Patent Grant
11021483
This application claims priority to CN application No. 201811423037.X filed on Nov. 27, 2018, which is herein incorporated by reference in its entirety.
The present invention is related to a method of preparing of tricyclic compounds. More particularly, the present invention is related to a method of preparing of tricyclic compounds for PARP inhibitor. The present invention is further related to a method of preparing of Rucaparib and related to crystalline of (S)-camphorsulfonate salt of Rucaparib as well as a method of preparing the same.
PARP (Poly(ADP-ribose) polymerase) is one kind of enzyme families participating the repair of DNA. According to recent research, PARP inhibitor is a new chemotherapeutic agent for treating various cancers. Also, Rucaparib is a PARP inhibitor for treatment of advanced ovarian cancer specifically associated with BRCA mutations.
As to the synthetic method of Rucaparib in U.S. Pat. No. 6,977,298, it discloses a synthesis scheme as shown in
In the aforesaid conventional synthesis, a plurality of synthetic steps and purification steps are required to obtain the Rucaparib of the formula (1). Accordingly, the complicated synthetic steps greatly reduce the total yield and take more time. Moreover, in the above conventional synthesis, NaBH3CN as reducing agent is used to reduce imine compounds (i.e., the compound of formula (3)) and toxic HCN gas is therefore generated in the process of reaction, which is disadvantageous for production in a large scale.
According to one embodiment of the present disclosure, the present invention provides a method of preparing a tricyclic compound of formula (I) below.
The method comprises steps of:
(i) converting a compound of formula (II) into a compound of formula (III);
(ii) hydrogenating the compound of formula (III) under hydrogen to produce the tricyclic compound of formula (I) in the presence of a hydrogenation catalyst, in which R1 is H or a C1-3 alkyl group and R2 is H, a halogen element or a C1-3 alkyl group.
In one embodiment of the present disclosure, the step of converting the compound of formula (II) into the compound of formula (III) comprises reacting the compound of formula (II) with methylamine to form the compound of formula (III).
In one embodiment of the present disclosure, the hydrogenated catalyst in the step of hydrogenating the compound of formula (III) is at least one selected from the group consisting of Pd catalyst, Ni catalyst, Pt catalyst and Rh catalyst.
In one embodiment of the present disclosure, the hydrogenation catalyst in the step of hydrogenating the compound of formula (III) to produce the tricyclic compound of formula (II) is Pd/C catalyst.
In one embodiment of the present disclosure, the step of converting the compound of formula (II) and the step of hydrogenating the compound of formula (III) are performed in succession without isolating the compound of formula (III).
In one embodiment of the step before converting the compound of formula (II) in the present disclosure, the method of preparing the tricyclic compound of formula (I) further comprises a step of reacting a compound of formula (IV) with a compound of formula (V) to form the compound of formula (II), in which X is a halogen element.
In one embodiment of the step before reacting the compound of formula (IV) with the compound of formula (V) in the present disclosure, the method of preparing the tricyclic compound of formula (I) further comprises a step of halogenating a compound of formula (VI) to produce the compound of formula (IV) below.
In one embodiment of the step before halogenating the compound of formula (VI) in the present disclosure, the method of preparing the tricyclic compound of formula (I) further comprises a step of converting a compound of formula (VII) into the compound of formula (VI) below.
Another embodiment of the present disclosure is to provide a method of preparing a tricyclic compound of formula (X).
wherein Y is a pharmaceutically acceptable acid.
The method comprises steps of:
(i) preparing a tricyclic compound of formula (I) using the method described above; and
(ii) reacting the tricyclic compound of formula (I) with a pharmaceutically acceptable acid to form the tricyclic compound of formula (X), in which R1 is H or a C1-3 alkyl group and R2 is H, a halogen element or a C1-3 alkyl group and Y is a pharmaceutically acceptable acid.
In one embodiment of the present disclosure, the pharmaceutically acceptable acid is camphorsulfonic acid.
Another embodiment of the present disclosure is to provide a method of preparing Rucaparib of formula (I).
