinum-based chemotherapy or in the treatment of deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies. Tablets or capsules may be useful in monotherapy, or in combination with other anti-cancer agents.
A skilled artisan will readily be able to prepare and use pharmaceutical dosage forms incorporating rucaparib or pharmaceutically acceptable salts thereof, for example, by those methods disclosed in U.S. Patent No. 10,130,636 and U.S. Patent No. 9,987,285, which are hereby incorporated by reference.
The examples mentioned below explain various aspects of the present invention. The examples are given to illustrate the details of the invention and should not be construed to limit the scope of the present invention.
EXAMPLES
Example 1: Preparation of Formula-C2

A solution of 8 M methylamine in methanol (62.5 L) and methylamine hydrochloride (3.0 moles, 202.56 g) were added to methanol (3.0 L). 4-Formylphenylboronic acid (Formula-H, 1 mole) was added to the solution which was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (1.3 moles, 81.7 g) was added to the reaction mixture. The pH was adjusted to 5 with methanolic HCl and the solution was stirred for about 2 hours at about 30 °C. The pH of the reaction mixture was maintained between 4 and 6 by addition of methanolic HCl as needed. The solvent was then removed from the reaction mixture by concentration under reduced pressure. The obtained residue was combined with water and brine to which dichloromethane was added to extract the target compound. Extractions were repeated as necessary and the combined organic fractions were concentrated and dried to yield crude (4-((methylamino)methyl)phenyl)boronic acid (Formula-I, ~85% yield).
Triethylamine (1.6 moles, 223.2 mL) was added to crude (4-((methylamino)methyl)phenyl)boronic acid (Formula-I, 1 mole, 179.02 g) dissolved in dichloromethane (1.48 L). The solution was then cooled to 5 °C. A solution of methyl chloroformate (1.3 moles, 100.4 mL) in dichloromethane (0.165 L) was slowly added, maintaining the solution temperature between 10 °C and 14 °C. The solution was then stirred at room temperature for 12 hours after which 0.99 L of water was added. The solution was agitated, the phases were allowed to separate, and the aqueous phase was removed. The organic phase was concentrated and dried to afford a compound of Formula-C2.
Example 2: Preparation of Formula-C2

4-(Bromomethyl)phenyl)boronicacid (Formula-J where L=Br, 1 mole) was dissolved in 4.3 L of tetrahydrofuran. A solution of 8 M methylamine in methanol (62.5 L) was added and the mixture was stirred at room temperature for 90 minutes. After completion of the reaction, a solution methanolic HCl was added and the pH was adjusted to 5, maintaining the temperature at about 30 °C. The reaction was stirred for 2 hours. The pH of the reaction mixture was maintained between 4 and 6 by adding methanolic HCl as needed. The solvent was then removed by concentration under reduced pressure. Water and brine was added to the obtained residue. Dichloromethane was added to extract the target compound. Extractions were repeated as necessary and the combined organic fractions were concentrated and dried to yield crude (4-((methylamino)methyl)phenyl)boronic acid (Formula-I, ~85% yield), which was used directly in the next step without further purification.
Triethylamine (1.6 moles, 223.2 mL) was added to crude (4-((methylamino)methyl)phenyl)boronic acid (Formula-I, 1 mole, 179.02 g) dissolved in dichloromethane (1.48 L). The solution was cooled to 5 °C after which a solution of methyl chloroformate (1.3 moles, 100.4 mL) in dichloromethane (0.165 L) was slowly added. The reaction temperature was maintained between 10 °C and 14 °C the stirred at room temperature for 12 hours. Water (0.99 L) was then added. The solution was agitated, the phases were allowed to separate, and the aqueous phase was removed. The organic phase was concentrated and dried to afford a compound of Formula-C2.
Example 3: Preparation of Formula-C3

