cas 1217630-38-0, (2S)-2-(2,5-DIFLUOROPHENYL)PYRROLIDINE

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Efficient preparation of (R)-2-(2,5-difluorophenyl)pyrrolidine via a recycle process of resolution
An efficient preparation of (R)-2-(2,5-difluorophenyl)pyrrolidine ((R)-1) from the racemate based on a recycle process of resolution/racemization was described. In the process, the desired (R)-1 was obtained by resolution with D-malic acid in 95% EtOH. Me
Lv, Xunlei,Chen, Liang,Pan, Jing,Meng, Xue,Bi, Siju,Liu, Weiyuan,Zhou, Ting,Lin, Kuaile,Ye, Deyong,Zhou, Weicheng
p. 931 - 937
(2021/10/19)

Zinc-Catalyzed Asymmetric Hydrosilylation of Cyclic Imines: Synthesis of Chiral 2-Aryl-Substituted Pyrrolidines as Pharmaceutical Building Blocks
The first successful enantioselective hydrosilylation of cyclic imines promoted by a chiral zinc complex is reported. In situ generated zinc-ProPhenol complex with silane afforded pharmaceutically relevant enantioenriched 2-aryl-substituted pyrrolidines in high yields and with excellent enantioselectivities (up to 99% ee). The synthetic utility of presented methodology is demonstrated in an efficient synthesis of the corresponding chiral cyclic amines, being pharmaceutical drug precursors to the Aticaprant and Larotrectinib. (Figure presented.).
W?glarz, Izabela,Michalak, Karol,Mlynarski, Jacek
supporting information
p. 1317 - 1321
(2020/12/09)

FIVE-AND-SIX-MEMBERED HETEROCYCLIC COMPOUND AND USE THEREOF AS PROTEIN RECEPTOR KINASE INHIBITOR
A class of five-membered fused with six-membered heterocyclic compounds represented by formula I and a pharmaceutical composition, preparation, and an application thereof are disclosed. These compounds have TRK kinase inhibitory activity and can treat diseases related to TRK dysfunction.
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Paragraph 0060; 0065-0066

(2021/12/18)

METHODS FOR PREPARING TYROSINE RECEPTOR KINASE INHIBITORS
The present disclosure relates to pyrazolo[1,5-α]pyrimidine compounds useful as TRK inhibitors and compounds useful in preparing pyrazolo[1,5-α]pyrimidine compounds, and methods of making and using same. This abstract is intended as a scanning tool for pu
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Paragraph 00460; 00463

(2021/10/22)

SIX-MEMBERED AND SIX-MEMBERED HETEROCYCLIC COMPOUND AND USES THEREOF SERVING AS PROTEIN RECEPTOR KINASE INHIBITOR
Provided are a preparation and applications of a six-membered fused with six-membered heterocyclic compound, specifically, provided in the present invention is a compound as represented by formula I as follows, where the definitions of the groups are as described in the description. The compound has TRK kinase inhibiting activity and can serve as a pharmaceutical composition for treating TRK dysfunction-related diseases.
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Paragraph 0078; 0083-0084

(2021/09/24)

Synthesis method of (R)-2-(2, 5-difluorophenyl) pyrrolidine
The invention belongs to the technical field of chemical pharmacy, and relates to a synthetic method of (R)-2-(2, 5-difluorophenyl)pyrrolidine. The synthesis method comprises the following steps: (1) carrying out dehydration condensation reaction on a compound as shown in a formula 1 and a chiral induction reagent (R) tert-butylsulfinamide to obtain a compound as shown in a formula 2; (2) carrying out addition reaction on the compound in the formula 2 and a Grignard reagent to obtain a compound in a formula 3; (3) carrying out a reduction/cyclization reaction on the compound shown in the formula 3, trifluoroacetic acid and triethylsilane to obtain a compound shown in a formula 4; (4) splitting the compound shown in the formula 4 by (D)-malic acid to obtain the (R)-2-(2, 5-difluorophenyl) pyrrolidine*D malate compound with EE being greater than 98% shown in the formula 5; and (5) dissociating the compound in the formula 5 with a sodium hydroxide solution to obtain (R)-2-(2, 5-difluorophenyl) pyrrolidine. By utilizing the synthetic method of (R)-2-(2,5-difluorophenyl)pyrrolidine, the cost is low, the optical purity is high, the subsequent separation process is simplified, the raw materials are easy to obtain, the process conditions are mild, and the synthetic method is suitable for synthesizing (R)-2-(2, 5-difluorophenyl) pyrrolidine in large-scale production.
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Paragraph 0089-0091

(2021/04/10)