The method comprises the steps of:
(i) reacting a compound of formula (6) with a compound of formula (IX) to produce a compound of formula (7);
(ii) converting the compound of formula (7) to a compound of formula (8);
(iii) converting the compound of formula (8) to a compound of formula (9);
(iv) reacting the compound of formula (9) with a compound of formula (V) to form a compound of formula (2);
(V) converting the compound of formula (2) to form a compound of formula (3); and
(Vi) hydrogenating the compound of formula (3) under hydrogen in the presence of hydrogenation catalyst to produce the Rucaparib of formula (1).
Another embodiment of the present disclosure is to provide a crystalline of a Rucaparib (S)-camphorsulfonate salt of formula (5),
wherein the Rucaparib (S)-camphorsulfonate salt of formula (5) has a X-ray powder diffraction pattern comprising characteristic peaks at two theta vales of 6.0°±0.2°, 6.2°±0.2°, 12.2°±0.2° and 13.5°±0.2°.
In one embodiment of the present disclosure, wherein the X-ray powder diffraction pattern further comprises characteristic peaks at two theta vales of 12.0°±0.2° and 25.7°±0.2°.
In one embodiment of the present disclosure, wherein the X-ray powder diffraction pattern further comprises characteristic peaks at two theta vales of 12.8°±0.2°, 14.8°±0.2°, 20.6°±0.2° and 25.1°±0.2°.
In one embodiment of the present disclosure, wherein the X-ray powder diffraction pattern is substantially the same as that shown in
In one embodiment of the present disclosure, the melting point of crystalline of the Rucaparib (S)-camphorsulfonate salt of formula (5) is about 304±2° C.
Another embodiment of the present disclosure is to provide a method of producing a Rucaparib (S)-camphorsulfonate salt of formula (5).
The method comprises steps of:
(i) reacting a Rucaparib of formula (1) with a (S)-camphorsulfonic acid in a methanol/water solution to form the Rucaparib (S)-camphorsulfonate salt of formula (5); and
(ii) filtrating a crystalline of the Rucaparib (S)-camphorsulfonate salt of formula (5) from the methanol/water solution, wherein the crystalline of Rucaparib (S)-camphorsulfonate salt of formula (5) has a X-ray powder diffraction pattern comprising characteristic peaks at two theta values of 6.0°±0.2°, 6.2°±0.2°, 12.2°±0.2° and 13.5°±0.2°.
The following disclosure provides many different embodiments, or examples, for implementing different features of the invention. Specific examples of components and arrangements are described below to simplify the present disclosure. These are, of course, merely examples and are not intended to be limiting. In addition, the present disclosure may repeat reference numerals and/or letters in the various examples. This repetition is for the purpose of simplicity and clarity and does not in itself dictate a relationship between the various embodiments and/or configurations discussed.
One embodiment of the present disclosure provides a method of preparing PARP inhibitor. PARP inhibitor as the present disclosure has the following structure of formula (I):
wherein R1 is H or a C1-3 alkyl group; and
R2 is H, a halogen element or a C1-3 alkyl group. Halogen is fluorine, chlorine, bromine or iodine.
In accordance with various embodiments of the present disclosure, the method of preparing of the tricyclic compound (i.e., PARP inhibitor) of formula (III) includes the following steps:
converting the following compound of formula (II) to form the following compound of formula (I); and
hydrogenating the compound of formula (III) under hydrogen to produce the tricyclic compound of formula (I) in the presence of a hydrogenation catalyst; wherein R1 is H or a C1-3 alkyl group; and R2 is H, a halogen element or a C1-3 alkyl group.
In one embodiment, the step of converting the compound of formula (II) into the compound of formula (III) comprises reacting the compound of formula (II) with methylamine to produce the compound of formula (III). Specifically, in some examples, equivalent ratio of the compound of formula (II) to methylamine is 1:1 to 1:5, for example, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4 or 1:4.5. Furthermore, the reaction of the compound of formula (II) and methylamine solution is conducted at 20° C. to 40° C. in some embodiments.
In one embodiment, the hydrogenation catalyst in the step of hydrogenating the compound of formula (III) to produce the tricyclic compound of formula (I) is selected from at least one from the group consisting of Pd catalyst, Ni catalyst, Pt catalyst and Rh catalyst.
Specifically, in some embodiments, the hydrogenation catalyst is Pd/C catalyst and amount added into the reaction is 5% to 10% Pd/C. It is worth mentioning that the catalytic hydrogenation method is used to replace reducing agent (e.g., NaBH3CN, etc.) used conventionally to reduce imine compounds (i.e., the compound of formula (III)) and avoid from generating the toxic HCN gas.