Diethanolamine (1.0 mole) was added to a solution of 4-formylphenylboronic acid (Formula-H, 1.0 mole, ~150 g) in methanol (1.5 L) and the resultant mixture was stirred for 30 minutes at ambient temperature. Thereafter, a solution of 8 M methylamine in methanol (62.5 L) added and stirring continued at room temperature. After completion of the reaction, sodium borohydride (1.0 mole, 37.83 g) was added and the pH of the solution was adjusted to 5 with methanolic HCl. The reaction was stirred for 2 hours at about 30 °C. The pH of the reaction mixture was maintained between 4 and 6 with methanolic HCl. The reaction mass was concentrated, and the obtained residue was diluted with water and brine. Dichloromethane was added to extract the target compound. Extractions were repeated as necessary and the combined organic fractions were concentrated and dried to yield a crude compound of Formula-L.
Crude Formula-L was dissolved in dichloromethane (2.1 L). Triethylamine (1.6 moles, 223.2 mL) was slowly added, maintaining the temperature of the mixture at 5 °C. A solution of methyl chloroformate (1.3 moles, 100.4 mL) in dichloromethane (0.23 L) was slowly added to the reaction mixture, maintaining the temperature between 10 °C and 14 °C. The mixture was stirring further at room temperature for 12 hours. Water (1.4 L) was then added to the reaction mixture. The organic phase was separated and concentrated to yield a compound of Formula-C3.

Example 4: Preparation of Formula-E (wherein L=Br, P=methyl carbamate)

A solution of 8 M methylamine in methanol (62.5 L) was added to a solution of 4-bromobenzaldehyde (Formula-F, wherein L=Br; 1.0 mole, 185 g) in methanol (1.8 L) and the combined mixture was stirred at room temperature. After completion of the reaction, sodium borohydride (1.0 mole, 37.83 g) was added and the pH was adjusted to 5 with methanolic HCl at about 30 °C. The reaction mixture was stirred for 2 hours maintaining the pH between 4 and 6 with methanolic HCl. The reaction mass was concentrated and obtained residue was diluted with water and brine. Dichloromethane was added, and the organic layer was separated from the aqueous layer and concentrated to afford a crude compound of Formula-G (where L=Br).
The prepared Formula-G was then dissolved in dichloromethane (1.8 L). Triethylamine (1.6 moles, 223.2 mL) was added at 5 °C. A solution of methyl chloroformate (1.3 moles, 100.4 mL in dichloromethane (0.2 L) was slowly added, maintaining the temperature of the mixture between about 10 °C and 14 °C. The reaction solution was stirred at room temperature for 12 hours. Water was added to the reaction mass and the organic phase was separated and concentrated to afford a compound of Formula-E (wherein L=Br, P=methyl carbamate).
Example 5: Preparation of Formula-D3

n-Butyl lithium (2.5 M in hexanes, 440 mL)) was added to a cooled solution (-70 °C) of Formula-A1 (1 mole) in 2.8 L of tetrahydrofuran and stirred for 30 minutes. A solution of bis(pinacolato)diborane (1.2 moles) in tetrahydrofuran (0.56 L) was then added and the reaction mass was stirred for 1 hour. The reaction was then quenched with a saturated aqueous ammonium chloride solution. Ethylene acetate was added to extract the target compound and the aqueous and organic layers were separated. The organic layer was concentrated to afford a compound of Formula-D3.
Example 6: Preparation of Formula-D1

n-Butyl lithium (2.5 M in hexanes, 440 mL) was added to cooled solution (-70 °C) of Formula-A1 (1 mole) in 2.8 L of tetrahydrofuran and stirred for 30 minutes. A solution of trimethyl borate (1.2 moles) in tetrahydrofuran (0.56 L) was then added and the reaction mass was stirred for 1 hour. The reaction was then quenched with a saturated aqueous ammonium chloride solution. Ethylene acetate was added to extract the target compound and the aqueous and organic layers were separated. The organic layer was concentrated to afford a compound of Formula-D1.
Example 7: Preparation of Formula-D2

Diethanolamine (1.05 moles) was added to a solution of Formula-D1 (1.0 mole) in tetrahydrofuran (2.5 L) and the mixture was stirred at ambient temperature. After completion of the reaction, the mixture was filtered to isolate the precipitated product which was washed and dried to yield a compound of Formula-D2.
Example 8: Preparation of Formula-B1
1,1’-Bis(diphenylphosphino)ferrocene palladium (II) dichloride (2.5 moles, 1.83 kg) was added to a solution of Formula-A1 (1.0 mole) in 4.2 L of a 1:2 mixture of dichloromethane and degassed dimethylacetamide. The reaction mass stirred for 1 hour at about 20 °C. Thereafter, the reaction mixture temperature was raised to 95 °C and stirred for 1 hour. In a separate vessel, Formula-C2 (1.2 moles) was dissolved dimethylacetamide (1.1 L) and 2.8 L of an aqueous solution of sodium carbonate (2.0 moles) was added. The mixture was stirred for 3 hours at 20 °C. The contents of the separate vessel were added to the first reaction mixture, maintaining the temperature above 90 °C. The combined reaction mixture was stirred for 2 hours, cooled to room temperature, and further stirring for 4 hours. Water (2.8 L) was added to the reaction mixture and the mixture was filtered to obtain a solid. The solid was then crystallized from methanol to yield a compound of Formula-B1.
Example 9: Preparation of Formula-B1

