* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Compound 13 (36 g, 90.37 mmol), ethanol (450 mL) and 50percent hydrazine hydrate (28.96 g, 452 mmol) were added into a fourth reactor and heated to reflux for 3 hours. Then the solvent was removed by distillation under reduced pressure and the crude product was washed with water, filtered, washed with ethanol and recrystal to obtain the final product of compound 1 (talazoparib, white solid, 31 g, yield 90.2percent), HPLC purity: 99.5percent (0080) LC-MS (ESI) m/z: 381(M+1)+. (0081) 1H-NMR (400 MHz, DMSO-d6): δ (ppm): 3.68 (s, 3H), 4.99-5.06 (m, 2H), 6.92-6.96 (m, 1H), 7.08-7.11 (m, 1H), 7.16-7.2 (t, J=8.8 Hz, 2H), 7.49-7.53 (m, 2H), 7.75 (s, 1H), 7.83 (s, 1H), 12.35 (s, 1H).
77%
With hydrazine hydrate In acetonitrile at 20℃; for 2 h;
Example 17B 100399] To a solution of (2R,3No.)-methyl 7-fluoro-2-(4-fluoropheny l)-3 -( 1 -methyl- 1 H- 1 ,2,4- triazol-5-yl)-4-oxo- l ,2,3,4-tetrahydroquinoline-5-carboxylate (6a) or (2S,35)-methyl 7-fluoro-2-(4- fluoropheny l)-3-( 1 -methyl- 1 H- 1 ,2,4-triazol-5-yl)-4-oxo- 1 ,2,3 ,4-tetrahydroquinoline-5-carboxy late (6b) (446 g) in acetoi. itrile ( 10 volume) was added hydrazine monohydrate (2.9 eq.), and the se+ution stirred at room temperature for 2 hours. The resulting solution was then concentrated to a volume of 2 mL and filtered. The crude product was re-slurried with water (3~5 volumes) at 15~16 °C. After drying in vacuum at 50 °C, this affords the title compound as a white solid (329 g, yield 77percent, 99.93percent purity). LC- MS (ESI) m/z: 381(M+ 1 )+; Ή-NMR (400 MHz, DMSO-d6) δ (ppm): 3.681 (s, 3H), 4.99-5.06 (m, 2H), 6.92-6.96 (m, 1 H), 7.08-7.1 1 (m, 1 H), 7. 16-7.21 (t, J = 8.8 Hz, 2H), 7.49-7.53 (m, 2H), 7.75 (s, 1 H), 7.83 (s, l H), 12.35 (s, 1 H).
With CHIRALPAK IA In methanol; diethylamineResolution of racemate
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 percent, > 98 percent ee) and 9.5 minute (20.4 g, recovery 78 percent, > 98 percent 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.
> 98 % ee
With CHIRALPAK IA column In methanol; carbon dioxide; diethylamineResolution of racemate
A chiral resolution of 5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (1) (52.5 g) was carried out on a super-fluid chromatography (SFC) unit using a CHIRALPAK IA column and CO2/methanol/diethylamine (80/30/0.1) as a mobile phase. This afforded two enantiomers with retention times of 7.9 minute (23.6 g, recovery 90percent, >98percent ee) and 9.5 minute (20.4 g, recovery 78percent, >98percent ee) as analyzed with a CHIRALPAK IA 0.46 cm.x.15 cm column and CO2/methanol/diethylamine (80/30/0.1) as a mobile phase at a flow rate of 2 g/minute.
In yet a further embodiment is a compound selected from: ... (8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, (8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, (8S,9R)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, (8R,9S)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, (8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, (8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, (8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, ...
A method of inhibiting poly(ADP-ribose)polymerase (PARP) in a subject having a disease or condition associated with a PTEN deficiency comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of: ... (8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, (8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, (8S,9R)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, (8R,9S)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, (8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, (8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, (8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, ...
In one aspect is a compound selected from: ... (8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; (8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; (8S,9R)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; (8R,9S)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; (8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; (8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; (8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; ...
2
[ 1207454-56-5 ]
[ 1207456-01-6 ]
[ 1207456-00-5 ]
Yield
Reaction Conditions
Operation in experiment
78%; 90%
With CHIRALPAK IA; In methanol; diethylamine;Resolution of racemate;
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.
With IA chiral column; In methanol; carbon dioxide; N,N-dimethyl-formamide;Resolution of racemate;Purification / work up;
5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one was dissolved in DMF and chiral resolution was performed using super-fluid chromatography (SFC) with IA chiral column and methanol (20%) and CO2 (80%) as the eluents.
