- Novel preparation method of olaparib
-
The invention relates to a novel preparation method of olaparib. The novel preparation method comprises the following preparation steps: 1, reacting 4-methylphthalazin-1(2H)-one with NBS and AIBN in a reaction solvent; 2, carrying out a coupling reaction on 4-(bromomethyl)phthalazin-1(2H)-one and (4-fluoro-3-(methoxycarbonyl)phenyl)boric acid in a reaction solvent under the action of a catalyst and an alkali; 3, hydrolyzing methyl 2-fluoro-5-((4-oxo-3, 4-phthalazin-1-yl)methyl)benzoate in a reaction solvent under the action of alkali; and 4, reacting the 2-fluoro-5-((4-oxo-3, 4-dihydrophthalazin-1-yl)methyl)benzoic acid with cyclopropyl (piperazine-1-yl)methyl ketone hydrochloride in a reaction solvent under the action of a condensing agent and alkali to obtain a crude olaparib product, and recrystallizing to obtain the high-purity olaparib. According to the process of the novel preparation method, the total yield can be effectively improved, impurities caused by cyano hydrolysis can be obviously reduced, and the purity and quality of the prepared olaparib are improved.
- -
-
-
- Novel synthesis method of olaparib bulk drug
-
The invention introduces a novel synthesis method of an antitumor drug, namely olaparib. According to the invention, a dimer impurity is effectively removed by an acid-base pouring method in virtue of the different chemical properties that the dimer impurity cannot form salt and a previous intermediate of olaparib can form salt, and the HPLC purity of the obtained finished product can reach 99.9%. According to a route in the invention, the yield of the olaparib finished product is effectively improved, the total yield of six steps reaches 42.4%, and the route has important significance on industrial production of olaparib.
- -
-
-
- A Nickel(II)-Mediated Thiocarbonylation Strategy for Carbon Isotope Labeling of Aliphatic Carboxamides
-
A series of pharmaceutically relevant small molecules and biopharmaceuticals bearing aliphatic carboxamides have been successfully labeled with carbon-13. Key to the success of this novel carbon isotope labeling technique is the observation that 13C-labeled NiII-acyl complexes, formed from a 13CO insertion step with NiII-alkyl intermediates, rapidly react in less than one minute with 2,2’-dipyridyl disulfide to quantitatively form the corresponding 2-pyridyl thioesters. Either the use of 13C-SilaCOgen or 13C-COgen allows for the stoichiometric addition of isotopically labeled carbon monoxide. Subsequent one-pot acylation of a series of structurally diverse amines provides the desired 13C-labeled carboxamides in good yields. A single electron transfer pathway is proposed between the NiII-acyl complexes and the disulfide providing a reactive NiIII-acyl sulfide intermediate, which rapidly undergoes reductive elimination to the desired thioester. By further optimization of the reaction parameters, reaction times down to only 11 min were identified, opening up the possibility of exploring this chemistry for carbon-11 isotope labeling. Finally, this isotope labeling strategy could be adapted to the synthesis of 13C-labeled liraglutide and insulin degludec, representing two antidiabetic drugs.
- Pedersen, Simon S.,Donslund, Aske S.,Mikkelsen, Jesper H.,Bakholm, Oskar S.,Papp, Florian,Jensen, Kim B.,Gustafsson, Magnus B. F.,Skrydstrup, Troels
-
p. 7114 - 7123
(2021/03/03)
-
- Preparation method of olaparib
-
The invention relates to a preparation method of olaparib. 2-(2-(4-fluoro-3-carboxylphenyl)acetyl)benzoate and a hydrazine reagent are subjected to a chemical reaction to obtain a 2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoic acid compound, then, 2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoic acid and 1-cyclopropyl formylpiperazine are subjected to a condensation reaction, and olaparib is prepared. Besides, 2-(2-(4-fluoro-3-carboxylphenyl)acetyl)benzoate is firstly subjected to the condensation reaction with 1-cyclopropyl formylpiperazine and then subjected to the chemical reaction with the hydrazine reagent, and olaparib is prepared.
- -
-
-
- 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.
- -
-
-
- Synthetic method of olaparib
-
The invention discloses a synthetic method of olaparib. The synthetic method comprises the following steps: with phthalhydrazide as a starting material, reacting with phosphorus oxychloride to generate 1-chloro-4-carbonylpyridazine, and further reacting with ethyl 2-fluoro-5-bromomethylbenzoate, so as to generate ethyl 2-fluoro-5-[(4-carbonyl-3,4-dihydropyridazin-1-yl)methyl]benzoate; and carryingout hydrolysis and acylation, and carrying out condensation reaction by virtue of ethyl 2-fluoro-5-[(4-carbonyl-3,4-dihydropyridazin-1-yl)methyl]benzoate and 1-(cyclopropylcarbonyl)-piperazine, so asto generate olaparib. The synthetic method has the beneficial effects that phthalhydrazide is taken as the starting material for the first time, is easily available and is environmentally friendly; by utilizing Neigishi coupling, organic metal is utilized for reaction, catecholborane with a relatively high cost is not used, and zinc powder is used, so that the production cost is lowered, and thetotal yield of the route reaches 70.2%; and the reaction route is relatively short, reaction conditions are mild, and the synthetic method is suitable for industrial production.
- -
-
-
- PROCESSES FOR PREPARING OLAPARIB
-
Provided herein are novel processes and methods for making 4-[(3-[(4-cyclopropylcarbonyl)piperazin-1-yl]carbonyl)-4-fluorophenyl]methyl(2H)phthalazin-1-one (Olaparib) and intermediates thereof. Olaparib is a poly ADP ribose polymerase (PARP) inhibitor useful in the treatment of cancers. Benefits of the present disclosure include the use of less toxic compounds and improved yields.