It is to be appreciated that the step of converting the compound of formula (II) and the step of hydrogenating the compound of formula (III) are performed in succession without isolating the compound of formula (III) in the various embodiments of the present disclosure. In detail, the isolation step of the compound of formula (III) is not performed and the mixture which contains the compound of formula (III) directly transfers to reactor, and the compound of formula (III) in the mixture is hydrogenated in the presence of hydrogenation catalyst to produce the tricyclic compound of formula (I). Therefore, the target product may be obtained directly without isolation of intermediate product (i.e., the compound of formula (III)) by way of the method of the present disclosure. Accordingly, the step for purification and the loss of the intermediate product may be reduced, and the manufacturing process may be simplified, thereby effectively reducing cost and improving yield. In some embodiments, yield of the tricyclic compound of formula (I) formed by the step of converting the compound of formula (II) and hydrogenation the compound of formula (III) to produce the tricyclic compound of formula (I) is higher than 70%, for example, 71%, 72% or 84%.
In one embodiment of the step before converting the compound of formula (II), the method of the present disclosure further includes a following step: reacting a compound of formula (IV) with a compound of formula (V) to form the compound of formula (III);
wherein X is a halogen element, such as fluorine, chlorine, bromine or iodine;
R1 is H or a C1-3 alkyl group; and R2 is H, a halogen element or a C1-3 alkyl group. Specifically, equivalent ratio of the compound of formula (IV) to the compound of formula (V) is 1:1 to 1:1.2 in some examples. In some examples, yield of the compound of formula (II) formed by reacting the compound of formula (IV) with the compound of formula (V) is 85% to 95%. For example, 87%, 89%, 92% or 93%.
In one embodiment of the step before reacting the compound of formula (IV) with the compound of formula (V), the present disclosure further comprises a following step:
halogenating a following compound of formula (VI) to produce the compound of formula (IV);
wherein R1 is H or a C1-3 alkyl group; and
R2 is H, a halogen element or a C1-3 alkyl group.
Specifically, the step of halogenating the compound of formula (VI) is performed by adding a halogenating agent. In some examples, the halogenating agent includes tetra-n-butylammonium tribromide, pyridinium tribromide, N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide, but not limiting herein. In some examples, equivalent ratio of the compound of formula (VI) to the halogenating agent is 1:1 to 1:2. In some examples, halogenating the compound of formula (VI) is performed at 0° C. to 20° C., such as 5° C., 10° C. or 15° C. Further, yield of the compound of formula (IV) formed by halogenating the compound of formula (VI) is 85% to 95%, for example 87%, 89%, 91% or 93%.
In one embodiment of the step before halogenating the compound of formula (VI), the present disclosure further comprises a following step:
converting a following compound of formula (VII) to form the compound of formula (VI);
wherein R1 is H or a C1-3 alkyl group; and
R2 is H, a halogen element or a C1-3 alkyl group.
In one embodiment, the step of converting the compound of formula (VII) into the compound of formula (VI) comprises reacting the compound of formula (VII) with methylamine to form the compound of formula (VI). Specifically, equivalent ratio of the compound of formula (VII) to methylamine is 1:1.5 to 1:3.0 in some examples. In some examples, converting the compound of formula (VII) is performed at 15° C. to 40° C., such as 20° C., 25° C., 30° C. or 35° C. In addition, in some examples, yield of the compound of formula (VI) formed by converting the compound of formula (VII) is 87% to 97%, for example 89%, 91%, 93% or 94%.
In one embodiment of the step before converting the compound of formula (VII), the present disclosure further comprises a following step: reacting a compound of formula (VIII) with a compound of formula (IX) to produce the compound of formula (VII);
wherein R1 is H or a C1-3 alkyl group; and
R2 is H, a halogen element or a C1-3 alkyl group.
In some embodiments, equivalent ratio of the compound of formula (VIII) to the compound of formula (IX) is 1:1.1 to 1:1.5, such 1:1.2, 1:1.3 or 1:1.4. In some examples, the reaction of the compound of formula (VIII) and the compound of formula (IX) is performed at 15° C. to 40° C., such as 20° C., 25° C., 30° C. or 35° C. In addition, in some examples, yield of the compound of formula (VII) formed by the reacting the compound of formula (VIII) with the compound of formula (IX) is 50% to 60%, for example 51%, 53%, 55% or 57%.
