- Niraparib preparation method
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The invention provides a niraparib preparation method, which comprises: carrying out photocatalysis on a compound 1 and bromobenzene under a Pd catalyst to obtain a niraparib key intermediate; carrying out chiral resolution on the niraparib key intermediate, and coupling the niraparib key intermediate with NBoc-1H-indazole-7-carboxamide under the catalysis of copper bromide to obtain protected niraparib; and removing the protective color of the protected niraparib under the action of methanesulfonic acid, and obtaining the target product niraparib under tetrahydrofuran pulping. The preparation method of niraparib is simple in synthesis process route, high in preparation efficiency, small in damage to human bodies and the environment and low in synthesis cost.
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- CRYSTALLINE FORMS OF NIRAPARIB FREEBASE
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Crystalline niraparib freebase is provided. Also provided are pharmaceutical compositions comprising crystalline niraparib freebase, and methods and uses pertaining to the same.
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Paragraph 000257
(2020/05/15)
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- NIRAPARIB SALTS
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Novel salts of niraparib are provided. Also provided are pharmaceutical compositions comprising those salts, as well as methods and uses pertaining to the same.
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Paragraph 000404-000406
(2020/05/15)
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- New method for preparing niraparib and intermediate thereof
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The present invention discloses a new method for preparing niraparib and an intermediate thereof. 2-aminobenzamide and (S)-4-(piperidin-3-yl)aniline are used as raw materials, and subjected to oxidative dehydrogenation coupling under microwave irradiation, an obtained coupled product is subjected to addition cyclization reaction with paraformaldehyde to synthesize a PARP inhibitor, namely, niraparib, and the total yield is 81%. The synthetic method of the invention is simple, the reaction condition is mild, the reaction time is short, the product yield is high, the raw material 2-aminobenzamide is cheap and easy to obtain, the production cost is low, a simple and efficient method is provided for synthesizing 2H-indazole compounds and the method has potential industrial application prospects.
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Paragraph 0024-0028
(2019/09/14)
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- COMPOUNDS, COMPOSITIONS, AND METHODS FOR TREATMENT OF DISEASES INVOLVING ACIDIC OR HYPOXIC DISEASED TISSUES
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Compounds for treatment of diseases having acidic or hypoxic diseased tissues and pharmaceutical compositions comprising the compounds, as well as methods for making and using the compounds and compositions.
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Page/Page column 136; 137
(2019/07/20)
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- PARP inhibitor key intermediate and its preparation method (by machine translation)
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The invention discloses a method for preparing Niraprib PARP inhibitors and used in the preparation method of the two key intermediates, the preparation method in order to 4 - bromophenylacetic acid methyl ester and (S) - Tert [...] sulfonamide as raw materials, after condensation, asymmetric alkylation, reduction, obtained by coupling the key intermediate compound 5; compound 5 by condensation obtained by coupling the compound 6; compound 6 in toluene sulfonic acid hydrolysis under the action of removing protecting group, to obtain the target product Niraprib. The beneficial effect of the present invention is: by introducing the hand natural auxiliary medicinal preparation of asymmetric alkylation induced chiral, has overcome the existing split and chiral source method, this method is easy and simple, mild condition, the yield is good, chemical purity and optical purity is relatively high, and the key intermediate 5 and SM3 condensation to obtain the target compound 1, breakthrough grinds originally Patent, is suitable for industrial production. (by machine translation)
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- NIRAPARIB COMPOSITIONS
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The present invention relates to compositions comprising the compound niraparib, in particular certain solid forms of niraparib.
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Paragraph 00127
(2018/10/25)
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- A nepal pulls handkerchief nepal and intermediate preparation method and intermediate compounds (by machine translation)
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The invention discloses a method for preparing nepal pulls handkerchief nepal intermediate, represented by the formula, comprising the following steps: to (S)- oxazolidone to the bromobenzene with acetic acid as the starting material, to amide condensation, Michael addition, lipid amide reduction, sulfuryl fat synthesis, ammoniation ring, with the reaction of the organic acid salt, can be. The invention also discloses the preparation of nepal pulls handkerchief nepal and intermediates therefor. Preparation method of the invention low cost, easy availability of raw materials, the yield is high, it is suitable for industrial production. (by machine translation)
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- Method for preparing Niraparib of PARP (poly-ADP-ribose polymerase) inhibitor
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The invention discloses a method for preparing 2-(4-((3S)-3-piperidyl) phenyl)-2H-indazole-7-formamide of a compound. Benzyl protected-piperidone is generated into piperidone of 3-triflic anhydride under the action of triflic anhydride, the piperidone and nitrobenzoic acid are subjected to Suzuki reaction to obtain a coupled product, 3-(4-aminophenyl) piperidine is obtained under the action of a palladium reagent, (S)-3-(4-halogenated phenyl) piperidine is prepared with a chirality resolution reagent, the (S)-3-(4-halogenated phenyl) piperidine is condensed with 3-formyl-2-methyl nitrobenzoate to form pyrazolone ring under the action of sodium azide, and the Niraparid (with the molecular entity of 2-(4-((3S)-3-piperidyl) phenyl)-2H-indazole-7-formamide) is prepared via aminolysis.
