- Preparation method of olaparib key intermediate
-
The invention provides a preparation method of an olaparib key intermediates 4-(3-bromo-4-fluorobenzyl)phthalazin-1(2H)-one (a compound shown as a formula IV) and 2-fluoro-5-[(4-oxo-3,4-dihydro-1-phthalazinyl)methyl]benzoic acid (a compound shown as a formula V). Specifically, (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonic acid dimethyl ester is used as a raw material to be subjected to a Wittig-Horner reaction with 3-bromo-4-fluorobenzaldehyde to obtain a formula III, the formula III and hydrazine hydrate are subjected to cyclization to obtain a formula IV, and the formula IV is subjected toa reaction with n-butyllithium and carbon dioxide to obtain an olaparib intermediate V. The method is economical and environment-friendly, and the yield is greatly improved.
- -
-
-
- Preparation method of Olaparib
-
The invention discloses a preparation method of Olaparib. The preparation method comprises the following steps: carrying out a reaction between phthalide (II) and 3-bromo-4-fluorobenzaldehyde (III) toobtain a compound IV, carrying out a reaction between the compound IV and hydrazine monohydrate to obtain a compound V, and carrying out a reaction between the compound V and 1-cyclopropylcarbonylpiperazine to obtain the final product of Olaparib (I). The raw materials used in the reaction are cheap and easy to obtain, and the preparation method is simple in process route, high in total yield andfew in byproducts and is applicable to industrial production.
- -
-
-
- Olaparib refining method
-
The invention discloses an olaparib refining method, which comprises: (1) dissolving an olaparib crude product in a mixed solvent of ethyl acetate and acetone, and controlling the temperature at 45-50DEG C until olaparib is completely dissolved; (2) adding active carbon, decolorizing, filtering, cooling the filtrate to a temperature of -10-0 DEG C, crystallizing, and growing the crystal; and (3)filtering, washing the filtered solid by using acetone, and carrying out vacuum drying to obtain the refined olaparib. With the refining method of the present invention, the purity of the obtained olaparib can reach more than 99.9%, the total impurity and the single impurity are respectively controlled within 0.1% and 0.05%, the quality of the product is remarkably improved, the refining process is easy to operate, and the refining method is suitable for industrial production.
- -
-
-
- PHTHALAZINE DERIVATIVES AS INHIBITORS OF PARP1, PARP2 AND/OR TUBULIN USEFUL FOR THE TREATMENT OF CANCER
-
The application relates to phthalazine derivatives of formula (I) which are inhibitors of PARP1, PARP2 and/or tubulin and thus useful for the treatment of cancer. Also disclosed are pharmaceutical formulations containing such compounds, as well as combinations of these compounds with at least one additional therapeutic agent.
- -
-
Paragraph 0189
(2018/04/11)
-
- Process for the Preparation of Olaparib and Intermediates Thereof
-
The present invention provides processes for the preparation of intermediate compounds of formulas (4) and (5) useful in the preparation of Olaparib. (X is chloride, bromide or iodide)
- -
-
Paragraph 0070; 0071; 0072; 0073
(2017/09/02)
-
- TRICYCLIC INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE
-
The invention provides for compositions comprising phosphorous containing tricyclic compounds, including phthalazin-l(2H)-one derivatives. The compounds are potent inhibitors of the enzyme poly(ADP-ribose)polymerase (PARP), particularly PARP-1 and potentially PARP-2. The also show good cellular activity in inhibiting poly(ADP- ribose) oligomer formation. The compounds may be useful as mono-therapy or in combination with other therapeutic agents in the treatment conditions where PARP is implicated, such as cancer, inflammatory diseases and ischemic conditions. Thus, also provided are methods for the treatment of a condition where PARP is implicated comprising administering to an effective amount of a compound of the invention to an individual in need thereof.
- -
-
-
- PHTHALAZINONE DERIVATIVES
-
A compound of the formula (I) wherein: A and B together represent an optionally substituted, fused aromatic ring or an optionally substituted, fused cyclohexene ring; D is selected from: (i), where Y1 is selected from CH and N, Y2 is selected from CH and N, Y3 is selected from CH, CF and N and Y4 is selected from CH and N; (ii) where Y1is selected from CH and N and Y2 is selected from CH and N; (iii) and where Q is O or S; and (iv), where Q is O or S; and RD is an optionally substituted C5-20 aryl group, bound to D by a carbon-carbon bond.
- -
-
Page/Page column 49-50
(2008/12/07)
-