Another embodiment of the present disclosure provides a method of preparing of a following tricyclic compound (the salt form of PARP inhibitor) of formula (X),
wherein Y is a pharmaceutically acceptable acid;
R1 is H or a C1-3 alkyl group; and
R2 is H, a halogen element or a C1-3 alkyl group.
In some examples, the pharmaceutically acceptable acids includes phosphoric acid, hydrochloric acid, ethanedisulfonic acid, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, maleic acid, malic acid, oxalic acid, tartaric acid, or the like but not limiting herein. Preferably, in one example, the pharmaceutically acceptable acid is camphorsulfonic acid.
The method of preparing the tricyclic compound of formula (X) includes the following steps: reacting the above described tricyclic compound of formula (I) with the pharmaceutically acceptable acid to form the tricyclic compound of formula (X).
In addition, in some examples, equivalent ratio of the tricyclic compound of formula (I) to the pharmaceutically acceptable acid is 1:1.1 to 1:1.3. In some examples, the reaction of the tricyclic compound of formula (I) and the pharmaceutically acceptable acid is performed at 65° C. to 85° C., for example 68° C., 70° C., 73° C., 77° C. or 81° C. Further, in some examples, yield of the compound of formula (X) formed by reacting the compound of formula (I) with the pharmaceutically acceptable acid is 76% to 86%, for example 78%, 80%, 81% or 84%.
In one embodiment, the tricyclic compound of formula (X) includes the Rucaparib (S)-camphorsulfonate salt with structure of formula (5).
In some examples, the Rucaparib (S)-camphorsulfonate salt is in a crystalline form. In one specific example, X-ray powder diffraction pattern of the crystalline of the Rucaparib (S)-camphorsulfonate salt of formula (5) comprising characteristic peaks at two theta values of 6.0°±0.2°, 6.2°±0.2°, 12.2°±0.2° and 13.5°±0.2°. In another specific example, X-ray powder diffraction pattern of crystalline of the Rucaparib (S)-camphorsulfonate salt of formula (5) comprising characteristic peaks at two theta values of 6.0°±0.2°, 6.2°±0.2°, 12.0°±0.2°, 12.2°±0.2°, 13.5°±0.2° and 25.7°±0.2°. In one specific example, melting point of crystalline of the Rucaparib (S)-camphorsulfonate salt is about 304±2° C.
In one embodiment, the method of preparing of crystalline of the Rucaparib (S)-camphorsulfonate salt of formula (5) comprises the step of reacting the (S)-camphorsulfonate salt with the Rucaparib of formula (1) within methanol/water solution to produce the Rucaparib (S)-camphorsulfonate salt of formula (5); and filtrating a crystalline of the Rucaparib (S)-camphorsulfonate salt of formula (5) from methanol/water solution.
Referring to
In one embodiment of the present disclosure, a compound of formula (6) is acted as a starting material for the reaction with the compound of formula (IX) to obtain a compound of formula (7). Then the compound of formula (7) is converted to form a compound of formula (8). The compound of formula (8) is halogenated to form a compound of formula (9). The compound of formula (9) is subsequently reacted with the compound of formula (V) to form the compound of formula (2). Next, the compound of formula (2) is converted to form the compound of formula (3). The compound of formula (3) is hydrogenated under hydrogen in the presence of hydrogenation catalyst to produce the Rucaparib of formula (1). Finally, Rucaparib with the structure of formula (1) is reacted with camphorsulfonic acid to produce the Rucaparib (S)-camphorsulfonate salt with the structure of formula (5).
The following examples are now exemplified to illustrate the method of preparing of PARP inhibitor in detail and its salt form in the present disclosure. However, the following examples are not limiting in the present disclosure.