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- Synthesis method of novel oral anticancer medicine Nirapairb
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The invention discloses a synthesis method of a novel oral anticancer medicine Nirapairb, the method comprises the following steps of subjecting a starting raw material 3-methyl-2-methyl bromobenzoate to a series of reactions of oxidization, aldimine condensation, cyclization, amidation, BOC (tert-Butyloxycarbonyl) removal, chiral separation and the like to obtain optically pure Niraparib of which the purity reaches 98.2 percent. The method is simple to operate, and is applicable to industrialized production; synthesis steps are few; a reaction condition is easily controlled.
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- A prepares Nepal to pull handkerchief Nepal method (by machine translation)
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The invention discloses a compound 2 - [4 - ((3S) - 3 - piperidinyl) phenyl] - 2H - indazole - 7 - carboxamide preparation method, through the 4 - nitro phenylpyridyl with reaction produced animal pen halogenphenmethyl season ammonium salt, by sodium borohydride reduction of the pyridine quaternary ammonium salt, in the palladium reagent obtained under the action of the 3 - (4 - aminophenyl) piperidine, in the chiral reagent obtained under the action of the (S)- 3 - (4 - halophenyl) piperidine, with 3 - formyl - 2 - nitro-benzoic acid methyl ester condensation and in sodium azide formed under the action of powder medicine, after preparing the amine Niraparib (molecular entity is: 2 - [4 - ((3S) - 3 - piperidinyl) phenyl] - 2H - indazole - 7 - carboxamide). (by machine translation)
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- Niraparib synthesis method
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The invention discloses a Niraparib synthesis method. The method comprises that through esterification, 3-methyl hydroformylation, 3-schiff base reaction, cyclization, amidation, BOC removal and chiral resolution, optically pure Niraparib with purity of 91% or more is prepared from 3-methyl-2-nitrobenzoic acid. The method has the advantages of simple process, high efficiency, easy operation and less equipment requirement, and is a method suitable for industrial production.
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- PHARMACEUTICALLY ACCEPTABLE SALTS OF 2-{4-[(3S)-PIPERIDIN-3- YL]PHENYL} -2H-INDAZOLE-7-CARBOXAMIDE
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The present invention relates to pharmaceutically acceptable salts of an amide substituted indazole which are inhibitors of the enzyme poly(ADP-ribose)polymerase (PARP), previously known as poly(ADP-ribose)synthase and poly(ADP-ribosyl)transferase. The compounds of the present invention are useful as mono-therapies in tumors with specific defects in DNA-repair pathways and as enhancers of certain DNA -damaging agents such as anticancer agents and radiotherapy. Further, the compounds of the present invention are useful for reducing cell necrosis (in stroke and myocardial infarction), down regulating inflammation and tissue injury, treating retroviral infections and protecting against the toxicity of chemotherapy.
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Page/Page column 37-38
(2009/09/04)
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- Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): A novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors
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We disclose the development of a novel series of 2-phenyl-2H-indazole-7- carboxamides as poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl] phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC50 = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC50 = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC50 in the 10-100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.
- Jones, Philip,Altamura, Sergio,Boueres, Julia,Ferrigno, Federica,Fonsi, Massimiliano,Giomini, Claudia,Lamartina, Stefania,Monteagudo, Edith,Ontoria, Jesus M.,Orsale, Maria Vittoria,Palumbi, Maria Cecilia,Pesci, Silvia,Roscilli, Giuseppe,Scarpelli, Rita,Schultz-Fademrecht, Carsten,Toniatti, Carlo,Rowley, Michael
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experimental part
p. 7170 - 7185
(2010/07/04)
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