1,1’-Bis(diphenylphosphino)ferrocene palladium (II) dichloride (2.5 moles, 1.83 kg) was added to a solution of Formula-A1 (1.0 moles) in a 1:2 mixture of 4.2 L of dichloromethane and degassed dimethylacetamide. The reaction mass was stirred for 1 hour at about 20 °C. Thereafter, the reaction mixture temperature was raised to 95 °C and stirred for 1 hour. In a separate vessel, Formula-C3 (1.2 moles) was dissolved in dimethylacetamide (1.1 L) and added to 2.8 L of an aqueous solution of sodium carbonate (2.0 moles) and stirred for 3 hours at 20 °C. The contents of the separate vessel were added to the first reaction mixture, maintaining the temperature above 90 °C. The combined reaction mixture was stirred for 2 hours, cooled to room temperature, and further stirred for 4 hours. Water (2.8 L) was added to the reaction mixture which was filtered. The obtained solid was crystallized in methanol to obtain a compound of Formula-B1.
Example 10: Preparation of Formula-B1

1,1’-Bis(diphenylphosphino)ferrocene palladium (II) dichloride (2.5 moles, 1.83 kg) was added to a solution of Formula-D1 (1.0 moles) in a 1:2 mixture of 3.7 L of dichloromethane and degassed dimethylacetamide. The reaction mass was stirred for 1 hour at about 20 °C. Thereafter, the reaction mixture temperature was raised to 95 °C and stirred for 1 hour. In a separate vessel, Formula-E1 (1.2 moles) was dissolved in dimethylacetamide (1.0 L) and added to 2.8 L of an aqueous solution of sodium carbonate (2.0 moles) and stirred for 3 hours at 20 °C. The contents of the separate vessel were added to the first reaction mixture, maintaining the temperature above 90 °C. The combined reaction mixture was stirred for 2 hours, cooled to room temperature, and further stirred for 4 hours. Water (2.5 L) was added to the reaction mixture which was filtered. The obtained solid was crystallized in methanol to obtain a compound of Formula-B1.

Example 11: Preparation of Formula-B1

1,1’-Bis(diphenylphosphino)ferrocene palladium (II) dichloride (2.5 moles, 1.83 kg) was added to a solution of Formula-D2 (1.0 moles) in a 1:2 mixture of 4.7 L of dichloromethane and degassed dimethylacetamide. The reaction mass was stirred for 1 hour at about 20 °C. Thereafter, the reaction mixture temperature was raised to 95 °C and stirred for 1 hour. In a separate vessel, Formula-E1 (1.2 moles) was dissolved in dimethylacetamide (1.2 L) and added to an aqueous solution of sodium carbonate (3.2 L) and stirred for 3 hours at 20 °C. The contents of the separate vessel were added to the first reaction mixture, maintaining the temperature above 90 °C. The combined reaction mixture was stirred for 2 hours, cooled to room temperature, and further stirred for 4 hours. Water (3.2 L) was added to the reaction mixture which was filtered. The obtained solid was crystallized in methanol to obtain a compound of Formula-B1.
Example 12: Preparation of Formula-B1

1,1’-Bis(diphenylphosphino)ferrocene palladium (II) dichloride (2.5 moles, 1.83 kg) was added to a solution of Formula-D3 (1.0 moles) in a 1:2 mixture of 5.0 L of dichloromethane and degassed dimethylacetamide The reaction mass was stirred for 1 hour at about 20 °C. Thereafter, the reaction mixture temperature was raised to 95 °C and stirred for 1 hour. In a separate vessel, Formula-E1 (1.2 moles) was dissolved in dimethylacetamide (1.3 L) and added to an aqueous solution of sodium carbonate (3.3 L) and stirred for 3 hours at 20 °C. The contents of the separate vessel were added to the first reaction mixture, maintaining the temperature above 90 °C. The combined reaction mixture was stirred for 2 hours, cooled to room temperature, and further stirred for 4 hours. Water (3.3 L) was added to the reaction mixture which was filtered. The obtained solid was crystallized in methanol to obtain a compound of Formula-B1.