2-(1,3-dioxoisoindolin-2-yl)acetaldehyde (2-DAA, i.e., the compound of formula (IX), 191.0 g, 1.3 eq.) and 6-fluoro-1H-indole-4-carboxylic acid methyl ester (6-FICAME, i.e., the compound of formula (6), 150.0 g, 1 eq.) in dichloromethane (CH2Cl2, 997.5 g) was added with triethylsilane (TES, 361.4 g, 4 eq.) and the mixture was stirred at room temperature. A solution of trifluoroacetic acid (TFA, 180.0 g, 2 eq.) in dichloromethane (CH2Cl2, 399.0 g) was added into the above mixture at 8° C. and kept stirring for 2 hours. Afterwards, it was stirred at room temperature for 86 hours and cooled to about 8° C. for another 2 hours. After filtrating, the solid were washed with CH2Cl2 and was added into ethyl acetate (EA). The mixture was heated to reflux for 2 hours and cooled to room temperature. After filtrating, the solids were washed with EA and dried under vacuum to obtain 3-(2-(phthalimido)ethyl)-6-fluoro-1H-indole-4-carboxylic acid methyl ester (i.e., the compound of formula (7), 157.16 g, 55%).
The compound of formula (7) (157.0 g, 1.0 eq.) was added to methylamine aqueous solutions (40% MeNH2 in H2O) (563.3 g) to form a mixture, and the mixture was stirred at room temperature for 24 hours. The deionized water (1099.0 g) was added into the mixture. Afterwards, the mixture was cooled to 0° C. to 5° C. and stirred for 2 hours. After filtrating, the solid was washed with the deionized water for three times and dried under vacuum to obtain 8-fluoro-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one (i.e., the compound of formula (8), 82.2 g, 94%).
The compound of formula (8) (77.60 g, 1.0 eq.) in CH2Cl2 (387.0 g) and THF (257.8 g) was added with pyridinium tribromide (Py·HBr3, 133.5 g, 1.1 eq.) at 10° C. The above mixture was stirred at 15° C. to 20° C. for 1 hour. The mixture was cooled to 10° C., the deionized water (194.0 g) was added into the mixture to quench the reaction. The above mixture was concentrated under vacuum with temperature not higher than 20° C. The residue was sequentially added with THF (54.9 g), deionized water (194.0 g) and 20% Na2CO3 solution (69.8 g Na2CO3 in 279.4 g water) with temperature not higher than 20° C. and the mixture was stirred to neutralize the generated acid. After filtrating the mixture, the solid was washed with deionized water for three times and dried under vacuum to obtain 2-bromo-8-fluoro-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]-indol-6-one (i.e., the compound of formula (9), 98.1 g, 91%).
The compound of formula (9) (97.5 g) in dimethylacetamide (DMAc, 549.9 g) was added with Pd(dppf)Cl2 ([1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium(II), (7.0 g) at room temperature. The mixture was heated to 90° C. to 95° C. and stirred for 1 hour to form the first solution. 4-formylphenylboronic acid (4-FPBA, 62.0 g) in dimethylacetamide (DMAc, 183.3 g) was stirred and 7% Na2CO3 solution (73.0 g Na2CO3 in 975.0 g water) was added into the above mixture to form the second solution. The second solution was added into the first solution at 93° C. under nitrogen atmosphere to form the third solution and it was heated to 98° C. for 1 hour and then was cooled to 88° C. The deionized water (1950.0 g) was added into the third solution and stirred at room temperature for 1 hour. After filtrating, the solid was washed with deionized water. The residue was added with MeOH (616.2 g) and heated to reflux for 1 hour and cooled to room temperature with stirring for another hour. After filtrating, the solid was washed with MeOH, and dried under vacuum to obtain 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd] indol-2-yl)-benzaldehyde (i.e., the compound of formula (2), 97.8 g, 92%).
The compound of formula (2) (50.0 g) in MeOH (437.0 g) and THF (223.0 g) with stirring at 25° C. was added with 30% CH3NH2 solution (in EtOH) (34.0 g) and kept stirring at 33° C. for 8 hours. The mixture was transferred to Hydrogenation reactor with 5% of Pd/C (10.5 g) therein to proceed hydrogenation. The reaction mixture was filtrated and the solid was washed with MeOH/THF=2.2/1 and with MeOH and dried under vacuum to obtain Rucaparib of formula (1) (37.9 g, 72%).
