- 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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Paragraph 0052; 0066-0068
(2021/11/14)
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- Intermediate for synthesizing niraparib, and preparation method thereof
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The invention relates to an intermediate for synthesizing niraparib, and a preparation method thereof, and specifically discloses an intermediate compound I. The compound can be used for preparing a key intermediate (S)-3-(4-bromophenyl)-piperidine for preparing niraparib. The invention also discloses a preparation method of the compound and a preparation method of (S)-3-(4-bromophenyl)-piperidine. The preparation methods provided by the invention do not involve noble metal catalytic reduction or coupling reaction, do not involve enantiomer resolution operation, and have the advantages of lowequipment requirements, low three wastes, short steps, low cost, simplicity in operation and high industrial feasibility.
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Paragraph 0092-0094
(2020/07/12)
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- Method for industrially producing (S)-3-(4-bromophenyl) piperidine
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The invention belongs to the field of chemical medicine synthesis, and provides a method for industrially producing (S)-3-(4-bromophenyl) piperidine. The method comprises the following steps: by taking (S)-1-tert-butyloxycarbonyl-3-hydroxypiperidine as an initial raw material, removing tert-butyloxycarbonyl protecting groups to obtain (S)-3-hydroxypiperidine hydrochloride A; condensing the intermediate A and thionyl chloride to generate a five-membered ring sulfinate intermediate B; oxidizing the intermediate B to generate a five-membered ring sulfonate C; carrying out nucleophilic substitution reaction on the compound C and aryl anions, and meanwhile, carrying out configuration inversion to generate the target product (S)-3-(4-bromophenyl) piperidine. According to the whole process, high-pressure hydrogenation, diazotization and other operations are not used, and no chiral resolution reagent is used, so that the total cost is lower, the operation is simple and convenient, higher chiral purity can be maintained, and the method is suitable for industrial large-scale production.
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- Preparation method of niraparib intermediate (S)-3-(4-bromophenyl) piperidine
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The invention discloses a preparation method of a niraparib intermediate that is (S)-3-(4-bromophenyl) piperidine, which comprises the following steps: by using chiral 1-phenylethylamine as a raw material, carrying out alkylation, condensation, cyclization and reduction, and finally removing an amino protection group to obtain the (S)-3-(4-bromophenyl) piperidine. The preparation method of the (S)-3-(4-bromophenyl) piperidine has the advantages of short route, few steps, simple and convenient process operation, avoidance of use of dangerous reagents, highly toxic reagents and irritant malodorous reagents, reduction of potential safety hazards to operators, reduction of the operation safety level of production, environmental protection, and facilitation of industrialization.
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Paragraph 0025; 0112-0113
(2020/11/01)
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- Niraparib intermediate, preparation method and application thereof, and synthesis method of niraparib
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The invention relates to a compound alpha-(3-aminopropyl)-p-bromophenylacetic acid, a preparation method and application thereof, (S)-3-(4-bromophenyl)-piperidine-2-one, a preparation method and application thereof, and synthesis methods of (S)-3-(4-bromophenyl)-piperidine) p-toluenesulfonate, N-Boc-(3S)-(4-bromophenyl)piperidine and niraparib. 4-bromophenylacetate 5 is used as a raw material, a nucleophilic reaction is carried out on the raw material and a nitrogen source reagent 4 under the action of an alkali to generate a compound 6; the compound 6 is subjected to deprotection and hydrolysis to obtain an amino acid compound 7; and the amino acid compound 7 is subjected to chiral column separation or chemical resolution to obtain compounds 8 and 9; and the separated enantiomer 8 can besubjected to racemization and resolution conversion (or chiral column separation) to obtain a compound 9, and the process material cost is greatly reduced. After the compound 9 is obtained, a compound1 can be obtained through conventional condensation reaction ring closing, reduction and BOC loading. Splitting operation is advanced, and the enantiomer 8 is subjected to racemization recovery treatment and is repeatedly applied to different splitting batches to continuously obtain the product 9, so the process material cost is lower.
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- Preparation method of niraparib intermediate
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The invention discloses a preparation method of a niraparib intermediate. The preparation method of the compound represented by formula III is characterized in that a compound represented by formula IV and a compound represented by formula V undergo a sub
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- Method of synthesizing (S)-3-(4-bromophenyl)-piperidine or salt thereof with chiral induction
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The invention relates to a method of synthesizing (S)-3-(4-bromophenyl)-piperidine or salt thereof with chiral induction. Particularly, the method comprises the following steps of by taking methyl ortho-4-bromophenylacetate and (S)-(-)-2-methyl-2-propanes
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- DEUTERATED (S)-2-(4-(PIPERIDIN-3-YL)PHENYL)-2H-INDAZOLE-7-CARBOXAMIDE
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A deuterated compound having the structure of Formula I: or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a salt of a prodrug thereof; or a hydrate or polymorph thereof; whereinY1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y9', Y10, Y10', Y11,
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Paragraph 0290; 0293-0294
(2019/10/15)
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- A Niraparib intermediate (S)-3 - (4 - bromophenyl) piperidine preparation method (by machine translation)
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The invention discloses a Niraparib intermediate (S)- 3 - (4 - bromophenyl) piperidine of preparation method, the method using the bromo ethyl acetate with N - boc - 3 - amino propyl bromide in alkali under the action of the nucleophilic reaction, ring un
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- Synthesis method for (R)-3-phenylpiperidine or/and (S)-3-phenylpiperidine and synthesis method for chiral intermediate of niraparib
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The invention belongs to the technical field of organic synthesis. The synthesis method firstly provided by the invention takes benzyl-4-oxopiperidine as a starting material, and the starting materialis subjected to Grignard reaction, elimination reaction, hydrogenation reduction reaction and chiral resolution in sequence to successfully obtain a target product (R)-3-phenylpiperidine or/ and (S)-3-phenylpiperidine. The synthesis method sencondly provided by the invention takes the same starting raw material for Grignard reaction, organic silicon reagent is used for removing a hydroxide radical, and benzyl is removed by catalytic hydrogenation reaction; finally, the chiral resolution is carried out to obtain a target product. The (S)-3-phenylpiperidine can be synthesized according to the synthesis method. (S)-3-p-aminosalicylic phenylpiperidine can be synthesized according to the third aspect; or according to the fourth aspect, (S)-3-p-bromophenyl piperidine is synthesized to serve asthe key intermediate for preparing the niraparib. According to the synthesis method for (R)-3-phenylpiperidine or/ and (S)-3-phenylpiperidine and the synthesis method for chiral intermediate of niraparib, production cost is obviously lowered, and the synthesis methods are favorable for the large-scale industrial production of a niraparib medicine.
