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Patent Issued for Processes of Synthesizing Dihydropyridophthalazinone Derivatives

July 14, 2014



By a News Reporter-Staff News Editor at Pharma Business Week -- From Alexandria, Virginia, NewsRx journalists report that a patent by the inventors Wang, Bing (San Jose, CA); Chu, Daniel (Santa Clara, CA); Liu, Yongbo (Shanghai, CN); Jiang, Quan (Shanghai, CN); Lu, Lei (Zhejiang Province, CN), filed on February 8, 2011, was published online on July 1, 2014 (see also BioMarin Pharmaceutical Inc.).

The patent's assignee for patent number 8765945 is BioMarin Pharmaceutical Inc. (Novato, CA).

News editors obtained the following quote from the background information supplied by the inventors: "The family of poly(ADP-ribose)polymerases (PARP) includes approximately 18 proteins, which all display a certain level of homology in their catalytic domain but differ in their cellular functions (Ame et al., BioEssays., 26(8), 882-893 (2004)). PARP-1 and PARP-2 are unique members of the family, in that their catalytic activities are stimulated by the occurrence of DNA strand breaks.

"PARP has been implicated in the signaling of DNA damage through its ability to recognize and rapidly bind to DNA single or double strand breaks (D'Amours, et al., Biochem. J., 342, 249-268 (1999)). It participates in a variety of DNA-related functions including gene amplification, cell division, differentiation, apoptosis, DNA base excision repair as well as effects on telomere length and chromosome stability (d'Adda di Fagagna, et al., Nature Gen., 23(1), 76-80 (1999)).

"Syntheses of dihydropyridophthalazinone derivatives are disclosed in U.S. Patent Publication No. US 2010/0035883 A1, the content of which is hereby incorporated by reference in its entirety. However, the synthetic routes disclosed in US 2010/0035883 A1 present scale-up challenges, inter alia. Accordingly, there exists a need to provide improved synthetic routes to this class of compounds, and particularly for 5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydr- o-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one and its stereoisomers."

As a supplement to the background information on this patent, NewsRx correspondents also obtained the inventors' summary information for this patent: "Provided herein are improved synthetic routes and new intermediates that provide scalable and efficient processes for making 5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydr- o-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, as shown in formula (1), and its enantiomer compounds, as shown in formulas (1a) and (1b):

"##STR00001## or salts thereof. In particular, the overall yield for the syntheses included herein are improved over the art.

"In a first embodiment, the method comprises the following steps:

"Step a) reacting a compound of formula (2):

"##STR00002## with 1-methyl-1H-1,2,4-triazole-5-carbaldehyde to produce a compound of formula (3):

"##STR00003## or a salt thereof;

"Step b) treating the compound of formula (3) with a lower alkyl alcohol, such as for example, HO--R, where R.dbd.C.sub.1-C.sub.4 alkyl, preferably methanol, to produce a compound of formula (4):

"##STR00004## or a salt thereof;

"Step c) reacting the compound of formula (4), or a salt thereof, with 4-fluorobenzaldehyde in the presence of a reducing reagent and an acid or a Lewis acid to produce a compound of formula (5):

"##STR00005## or a salt thereof;

"Step d) performing a separation, for example, a chiral chromatography separation, of the compound of formula (5) to yield two enantiomer compounds of formulas (6a) and (6b):

"##STR00006##

"Step e) reacting the enantiomer of formula (6a) or (6b) with hydrazine to obtain the enantiomer of formula (1a) or (1b).

"In a second embodiment, the enantiomer of formula (1a) or (1b) is prepared by first treating the compound of formula (5) with hydrazine to afford the racemate of formula (1) and then performing chiral chromatography separation to yield the two enantiomers of formulas (1a) and (1b).

"In a third embodiment, an alternative method comprises the following steps:

"Step a) reacting the compound of formula (3), or a salt thereof, with hydrazine hydrate to produce a compound of formula (7):

"##STR00007## or a salt thereof;

"Step b) reacting the compound of formula (7) with 4-fluorobenzaldehyde in an inert solvent at elevated temperature to produce a compound of formula (8):

"##STR00008## or a salt thereof;

"Step c) treating the compound of formula (8) with a base in an inert solvent to produce the compound of formula (1); and

"Step d) performing chiral chromatography separation of the compound of formula (1) to yield the two enantiomers of formulas (1a) and (1b).

"In the fourth embodiment, yet another alternative method comprises the following steps:

"Step a) reacting the compound of formula (4) with 4-fluorobenzaldehyde in the presence of a base, to produce a compound of formula (9):

"##STR00009## or a salt thereof; wherein R is C.sub.1-C.sub.6 alkyl (lower alkyl).

"Step b) reacting the compound of formula (9) with a reducing reagent to produce the compound of formula (5) or a compound of formula (10):

"##STR00010## or a salt thereof, wherein R is C.sub.1-C.sub.6 alkyl;

"Step c) reducing the compound of formula (10) with a reducing reagent to produce the compound of formula (5);

"Step d) performing a chiral chromatography separation of the compound of formula (5) to obtain the enantiomers of formulas (6a) and (6b); and

"Step e) reacting the enantiomer of formula (6a) or (6b) with hydrazine hydrate to produce the enantiomer of formula (1a) or (1b).

"In a fifth embodiment, yet another method comprises reacting the compound of formula (9) with hydrazine to produce the compound of formula (1) and separating via chiral chromatography separation to yield the two enantiomers (1a) and (1b)."

For additional information on this patent, see: Wang, Bing; Chu, Daniel; Liu, Yongbo; Jiang, Quan; Lu, Lei. Processes of Synthesizing Dihydropyridophthalazinone Derivatives. U.S. Patent Number 8765945, filed February 8, 2011, and published online on July 1, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8765945.PN.&OS=PN/8765945RS=PN/8765945

Keywords for this news article include: BioMarin Pharmaceutical Inc., Hydrazines, DNA Research, Organic Chemicals.

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Source: Pharma Business Week


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