- -
-
-
- Olaparib compound refining method
-
The invention relates to an olaparib compound refining method. The method includes synthesis of a crude olaparib product and refining of olaparib. Refining includes steps: 1) adding ethyl acetate petroleum ether mixed liquid and the crude olaparib product into a reaction bottle, slowly heating to 50-55 DEG C, performing heat-preservation stirring for 20min, heating to 70-75 DEG C, stirring, and dissolving the crude product to obtain crude product solution; adding activated carbon into the crude product solution, decolorizing, filtering and collecting filtrate; 2) slowly cooling the filtrate to 20-25 DEG C, keeping the temperature and stirring; 3) cooling the filtrate to 0 DEG C or below, controlling a stirring speed at 15r/min, adding seed crystal, controlling the temperature and the stirring speed to grow the crystal for 1.5h, filtering, flushing a filter cake with a small quantity of ethyl acetate petroleum ether mixed liquid, and drying to obtain a refined olaparib product. The refining method has advantages of simple conditions, reduction of olaparib disubstituted substances, high product purity and the like.
- -
-
-
- Compounding method for olaparib compound
-
The invention relates to a compounding method for an olaparib compound. The compounding method comprises the following steps: 1) taking bromobenzene (compound 8) as an initial raw material to react with a compound 6 under the existence of potassium tert-butoxide, thereby acquiring a compound 5; 2) by taking methyl phthalate (compound 4) as a raw material, and taking diisopropyl carbodiimide (DIC) and 4-N,N-dimethyl pyridine (DMAP) as catalysts, reacting with cyclopropyl-1-piperazinyl (compound 3), thereby acquiring a compound 2; 3) by taking [Emim] Cl-AlCl3 ionic liquid as the catalyst, enabling the compound 5 to react with the compound 2 to generate the olaparib (compound 1). The invention overcomes the problems of more side effects, low yield, low purity and the like of the prior art and forms a new technology with short reaction route, mild reaction condition, high yield and purity and simplicity and convenience in operation.
- -
-
-
- PROCESS FOR THE PREPARATION OF OLAPARIB AND POLYMORPHS THEREOF
-
The present invention is directed to process for preparation of Olaparib of formula (I). The present invention further relates to novel polymorphic forms of Olaparib, pharmaceutical compositions containing them, and method of treatment using the same.
- -
-
-
- Preparing method for Olaparib
-
The invention discloses a preparing method for Olaparib. 5-bromomethyl-2-fluorobenzaote serves as a raw material and is subjected to a boric acid reaction with catecholborane, and a compound 3 is obtained; the compound 3 is subjected to a Suzuki coupling reaction, and a compound 5 is obtained; the compound 5 is subjected to a hydrolysis reaction, and a compound 6 is obtained; the compound 6 reacts with a compound 7 under the action of a CDI catalyst, and Olaparib is obtained. According to the preparing method, the raw material is easy to obtain, the course is short, operation and posttreatment are simple, the reaction conditions in all the steps are mild, the reaction yields of all the steps reach 90% or above, the total yield is increased to 82.3% from 49% achieved in the prior art, and the preparing method is environmentally friendly and suitable for industrial production.
- -
-
-
- Synthesis and evaluation of a radioiodinated tracer with specificity for poly(ADP-ribose) polymerase-1 (PARP-1) in vivo
-
Interest in nuclear imaging of poly(ADP-ribose) polymerase-1 (PARP-1) has grown in recent years due to the ability of PARP-1 to act as a biomarker for glioblastoma and increased clinical use of PARP-1 inhibitors. This study reports the identification of a lead iodinated analog 5 of the clinical PARP-1 inhibitor olaparib as a potential single-photon emission computed tomography (SPECT) imaging agent. Compound 5 was shown to be a potent PARP-1 inhibitor in cell-free and cellular assays, and it exhibited mouse plasma stability but approximately 3-fold greater intrinsic clearance when compared to olaparib. An 123I-labeled version of 5 was generated using solid state halogen exchange methodology. Ex vivo biodistribution studies of [123I]5 in mice bearing subcutaneous glioblastoma xenografts revealed that the tracer had the ability to be retained in tumor tissue and bind to PARP-1 with specificity. These findings support further investigations of [123I]5 as a noninvasive PARP-1 SPECT imaging agent.
- Zmuda, Filip,Malviya, Gaurav,Blair, Adele,Boyd, Marie,Chalmers, Anthony J.,Sutherland, Andrew,Pimlott, Sally L.
-
p. 8683 - 8693
(2015/11/25)
-
- PHTHALAZINONE DERIVATIVES
-
Compounds of the formula (I): wherein A and B together represent an optionally substituted, fused aromatic ring; X can be NRX or CRXRY; if X NRX then n is 1 or 2 and if X = CRXRY then n is 1; RX is selected from the group consisting of H, optionally substituted C1-20 alkyl, C5-20 aryl, C3-20 heterocyclyl, amido, thioamido, ester, acyl, and sulfonyl groups; RY is selected from H, hydroxy, amino; or RX and RY may together form a spiro-C3-7 cycloalkyl or heterocyclyl group; RC1 and RC2 are both hydrogen, or when X is CRX RY, RC1, RC2, RX and RY, together with the carbon atoms to which they are attached, may form an optionally substituted fused aromatic ring; and R1 is selected from H and halo.
- -
-
-