Synthesis method of larotrectinib intermediate (2R)-2-(2, 5-difluorophenyl) pyrrolidine
The invention discloses a synthesis method of a larotrectinib intermediate (2R)-2-(2, 5-difluorophenyl) pyrrolidine, and belongs to the field of drug synthesis. The preparation method comprises the following steps: taking p-difluorobenzene and L-pyroglutamic acid as raw materials to obtain an intermediate I under the action of an Eaton reagent; reducing the intermediate I to obtain an intermediateII; and performing chiral resolution to obtain (2R)-2-(2, 5-difluorophenyl) pyrrolidine. The method has the advantages of short synthesis route, mild reaction conditions, cheap and easily available raw materials, high yield and good product purity.
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(2020/07/12)

Preparation method of larotinib intermediate, and intermediate compound
The invention discloses a preparation method of a larotinib intermediate represented by V, and an intermediate compound. The method comprises the following steps: taking 2,5-difluorobromobenzene and N-tert-butoxycarbonyl-L-pyroglutamate as initial raw mat
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Paragraph 0067-0072

(2020/11/09)

Method for preparing larotrectinib intermediate through one-pot method
The invention discloses a method for preparing a larotrectinib intermediate through a one-pot method. The preparation method is characterized by comprising the following steps: 1) dissolving a compound VI serving as a raw material in a solvent, adding isopropyl magnesium chloride to generate a Grignard reagent, and reacting with N-Boc-pyrrolidone to obtain a compound I; 2) adding an acid into thereaction solution, and carrying out a Boc removal reaction on the compound I to obtain a compound II; 3) adding an alkali into the reaction solution, and carrying out a ring closing reaction on the compound II to obtain a compound III; 4) carrying out reduction on the compound III in the reaction solution to obtain a compound IV; and 5) carrying out salification on the compound IV and D-malic acid, and re-crystallizing to obtain a compound V.
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(2020/07/15)

Preparation method of (R)-2-(2,5-difluorophenyl)-pyrrolidine
The invention discloses a preparation method of (R)-2-(2, 5-difluorophenyl)-pyrrolidine, and a preparation method of a compound represented by a formula III, wherein the method comprises the followingstep: in an organic solvent, carrying out a reaction defined in the specification on a compound represented by a formula II and a compound represented by a formula I to obtain a compound representedby the formula III at a high yield and a high ee value. The preparation method is simple in reaction condition, convenient to operate, low in cost and high in industrial value.
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Paragraph 0091; 0098-0100

(2020/06/02)

Pharmaceutical compound, composition and application thereof
The invention provides a novel compound, which shows biological activity and can be used as a TRK kinase inhibitor, such as drugs for treatment of TRK-mediated diseases or symptoms and for treatment and prevention of cancers, dermatitis or asthma and the like.
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Paragraph 0068-0070

(2020/07/15)

Preparation and application of imidazo aromatic ring compounds
The invention provides preparation and application of imidazo aromatic ring compounds, and particularly provides compounds as shown in the following formula I. The definition of each group is as shownin the specification. The compounds have TRK kinase inh
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Paragraph 0114-0115; 0122-0124

(2020/05/02)

Preparation and application of protein receptor kinase inhibitor
The invention provides a preparation method of a protein receptor kinase inhibitor. Specifically, the invention discloses a compound as shown in a formula I or a stereoisomer or racemate or pharmaceutically acceptable salt thereof, and the definition of each group is as shown in the specification. The invention also discloses application of the compound as a TRK kinase inhibitor.
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Paragraph 0121-0122; 0129-0131

(2020/05/02)

Preparation and application of imidazo aromatic ring compounds
The invention provides preparation and application of an aromatic amide compound, and particularly provides a compound as shown in the following formula I. The definition of each group is as shown inthe specification. The compound has TRK kinase inhibition activity and can be used as a pharmaceutical composition for treating diseases related to TRK dysfunction.
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Paragraph 0110; 0117-0119

(2020/07/02)

Direct Synthesis of Chiral NH Lactams via Ru-Catalyzed Asymmetric Reductive Amination/Cyclization Cascade of Keto Acids/Esters
Lactams with a stereogenic center adjacent to the N atom have existed in many medicinal agents and bioactive alkaloids. Herein we report a broadly applicable synthesis of enantioenriched NH lactams through a one-pot asymmetric reductive amination/cyclization sequence of easily available keto acids/esters. Such cascade processes alleviate the demand for protecting group manipulations as well as intermediate purification. This strategy is capable of constructing enantioenriched lactams and benzo-lactams of a five-, six-, or seven-membered ring in generally high yield and with excellent enantioselectivities (up to 97% ee). Scalable and concise syntheses of key drug intermediates have further displayed the importance of this methodology.
Shi, Yongjie,Tan, Xuefeng,Gao, Shuang,Zhang, Yao,Wang, Jingxin,Zhang, Xumu,Yin, Qin
p. 2707 - 2713
(2020/03/30)