,CLAIMS:
1. A process for the preparation of rucaparib comprising the steps of:
a. reacting a compound of Formula-A with a compound of Formula-C to give a compound of Formula-B or its salt;

b. deprotecting the compound of Formula-B to yield rucaparib
; and
c. optionally converting rucaparib into its pharmaceutically acceptable salts.
wherein “L” is a leaving group and “P” is an amine protecting group and each “R” is independently selected from the group consisting of hydrogen (H) and an alkyl moiety, or together, the “R” moieties form a cyclic ring, optionally containing one or more of O or N and optionally substituted with an alkyl moiety.
2. The process as claimed in claim 1, wherein the leaving group L is a halogen selected from the group consisting of -F, -CI, -Br, and -I; protecting group P is methyl carbamate; “R” is either H or together, the “R” moieties combine to form a heterocyclic ring.
3. The process as claimed in claim 1, where in “R” is H in Formula-C (i.e. Formula-C1).
4. The process as claimed in claim 3, wherein the process for the preparation of Formula-C1 comprising the steps of:
a. subjecting a compound of Formula-H to reductive amination to give a compound of Formula-I
; and
b. protecting the compound of Formula-I in a solvent to give a compound of Formula-C1
,
wherein “P” is an amine protecting group.
5. The process as claimed in claim 4, wherein the solvent is selected from the group consisting of 1,4-dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dichloromethane, toluene, acetone, dimethyl formamide, and mixtures thereof.
6. The process as claimed in Claim 3, wherein the process for the preparation of Formula-C1 comprising the steps of:
a. reacting a compound of Formula-J with methylamine in a solvent to give a compound of Formula-I
; and
b. protecting the compound of Formula-I in a solvent to give a compound of Formula-C1
,
wherein “L” is a leaving group and “P” is an amine protecting group.
7. The process as claimed in claim 6, wherein the solvent is selected from the group consisting of ethers, polar aprotic solvents, and mixtures thereof selected from diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidine, and mixtures thereof.
8. A process for the preparation of rucaparib comprising the steps of:
a. reacting a compound of Formula-D with a compound of Formula-E to give a compound of Formula-B or its salt;

b. deprotecting the compound of Formula-B to yield rucaparib
; and
c. optionally converting Rucaparib or its pharmaceutically acceptable salts.
wherein “L” is a leaving group and “P” is an amine protecting group, and each “R” is independently selected from the group consisting of hydrogen (H) and an alkyl moiety, or together, the “R” moieties form a cyclic ring, optionally containing one or more of O or N and optionally substituted with an alkyl moiety.
9. The process as claimed in claim 8, wherein each “R” is H.
10. The process as claimed in claim 8, wherein the process for the preparation of Formula E comprising the steps of:
a. subjecting a compound of Formula-F to reductive amination to give a compound of Formula-G
; and
b. protecting the compound of Formula-G to give a compound of Formula-E.
,
wherein “L” is a leaving group and “P” is an amine protecting group.
11. The process as claimed in claim 8, where in the process for the preparation of Formula D comprises converting Formula-A into a compound of Formula-D with a suitable reagent in the presence of a base and a solvent.
,
wherein “L” is a leaving group and each “R” is independently selected from the group consisting of hydrogen (H) and an alkyl moiety, or together the “R” moieties form a cyclic ring, optionally containing one or more of O or N and optionally substituted with an alkyl moiety.
12. The process as claimed in claim 11, wherein the suitable reagent is selected from the group consisting of trimethyl borane, sequential trimethyl borane and diethanolamine, bis(pinacolato)diborane, and trialkylborates.
13. A process for the preparation of a compound of Formula-M comprising:
a. reacting a compound of Formula-H with diethanolamine in a solvent to give a compound of Formula-K
;
b. subjecting the compound of Formula-K to reductive amination to give a compound of Formula-L
; and
c. protecting the compound of Formula-L to give a compound of Formula-M.

wherein “P” is an amine protecting group.
14. The process as claimed in claim 13, wherein the solvent is selected from the group consisting of methanol, ethanol, propanol, butanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, toluene, diisopropyl ether, methyl t-butyl ether, isopropyl ether, isopropanol, dichloromethane, chloroform, and mixtures thereof.
15. A compound selected from the group consisting of Formula-C1, Formula-C2, Formula-C3, Formula-D1, Formula-D2, Formula-D3, and Formula-L.