With CHIRALPAK IA column; In methanol; carbon dioxide; diethylamine;Resolution of racemate;
A chiral resolution of 5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (1) (52.5 g) was carried out on a super-fluid chromatography (SFC) unit using a CHIRALPAK IA column and CO2/methanol/diethylamine (80/30/0.1) as a mobile 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×15 cm column and CO2/methanol/diethylamine (80/30/0.1) as a mobile phase at a flow rate of 2 g/minute.
With IA chiral column; In methanol; N,N-dimethyl-formamide;Resolution of racemate;
Example 3 Enantiomers of (8i?,95 -5-fluoro-8-(4-fluorophenyl)-9-( l-methyl- lH- l ,2,4-triazol-5-yl)-8,9-dihydro-2//- pyrido[4,3 ,2-i/e] phthalazin-3 (7 )-one and (8 9i?)-5-fluoro-8-(4-fluorophenyl)-9-( 1 -methyl- 1 //- 1 ,2,4- triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-ife]phthalazin-3(7 )-one [003771 5-Fluoro-8-(4-fluorophenyl)-9-( l -methyl- l i- l,2,4-triazol-5-yl)-8,9-dihydro-2//- pyrido[4,3,2-de]phthalazin-3(7H)-one was dissolved in DMF and chiral resolution was performed using super-fluid chromatography (SFC) with IA chiral column and methanol (20%) and CO? (80%) as the eluents.
In dichloromethane; acetonitrile; at 25 - 40℃; for 0.0180556h;Product distribution / selectivity;
(85,,9i?)-5-fluoro-8-(4- fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-y^3(7H)-one (120 mg, 0.316 mmol) was suspended in CH2C12 (5 mL) and CH3CN (5 mL) at 40 C, then TsOH (66 mg, 0.348 mmol) was added, after adding, the solution was clear. After 5 seconds, a white solid was precipitated from the solution, continued to stir at 25 C for 1 h, filtered to obtain the white crystal solid, the solid was washed by CH3CN (2 mL), dried under vacuum at 45 C for 3 days. Microscopy: birefringent, crystalline. Results based on microscopy, XRPD (Table 11), DSC (Table 12a and Figure 3a), and TGA (Table 12b and Figure 3b) suggest that this tosylate salt is substantially a single crystalline form.
The following example provides the preparation and characterization of(8^,9i?)-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9-dihydro-2H- pyrido[4,3,2-
In tetrahydrofuran; ethanol; at 40℃;Product distribution / selectivity;
The following example provides the preparation and characterization of(8^,9i?)-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9-dihydro-2H- pyrido[4,3,2-
With phosphoric acid; In methanol; water; acetone; at 20 - 52℃;Product distribution / selectivity;
The following example provides the preparation and characterization of(8^,9i?)-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9-dihydro-2H- pyrido[4,3,2-
With hydrogenchloride; In tetrahydrofuran; at 5 - 60℃;Product distribution / selectivity;
The following example provides the preparation and characterization of(8^,9i?)-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9-dihydro-2H- pyrido[4,3,2-<ie]phthalazin-3(7H)-one salt and free base polymorphs. Properties of a tosylate salt are shown to be superior to those of other salt and free base forms of (85',9i?)-5-fluoro-8-(4- fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-(ie]phthalazin-3(7H)-one. These improved properties include, but are not limited to, presence of a single crystalline form, no solvation, high melting point, non-hygroscopicity, and/or thermal stability.[00134] Salt forms of (8^,9i?)-5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5- yl)-8,9-dihydro-2H-pyrido[4,3,2-(ie]phthalazin-3(7H)-one were prepared by treating the compound under a given condition with an acid. Salts forms, nos. 1-18, are identified in Table 1 below, where the acid used to treat (85,,9i?)-5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4- triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-(ie]phthalazin-3(7H)-one are provided in the column under "Acid," and the conditions used during treatment are provided in the column under"Condition."[00135] Polymorphs of free base (8,S,9i?)-5-Fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH- l,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-(ie]phthalazin-3(7H)-one were prepared from solutions prepared with different solvents. Characterizations of free base forms, nos. 19-24, are summarized in Table 2 and paragraphs referring to Table 2.[00136] Microscopy and other standard laboratory measurements were employed to characterize solid forms, melting temperatures, solvation and/or hydration, and otherphysiochemical properties (including, but not limited to, solubility, PKa, and Log P), of the salt forms and free base polymorphs
Compound 13 (36 g, 90.37 mmol), ethanol (450 mL) and 50% hydrazine hydrate (28.96 g, 452 mmol) were added into a fourth reactor and heated to reflux for 3 hours. Then the solvent was removed by distillation under reduced pressure and the crude product was washed with water, filtered, washed with ethanol and recrystal to obtain the final product of compound 1 (talazoparib, white solid, 31 g, yield 90.2%), HPLC purity: 99.5% (0080) LC-MS (ESI) m/z: 381(M+1)+. (0081) 1H-NMR (400 MHz, DMSO-d6): delta (ppm): 3.68 (s, 3H), 4.99-5.06 (m, 2H), 6.92-6.96 (m, 1H), 7.08-7.11 (m, 1H), 7.16-7.2 (t, J=8.8 Hz, 2H), 7.49-7.53 (m, 2H), 7.75 (s, 1H), 7.83 (s, 1H), 12.35 (s, 1H).