Synthesis method of R-2-(2, 5-difluorophenyl) pyrrolidine
The invention relates to a synthesis method of R-2-(2, 5-difluorophenyl) pyrrolidine, and the method comprises the following steps: 1) reacting pyrrolidone serving as a raw material with di-tert-butylcarbonate in a polar or non-polar solvent in the presence of alkali to obtain tert-butyl pyrrolidone formate; 2) in an organic solvent, enabling the tert-butyl pyrrolidone formate to react with a Grignard reagent of 2, 5-difluorobromobenzene to obtain tert-butyl 2-(2, 5-difluorophenyl)-2-hydroxypyrrole-1-formate; 3) carrying out acid catalytic dehydration and deprotection on the tert-butyl 2-(2,5-difluorophenyl)-2-hydroxypyrrole-1-formate in an organic solvent to obtain 5-(2, 5-difluorophenyl)-3, 4-dihydro-2H-pyrrole; and 4) reducing the 5-(2, 5-difluorophenyl)-3, 4-dihydro-2H-pyrrole in anorganic solvent by using chiral acid and ammonia borane to obtain the R-2-(2, 5-difluorophenyl) pyrrolidine with high enantioselectivity. The synthesis method disclosed by the invention is simple, mild in condition, simple to operate and low in production cost, and can be used for industrial production.
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Page/Page column 8-12

(2020/04/29)

Stereocomplementary Synthesis of Pharmaceutically Relevant Chiral 2-Aryl-Substituted Pyrrolidines Using Imine Reductases
Exploring a collection of naturally occurring imine reductases (IREDs) identified two stereocomplementary IREDs with reducing activity toward sterically hindered 2-aryl-substituted pyrrolines. Using (R)-selective ScIR and (S)-selective SvIR, various chiral 2-aryl-substituted pyrrolidines with excellent enantioselectivity (>99% ee) were stereocomplementarily synthesized in good yield (60-80%), demonstrating the feasibility of IREDs for generating pharmaceutically relevant chiral 2-aryl-substituted pyrrolidine intermediates.
Chen, Fei-Fei,Chen, Qi,Li, Bo-Bo,Xu, Jian-He,Zhang, Yu-Hui,Zheng, Gao-Wei,Zhou, Xin-Yi
supporting information
p. 3367 - 3372
(2020/04/21)

AMINO PYRAZOLOPYRIMIDINE COMPOUND USED AS NEUROTROPHIC FACTOR TYROSINE KINASE RECEPTOR INHIBITOR
Provided is an amino pyrazolopyrimidine compound as represented by the following structural formula used as a neurotrophic factor tyrosine kinase receptor inhibitor. The compound can inhibit the activity of Trk kinase and can treat diseases mediated by a Trk tyrosine kinase receptor in mammals.
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(2019/09/15)

Enantioselective Imine Reduction Catalyzed by Phosphenium Ions
The first use of phosphenium cations in asymmetric catalysis is reported. A diazaphosphenium triflate, prepared in two or three steps on a multigram scale from commercially available materials, catalyzes the hydroboration or hydrosilylation of cyclic imin
Lundrigan, Travis,Welsh, Erin N.,Hynes, Toren,Tien, Chieh-Hung,Adams, Matt R.,Roy, Kayelani R.,Robertson, Katherine N.,Speed, Alexander W. H.
p. 14083 - 14088
(2019/10/11)

Synthesis method of Larotrectinib intermediate and Larotrectinib
The invention discloses a synthesis method of Larotrectinib and a Larotrectinib intermediate. N-Boc pyrrolidone and 2,5-difluorophenyl magnesium bromide serve as raw materials, an intermediate A-1 isprepared, the intermediate A-1 is subjected to chiral catalysis hydrogenation, cyclization or first cyclization and afterwards chiral catalysis hydrogenation to obtain a chiral pyrrodlidine intermediate A-4, the intermediate A-4 and an intermediate B-3 are condensed to obtain an intermediate AB-1, the intermediate AB-1 is reduced to obtain an intermediate AB-2, the AB-2 is acylated to obtain an intermediate AB-3, and the AB-3 is subjected to a substitution reaction to obtain the target product Larotrectinib (AB-4). The intermediate A-4 with a high yield and high chiral purity is obtained through a chiral catalysis method, the B-3 with a high yield is obtained through a solvent-free one-pot method, and the Larotrectinib (AB-4) with a high yield and high purity is obtained. According to themethod, the reaction condition can also be applied to large-scale preparation, the method is suitable for industrial production, and therefore, the method has high practical values and social and economic benefits.
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Paragraph 0045; 0093-0094

(2019/02/27)