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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 intermittent S-3-(4-bromophenyl) piperidine
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The invention discloses a method for preparing a niraparib intermittent, namely S-3-(4-bromophenyl) piperidine. The method comprises the following steps: (1) performing diazo reaction on S-3-(4-aminophenyl) piperidine and nitrous acid to generate an intermittent compound; (2) enabling the intermittent compound to react with bromide to generate a target product, namely the niraparib intermittent,namely S-3-(4-bromophenyl) piperidine. By adopting the method, S-3-(4-amino phenyl) piperidine is adopted as a raw material, the niraparib intermittent, namely S-3-(4-bromophenyl) piperidine, is synthesized through two steps of diazo reaction and bromination reaction, the process is simplified, the operation is simple to carry out, reaction conditions are gentle, the industrial production difficulties are reduced, in addition, no expensive raw material is used, the production cost can be controlled, and the obtained niraparib intermittent is high in purity and high in yield.
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Paragraph 0042-0044; 0047; 0050; 0053; 0056
(2018/03/23)
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- Preparation method of niraparib intermediate 4-(3S-piperidine-3-yl)bromobenzene
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The invention discloses a preparation method of niraparib intermediate 4-(3S-piperidine-3-yl)bromobenzene. The preparation method is characterized by comprising steps as follows: 1) a compound shown in a formula I and hydroxylammonium chloride are subjected to a contact reaction to produce a compound shown in a formula II; 2) the compound shown in the formula II and phenyl dichlorophosphate are subjected to a catalytic reaction to produce a compound shown in a formula III; 3) the compound shown in the formula III is subjected to a reduction reaction to produce niraparib intermediate 4-(3S-piperidine-3-yl)bromobenzene shown in a formula X, and the specific reaction process is shown in the specification. A new synthesis way is provided for the niraparib intermediate 4-(3S-piperidine-3-yl)bromobenzene, metal catalysts, expensive transaminase and the like are not used in the reaction process, the production cost is low, and the product has the good yield and stereoselectivity.
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- Preparation method of niraparib tosilate monohydrate
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The invention discloses a preparation method of a compound 2-[4-((3S)-3-piperidyl)phenyl]-2H-indazole-7-formamide tosilate monohydrate. The method includes: carrying out Ulman reaction on 1H-indazole-7-methyl formate and (S)-3-(4-halogenophenyl)piperidine-1-tert-butyl formate to prepare 2-[4-((3S)-3-piperidyl)phenyl]-2H-indazole-7-methyl formate, then under the conditions of ammonia gas and p-toluenesulfonic acid, preparing 2-[4-((3S)-3-piperidyl)phenyl]-2H-indazole-7-formamide tosilate monohydrate. The invention aims to avoid the disadvantages of existing methods, shortens the preparation route, and provides the preparation method of the 2-[4-((3S)-3-piperidyl)phenyl]-2H-indazole-7-formamide tosilate monohydrate with high chiral purity, and the method has the characteristics of mild reaction and easy operation.
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Paragraph 0042; 0043
(2017/07/21)
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- Process development of C-N cross-coupling and enantioselective biocatalytic reactions for the asymmetric synthesis of niraparib
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Process development of the synthesis of the orally active poly(ADP-ribose)polymerase inhibitor niraparib is described. Two new asymmetric routes are reported, which converge on a high-yielding, regioselective, copper-catalyzed Narylation of an indazole derivative as the late-stage fragment coupling step. Novel transaminase-mediated dynamic kinetic resolutions of racemic aldehyde surrogates provided enantioselective syntheses of the 3-aryl-piperidine coupling partner. Conversion of the C-N cross-coupling product to the final API was achieved by deprotection and salt metathesis to isolate the desired crystalline salt form.
- Chung, Cheol K.,Bulger, Paul G.,Kosjek, Birgit,Belyk, Kevin M.,Rivera, Nelo,Scott, Mark E.,Humphrey, Guy R.,Limanto, John,Bachert, Donald C.,Emerson, Khateeta M.
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p. 215 - 227
(2014/05/20)
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