77%
With hydrazine hydrate; In acetonitrile; at 20℃; for 2h;
Example 17B 100399] To a solution of (2R,3No.)-methyl 7-fluoro-2-(4-fluoropheny l)-3 -( 1 -methyl- 1 H- 1 ,2,4- triazol-5-yl)-4-oxo- l ,2,3,4-tetrahydroquinoline-5-carboxylate (6a) or (2S,35)-methyl 7-fluoro-2-(4- fluoropheny l)-3-( 1 -methyl- 1 H- 1 ,2,4-triazol-5-yl)-4-oxo- 1 ,2,3 ,4-tetrahydroquinoline-5-carboxy late (6b) (446 g) in acetoi. itrile ( 10 volume) was added hydrazine monohydrate (2.9 eq.), and the se+ution stirred at room temperature for 2 hours. The resulting solution was then concentrated to a volume of 2 mL and filtered. The crude product was re-slurried with water (3~5 volumes) at 15~16 C. After drying in vacuum at 50 C, this affords the title compound as a white solid (329 g, yield 77%, 99.93% purity). LC- MS (ESI) m/z: 381(M+ 1 )+; ?-NMR (400 MHz, DMSO-d6) delta (ppm): 3.681 (s, 3H), 4.99-5.06 (m, 2H), 6.92-6.96 (m, 1 H), 7.08-7.1 1 (m, 1 H), 7. 16-7.21 (t, J = 8.8 Hz, 2H), 7.49-7.53 (m, 2H), 7.75 (s, 1 H), 7.83 (s, l H), 12.35 (s, 1 H).
With hydrazine hydrate; In methanol; at 25℃; for 10h;
Chiral separation of b to obtain c was achieved usingSupercritical Fluid Chromatography (SFC). Sample was prepared using methanol as a solvent (b: 45 mg/mL), by heated to 40-50 C and filtrated before the injection. A CHIRALPAK IC, 250*30 mm (I.D.), column and C02/methanol (80/20) mobile phase was employed with a flow rate of 65 g/minute. The column temperature was maintained at 35 C. The desired fraction came out of the column as the first peak having a retention time of 2.3 minute and another enantiomer having a retention time of 4.3 minute. UV detection was at 254 nm. The recovery of c was about 92% with >98% ee.
Free base, 19, from acetone: Microscopy, XRPD and DSC results were consistent with a mixture of forms.TABLE 19: X-Ray Powder Diffraction: Selected Peaks of free base 19** Peaks with Relative Intensity of less than 30% are not reportedTABLE 20: Results of Differential Scanning Calorimetry of free base 19Ramp 10.00 0C/min to 300.00 CTABLE 21: Results of Thermo gravimetric Analysis of free base 19Ramp 10.00 0C/min to 300.00 C m The following example provides the preparation and characterization of(8^,9i?)-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9-dihydro-2H- pyrido[4,3,2-
(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With hydrogenchloride; In tetrahydrofuran; at 5 - 60℃;
[00402] Salt forms of (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-( l -methyl-l H- l ,2,4-triazoi-5-yl)-8,9- dihydro-2H-pyrido[4,3,2-Je]phthalazin-3(7 )-one were prepared by treating the compound under a given condition with an acid. Salts forms, nos. 1-18, are identified in Table 1 below, where the acid used to treat (8S,9/?)-5-fiuoro-8-(4-fluorophenyl)-9-( l -methyl- lH- l ,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2- i/t']phthalazin-3(7//)-one are provided in the column under "Acid," and the conditions used during treatment are provided in the column under "'Condition."