The compound of formula (2) (35.0 g) in MeOH (305.5 g) and THF (156.0 g) with stirring at 25° C. was added with 30% CH3NH2 solution (in EtOH) (35.3 g) and kept stirring at 33° C. for 12 hours. The mixture was transferred to Hydrogenation reactor with 10% of Pd/C (7.25 g) therein to proceed hydrogenation. The reaction mixture was filtrated and the solid was washed with MeOH and dried under vacuum to obtain Rucaparib of formula (1) (30.8 g, 84%).
The compound of formula (2) (76.5 g) in MeOH (665.0 g) and THF (339.0 g) with stirring at 25° C. was added with 30% CH3NH2 solution (in EtOH) (52.0 g) and kept stirring at 33° C. for 8 hours. The mixture was transferred to Hydrogenation reactor with 10% of Pd/C (8.04 g) therein to proceed hydrogenation. The active carbon (3.82 g) was added into the mixture with stirring at 40° C. for 2 hours. After filtrating, the solid was washed with MeOH and dried under vacuum to obtain Rucaparib of formula (1) (57.0 g, 71%).
As described above, the method of the present disclosure may be used to reduce the step of purification and the loss of the intermediate product. To be more specific that as shown in examples 5-1 to 5-3, the isolation step of the compound of formula (3) is not conducted and the generated mixture is directly hydrogenated to form Rucaparib of formula (1). In other words, the method of the present disclosure, compared to the conventional synthesis scheme (as shown in
Further, it is worth mentioning that in conventional synthesis scheme (as shown in
In order to facilitate understanding the advantage of the present disclosure, the yields of Examples 5-1 to 5-3 and the yield of formation of Rucaparib of formula (1) formed with the conventional synthesis scheme are reported in Table 1 below.
From the contents of Table 1, it is known that the synthesis of Rucaparib of formula (1) with the conventional synthesis scheme as shown in
Rucaparib of formula (1) (75.00 g) in MeOH (685.38 g) and H2O (204.42 g) with stirring was added with (S)-Camphorsulfonic acid (CSA, 64.50 g) in H2O (55.19 g) and heated to reflux for 1 hour. After hot filtration, the filtrate was heated to reflux and gradually cooled to 40° C. for 8 hours and to room temperature for 8 hours and to 0° C. to 5° C. for another 12 hours. After filtrating, the solids were washed with H2O, and dried under vacuum to obtain crystalline of the Rucaparib (S)-camphorsulfonate salt of formula (5) (1.36 g, 81%).
X-ray diffraction spectrometer (Bruker D8 Advance) is used to determine X-ray powder diffraction pattern of crystalline of the Rucaparib (S)-camphorsulfonate salt of formula (5) to obtain X-ray powder diffraction pattern as shown in
In
Differential scanning thermal analysis of crystalline of the Rucaparib (S)-camphorsulfonate of formula (5) is performed by use of differential scanning calorimeter (Mettler_Toledo DSC 2 STARe system) to obtain differential scanning thermal analysis spectrum as shown in
As shown in
In summary, the method of preparing PARP inhibitor, the salt thereof and the crystalline form thereof disclosed herein are more simplified than the conventional process in saving reaction time and effectively improving overall yield. Further, generation of toxic gas such as HCN is avoided since without using NaBH3CN as reducing agent, the method of the present disclosure is therefore suitable for mass production.
Although the present invention has been described in considerable detail with reference to certain embodiments thereof, other embodiments are possible. Therefore, the scope of the claims and the scope of the claims are not limited to the description contained in the embodiments herein.
It will be apparent to those skilled in the art that various modifications and variations can be made to the structure of the present invention without departing from the scope of the invention. In view of the foregoing, it is intended that the present invention cover modifications and variations of this invention provided they fall within the scope of the following claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 201811423037.X | Nov 2018 | CN | national |
| Number | Name | Date | Kind |
|---|---|---|---|
| 6977298 | Webber et al. | Dec 2005 | B2 |
| 8754072 | Basford | Jun 2014 | B2 |
| Entry |
|---|
| Afanasyev et al., Chem. Rev. 2019, 119, 11857-11911. |
| Gillmore, et al., “Multkilogram Scale-Up of a Reductive Alkylation Route to a Novel PARP Inhibitor”, American Chemical Society, dx.doi.org/10.1021/op200238p, Org. Process Res. Dev., 2012, 16, 1897-1904. |
| Number | Date | Country | |
|---|---|---|---|
| 20200165261 A1 | May 2020 | US |