(S)-4-chlorine-1-(2,5)-difluoro phenyl butane-1-alcohol as well as preparation method and application thereof
The invention discloses (S)-4-chlorine-1-(2,5)-difluoro phenyl butane-1-alcohol as well as a preparation method and application thereof. The (S)-4-chlorine-1-(2,5)-difluoro-phenyl butane-1-alcohol isof a chemical structure of formula I as shown in the description. The (S)-4-chlorine-1-(2,5)-difluoro-phenyl butane-1-alcohol is prepared from a raw material 4-chlorine-1-(2,5)-difluoro-phenyl butanewhich is low in price and easy to obtain by using a biological enzyme method, and furthermore a larotrectinib key intermediate (R)-2-(2,5-difluorophenyl) pyrrolidine from the (S)-4-chlorine-1-(2,5)-difluoro-phenyl butane-1-alcohol in two or three steps. The compound has the advantages of being high in yield, simple to operate, low in production cost, mild in reaction condition and the like, has avery high practical value for industrialization on larotrectinib.
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Paragraph 0086; 0087; 0088; 0089; 0090; 0113-0117

(2018/09/20)

Neurotrophic factor tyrosine kinase receptor inhibitor
The invention provides a neurotrophic factor tyrosine kinase receptor inhibitor. The tyrosine kinase receptor inhibitor provided by the invention has a tricyclic parent core structure, can inhibit theactivity of Trk kinase and can be used for treating mammalian diseases mediated by the Trk kinase.
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(2018/05/30)

Synthesis process of chiral pyrrolidine and intermediates
The invention discloses a synthesis process of chiral pyrrolidine and intermediates. The synthesis process adopts 2, 5-difluorohalobenze or 5-fluoro-3 halogenated pyridine as the raw material substrate, and employs a chiral catalyst to induce chiral react
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(2018/06/26)

Preparation method of (R)-2-(2-substitution-5-fluorobenzene)pyrrolidine
The invention belongs to the technical field of organic synthesis, and provides a preparation method of (R)-2-(2-substitution-5-fluorobenzene)pyrrolidine. The preparation method comprises the following steps of: taking 2-substitution-5-fluorobenzaldehyde
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(2019/01/14)

METHODS OF TREATING PEDIATRIC CANCERS
A method of treating a pediatric cancer in a subject in need thereof. The method includes administering to the subject a therapeutically effective amount of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrro
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Paragraph 0382; 0413

(2017/10/18)

Method for preparing lapatinib intermediate
The invention discloses a method for preparing a lapatinib intermediate (R)-2-(2,5-difluorophenyl)tetrahydropyrrolidine. The method comprises the following steps: by taking taking chiral induced reagent (7aR,10R,12S)-10-(1-benzotriazole)-12-phenyl-7a,8,9,10-tetrahydro-12H-naphthol[1,2-e]pyrrolo[2,1-b][1,3]oxazine and a Grignard reagent 2,5-difluorophenyl magnesium bromide as raw materials, performing a substitution reaction, a reduction reaction and a debenzylation reaction to prepare the lapatinib intermediate (R)-2-(2,5-difluorophenyl)tetrahydropyrrolidine. Compared with the prior art, the method is simple in process, mild in condition, less in side reaction, low in cost and suitable for industrial production and can promote development of the bulk drug economic technology.
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Paragraph 0031; 0032; 0034

(2018/04/01)

Synthesis method and intermediate of (R)-2-(2,5-difluorophenyl)pyrrolidine
The present invention discloses a synthesis method of (R)-2-(2,5-difluorophenyl)pyrrolidine. The synthesis method comprises that the Grignard reagent of halogenated propyl acetal and an imine compound I are subjected to an addition reaction; the obtained
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Paragraph 0073; 0074; 0075

(2017/11/04)

FUSED RING HETEROARYL COMPOUNDS AND THEIR USE AS TRK INHIBITORS
The disclosure provides novel chemical compounds represented by Formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. The compounds can be used as an inhibitor of Trk and are useful in the treatment of pain, cancer, inflammation, neurodegenerative disease and certain infectious diseases. In some compounds of Formula I, Q is —CH═CR3C(O)NR4R5, —C≡CC(O)NR4R5, or
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(2016/07/05)

SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS
Compounds of Formula (I) and salts thereof in which R1, R2, R3, R4, X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor such as pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.
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(2011/02/24)

SUBSTITUTED IMIDAZO[1,2B]PYRIDAZINE COMPOUNDS AS TRK KINASE INHIBITORS
Compounds of Formula (I): in which R1, R2, R3, R4, X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor.
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Page/Page column 34

(2010/04/25)

SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS
Compounds of Formula (I) in which R1, R2, R3, R4, X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor.
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Page/Page column 45

(2010/05/13)

COMPOUNDS AND COMPOSITIONS AS KINASE INHIBITORS
The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly Ros, KDR, FMS, c-FMS, FLT3, c-Kit, JAK2, JAK3, Aurora, PDGFR, Lck, TrkA, TrkB, TrkC, IGF-1R, ALK4, ALK5 and ALK or combinations thereof.
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(2009/12/23)