(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
In dichloromethane; acetonitrile; at 25 - 40℃; for 1h;
[00402] Salt forms of (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-( l -methyl-l H- l ,2,4-triazoi-5-yl)-8,9- dihydro-2H-pyrido[4,3,2-Je]phthalazin-3(7 )-one were prepared by treating the compound under a given condition with an acid. Salts forms, nos. 1-18, are identified in Table 1 below, where the acid used to treat (8S,9/?)-5-fiuoro-8-(4-fluorophenyl)-9-( l -methyl- lH- l ,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2- i/t']phthalazin-3(7//)-one are provided in the column under "Acid," and the conditions used during treatment are provided in the column under "'Condition."
(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one mesylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
In methanol; acetonitrile; at 25 - 50℃; for 1h;
[00402] Salt forms of (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-( l -methyl-l H- l ,2,4-triazoi-5-yl)-8,9- dihydro-2H-pyrido[4,3,2-Je]phthalazin-3(7 )-one were prepared by treating the compound under a given condition with an acid. Salts forms, nos. 1-18, are identified in Table 1 below, where the acid used to treat (8S,9/?)-5-fiuoro-8-(4-fluorophenyl)-9-( l -methyl- lH- l ,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2- i/t']phthalazin-3(7//)-one are provided in the column under "Acid," and the conditions used during treatment are provided in the column under "'Condition."
(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one isethionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
In tetrahydrofuran; ethanol; at 40℃;
[00402] Salt forms of (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-( l -methyl-l H- l ,2,4-triazoi-5-yl)-8,9- dihydro-2H-pyrido[4,3,2-Je]phthalazin-3(7 )-one were prepared by treating the compound under a given condition with an acid. Salts forms, nos. 1-18, are identified in Table 1 below, where the acid used to treat (8S,9/?)-5-fiuoro-8-(4-fluorophenyl)-9-( l -methyl- lH- l ,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2- i/t']phthalazin-3(7//)-one are provided in the column under "Acid," and the conditions used during treatment are provided in the column under "'Condition."
2-((8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-3-oxo-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-7(3H)-yl)acetic acid[ No CAS ]
2-((8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-3-oxo-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-7(3H)-yl)acetyl azide[ No CAS ]
(2S,3R,4S,5S,6S)-2-(2-(3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanamido)-4-((((((8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-3-oxo-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-7(3H)-yl)methyl)carbamoyl)oxy)methyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate[ No CAS ]
(2S,3S,4S,5R,6S)-6-(2-(3-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)propanamido)-4-((((((8S, 9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-3-oxo-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-7(3H)-yl)methyl)carbamoyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid[ No CAS ]
ethyl 2-((8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-3-oxo-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-7(3H)-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
[04801 Synthesis of ethyl 2-((85, 9R)-5-fluoro-8-(4-fluorophenyl)-9-(] -methyl-]H-], 2,4- triazol-5-yl)-3-oxo-8, 9-dihydro-2 H-pyrido[4, 3, 2-de]phthalazin- 7(3H)-yl)acetate (7.3): [0481] A flame dried flask was charged with (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(i- methyl-i H-i ,2,4-triazol-5-yl)-8 ,9-dihydro-2H-pyrido [4,3 ,2-delphthalazin-3(7H)-one (7.0, 49 mg, i29 imol) in 2.2 mL anhydrous THF. The solution was stirred at -80C under N2 and nbutyl lithium (77 tL, i88 imol) as a 2.5 M solution was added dropwise and the resulting reaction was stirred for an additional i0 mm at -80C. Ethyl iodoacetate (7.2, 3i tL, 258 imol) was then added as a solution in i mL of anhydrous THF. Subsequently, the reaction mixture was stirred under nitrogen at 0C until LC/MS revealed conversion to product was complete. The reaction mixture was then cooled to -80 C and quenched with saturated ammonium chloride, diluted with dichloromethane, and washed with sodium bicarbonate. The aqueous layer was then extracted with dichloromethane, and the combined organics were washed with brine, dried over sodium sulfate, and concentrated to dryness. The crude product was purified over silica via a Biotage column eluting with methanol:dichloromethane mixtures to provide 7.3 (43 mg, 72%). Analytical UPLC-MS: tr = 1.79 mm, m/z (ES+) found467.55.
