BMN 673 synthesis

10synthesis methods

Product Name:BMN 673
CAS Number:1207456-01-6
Molecular formula:C19H14F2N6O
Molecular Weight:380.35

Talazoparib, also known as BMN-673 and MDV-3800, is an orally bioavailable inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) with potential antineoplastic activity (PARP1 IC50 = 0.57 nmol/L). Talazoparib acts as an inhibitor of poly ADP ribose polymerase(PARP) which aids in single strand DNA repair. Cells that have BRCA1/2 mutations are susceptible to the cytotoxic effects of PARP inhibitors because of an accumulation of DNA damage. Talazoparib is theorized to have a higher potency than olaparib due to the additional mechanism of action called PARP trapping. PARP trapping is the mechanism of action where the PARP molecule is trapped on the DNA, which interferes with the cells ability to replicate. Talazoparib is found to be ~100 fold more efficient in PARP trapping than olaparib Synthetic Description Reference: Wang, Bing; Chu, Daniel; Feng, Ying; Shen, Yuqiao; Aoyagi-Scharber, Mika; Post, Leonard E. Journal of Medicinal Chemistry. Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent. Journal of Medicinal Chemistry. Volume 59. Issue 1. Pages 335-357. Journal; Online Computer File. (2016). Synthetic Description Reference: Xu, Yong; Yohi, Peter W.; Xu, Michael; Cruise, Douglas; Huang, Lu. Preparation of PARP inhibitor talazoparib and intermediates thereof. Assignee Guangzhou Wellhealth Bio-Pharmaceutical Co., Ltd., Peop. Rep. China; Guangzhou Bio Blue Technology Co., Ltd. WO 2017215166. (2017). Synthetic Description Reference: Henderson, Mark. Process for the preparation of triazole intermediates useful in the synthesis of protected N-alkyltriazolecarbaldehydes. Assignee BioMarin Pharmaceutical Inc., USA. WO 2015069851. (2015). Synthetic Description Reference: Wang, Bing; Chu, Daniel. Dihydropyridophthalazinone derivatives as poly(ADP-ribose)polymerase (PARP) inhibitors and their preparation and use for the treatment of cancer. Assignee BioMarin Pharmaceutical Inc., USA. WO 2011130661. (2011).

Synthetic Routes

ROUTE 1

ROUTE 2

ROUTE 3

ROUTE 4

Reference: Wang, Bing; Chu, Daniel; Feng, Ying; Shen, Yuqiao; Aoyagi-Scharber, Mika; Post, Leonard E. Journal of Medicinal Chemistry. Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent. Journal of Medicinal Chemistry. Volume 59. Issue 1. Pages 335-357. Journal; Online Computer File. (2016).

1207454-56-5
28 suppliers
$2970.00/500mg

1207456-01-6
162 suppliers
$28.00/1unit

1207456-00-5 Synthesis

1207456-00-5
57 suppliers
$109.00/5mg

Yield:1207456-00-5 90% ，1207456-01-6 78%

Reaction Conditions:

with CHIRALPAK IA in methanol;diethylamineResolution of racemate;

Steps:

15 Example 15 (8R,95 -5-fluoro-8-(4-f1uorophenyl)-9-( l -methyl-lH-l ,2,4-triazoI-5-yl)-8,9-dihydro-2H-pyrido[4,3,2- ife]phthalazin-3(7No.)-one ( 1 a) and (8S,9R)-5-fluoro-8-(4-fiuoropheny l)-9-( 1 -methyl- 1 H- 1 ,2,4-triazol-5- ( 1 ) ( la) ( l b)
Example 15 (8R,95 -5-fluoro-8-(4-f1uorophenyl)-9-( l -methyl-lH-l ,2,4-triazoI-5-yl)-8,9-dihydro-2H-pyrido[4,3,2- ife]phthalazin-3(7No.)-one ( 1 a) and (8S,9R)-5-fluoro-8-(4-fiuoropheny l)-9-( 1 -methyl- 1 H- 1 ,2,4-triazol-5- ( 1 ) ( la) ( l b) 100394] A chiral resolution of 5-fluoro-8-(4-fluorophenyl)-9-( l-methyl- l - l ,2,4-triazol-5-yl)-8,9- dihydro-2H-pyrido[4,3,2-ife]phthalazin-3(7//)-one (1) (52.5 g) was carried out on a super-fluid chromatography (SFC) unit using a CHIRALPAK 1A column and C(¾/ methano l/di ethy lam ine (80/30/0.1 ) as a mobi le phase. This afforded two enantiomers with retention times of 7.9 minute (23.6 g. recovery 90 %, > 98 % ee) and 9.5 minute (20.4 g, recovery 78 %, > 98 % ee) as analyzed with a CHIRALPAK IA 0.46 cm x 15 cm column and C02/methanol/diethylamtne (80/30/0. 1 ) as a mobile phase at a flow rate of 2 g/minute.

References:

BIOMARIN PHARMACEUTICAL INC.;FENG, Ying;GUTIERREZ, Andres, A.;SHEN, Yuqiao;WANG, Evelyn, W.;OKHAMAFE, Augustus, O.;PRICE, Christopher, P.;CHOU, Tianwei WO2013/28495, 2013, A1 Location in patent:Paragraph 00394

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