A vial was charged with <strong>[1207456-01-6]talazoparib</strong> (195 mg, 0.513 mmol), and ethanol (4 mL), 37%) formaldehyde (300 muL, 4.07 mmol), and N,N-dimethylethylenediamine (675 muL,6.15 mmol) were added. The vial was capped, and stirred at 80 C for 2 h. The reaction was cooled to room temperature, diluted with ethyl acetate (30 mL), and the ethyl acetate washed with saturated sodium bicarbonate (2 x 15 mL) and brine (15 mL). The organic layer was dried with magnesium sulfate, and the solvent removed in vacuo. The remaining residue was dissolved in DMF (8 mL), and 9A (229 mg, 0.559 mmol) was added, followed by diisopropylethylamine (1.26 mL, 7.19 mmol) and DMAP (93.1 mg, 0.762 mmol) were added. The reaction was stirred at room temperature for 2 h, and the solution loaded onto a 50 g Isco C18 column. Elution with 5%> to 50%) acetonitrile in water with 0.1%> TFA provided 9B contaminated with a small amount of alcohol 8B. The eluent from this column was diluted with an equal amount of water, and reloaded onto a preparative HPLC column, eluting with 5% to 40% acetonitrile in water with 0.1% TFA to provide 9B trifluoroacetate salt (1 10 mg, 0 126 mmol, 24% yield). LCMS M/Z = 756.5 (M + 1).
AEQNPIYWARYADWLFTTPLLLLDLALLVDADEC{{2-[([(11S,12R)-7-fluoro-11-(4-fluorophenyl)-12-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-2,3,10-triazatricyclo[7.3.1.0<SUP>5</SUP>,<SUP>13</SUP>]trideca-1,5,7,9(13)-tetraen-10-yl]methyl}carbamoyl)oxy]ethyl}sulfanyl}G[ No CAS ]
[ 1207456-01-6 ]
Yield
Reaction Conditions
Operation in experiment
With GLUTATHIONE; In aq. buffer; at 37℃;
General procedure: To (2S)-2-amino-5-[[(lR)-2-(carboxymethylamino)-2-oxo-l-(sulfanylmethyl)ethyl] amino]-5-oxo-pentanoic acid (4.90 mg, 0.0159 mmol) was added 2 mL of 1M Tris HC1 buffer (pH 7.0) to create an 8 mM solution. An aliquot of 1 mL of this solution was added to Example 3 (0.400 mg, 9.8lxl05mmol) to create a 100 mM solution. This mixture was heated at 37 C with time points taken at 15 minute intervals to measure for conjugate integrity. A steady loss of conjugate is observed with commensurate appearance of 2-[4- (hydroxymethyl)phenyl]-l~{H}-benzimidazole-4-carboxamide. The cleavage was complete by the 60 min time point as observed/confirmed by MSD. HPLC conditions: ES Industries Sonoma 4.6x50 mm; 5-100% CH3CN/H2O (0.1% TFA); 5.5 min run Conjugate RT: 3.71 Product RT: 2.24.
With n-butyllithium In tetrahydrofuran; hexane at -80℃; for 0.166667h; Inert atmosphere;
3.2.1. Synthesis of (8S,9R)-5-Fluoro-8-(4-uorophenyl)-9-(1-methyl-1 H-1,2,4-triazol-5-yl)-2-((6-nitrobenzo[d][1,3]dioxol-5-yl)methyl)-2,7,8,9-tetrahydro-3H pyrido[4,3,2-de]phthalazin-3-one (3)
To a solution of Talazoparib (70 mg, 0.18 mmol) in anhydrous tetrahydrofuran (THF) (30 mL)was added to a 100 mL, two-necked flask with a magnetic stir bar. The flask was evacuated andbackfilled with argon three times. Then 2.5 M n-Butyllithium (108 L, 0.27 mmol) in hexanes wereadded the reaction solution, and the mixture was cooled at 80 C. After stirring for 10 min, a solutionof 5-(bromomethyl)-6-nitrobenzo[d][1,3] dioxole (93.9 mg, 0.27 mmol) in anhydrous THF was slowlyadded to the mixture, was warmed to 0 C, and stirred overnight. When the reaction was completed,the mixture was carefully quenched by ammonium chloride saturated solution, and was extracted withethyl acetate (50 mL 3). The combined organic layers were washed with brine, dried over anhydroussodium sulfate, and concentrated. The crude product was purified by column chromatography(dichloromethane/methanol = 50:1) to give compound 3 (46 mg, yield 45.7%) as a light yellow solid;1H NMR (400 MHz, DMSO-d6) 7.79 (s, 1H); 7.73 (s, 1H); 7.63 (s, 1H); 7.53-7.45 (m, 2H); 7.20-7.13(m, 2H); 7.10 (dd, J = 9.0, 2.4 Hz, 1H); 6.93 (dd, J = 11.1, 2.5 Hz, 1H); 6.61 (s, 1H); 6.22-6.21 (m, 2H);5.40-5.29 (m, 2H); 5.08-5.00 (m, 2H); 3.56 (s, 3H). ESI m/z (M + H)+ calculated for C27H20F2N7O5+560.15 found 560.15.