cas 330156-50-8, (R)-1-(2,6-Dichloro-3-fluorophenyl)ethanol

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Biotransformation-mediated synthesis of (1S)-1-(2,6-dichloro-3- fluorophenyl)ethanol in enantiomerically pure form
An efficient four-step biotransformation-mediated synthesis of (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol in enantiomerically pure form is described. This compound is a key intermediate required for the preparation of PF-2341066, a potent inhibitor of c-
Martinez, Carlos A.,Keller, Eric,Meijer, Renzo,Metselaar, Gerard,Kruithof, Gerlof,Moore, Curtis,Kung, Pei-Pei
p. 2408 - 2412
(2010)
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Preparation method of deuterated crizotinib and derivatives thereof
The invention relates to a preparation method of deuterated crizotinib and derivatives thereof, and belongs to the technical field of synthesis of medical compounds. Four deuterated crizotinib with different configurations are synthesized, the influence of the deuterated position and different chirality of the deuterated crizotinib on the biological activity and the drug metabolism property of thecrizotinib is investigated, and the result shows that the deuterated crizotinib and the crizotinib have similar anti-cancer activity. Compared with a deuterated crizotinib raceme and crizotinib, thedeuterated crizotinib has certain physicochemical property advantages, has good anticancer application prospects, and provides a new compound for synthesis of novel antitumor drugs. The resolution ofthe racemate phenylethanol derivative is a key step for synthesizing the deuterated crizotinib, the ee value of the racemate phenylethanol derivative directly influences the ee value of a final product, and the resolution method has the characteristics of easiness in operation, low cost and the like.
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Paragraph 0068-0070; 0079

(2020/12/31)

Manganese-Catalyzed Enantioselective Hydrogenation of Simple Ketones Using an Imidazole-Based Chiral PNN Tridentate Ligand
A series of Mn(I) catalysts containing imidazole-based chiral PNN tridentate ligands with controllable 'side arm' groups have been established, enabling the inexpensive base-promoted asymmetric hydrogenation of simple ketones with outstanding activities (up to 8200 TON) and good enantioselectivities (up to 88.5percent ee). This protocol features wide substrate scope and functional group tolerance, thereby providing easy access to a key intermediate of crizotinib.
Chen, Jiachen,Hou, Huacui,Ling, Fei,Nian, Sanfei,Wu, Feifei,Xu, Min,Yi, Xiao,Zhong, Weihui
supporting information
p. 285 - 289
(2020/02/18)

Novel synthesis method of crizotinib intermediate (by machine translation)
The invention relates to a synthesis method of an organic compound, in particular to a novel synthesis method of a crizotinib intermediate, which comprises the following steps: taking cheap and easily available 2,6 - dichloro -3 - fluoroacetophenone as a starting raw material and reducing the CBS system to obtain S-shaped chiral alcohol. , 2 - Aminopyridine is taken as a raw material and bromine is brominated to obtain 3,5 - dibromo -2 - aminopyridine. The compound is condensed into an ether with a chiral alcohol under the action of an acid-binding agent to obtain the intermediate of the required configuration. The method is simple in reaction, short in route, less in three wastes, environment-friendly, high in yield of all steps, and less in raw material and reagent waste. (by machine translation)
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Paragraph 0023

(2021/01/04)

Chiral ferrocene phosphine-nitrogen-nitrogen tridentate ligand as well as preparation method and application thereof
The invention discloses a chiral ferrocene phosphine-nitrogen-nitrogen tridentate ligand as well as a preparation method and an application thereof. The general structural formula of the chiral ferrocene phosphine-nitrogen-nitrogen tridentate ligand is shown in formula (I) or formula (II), wherein R1 and R2 are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, aryl or heterocyclic aryl respectively; R3 is aryl, heterocyclic aryl or C1-C6 alkyl, and R4 is hydrogen, C1-C6 alkyl, aryl or heterocyclic aryl; the general structural formula in the formula (I) and the formula (II) contains animidazole group or a substituted benzimidazole group respectively; one or more substituent groups exist on a benzene ring of the substituted benzimidazole group, and each substituent group is independently selected from H or C1-C4 alkyl. The chiral ferrocene phosphine-nitrogen-nitrogen tridentate ligand has the advantages that the tridentate ligand is convenient to synthesize, exists in the air stably and can be coordinated with cheap metal to prepare a cheap metal catalyst, and the cheap metal catalyst is well applied to asymmetric hydrogenation reactions of ketone.
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Paragraph 0079-0082; 0084

(2019/10/01)

Towards practical earth abundant reduction catalysis: Design of improved catalysts for manganese catalysed hydrogenation
Manganese catalysts derived from tridentate P,N,N ligands can be activated easily using weak bases for both ketone and ester hydrogenations. Kinetic studies indicate the ketone hydrogenations are 0th order in acetophenone, positive order in hydrogen and 1st order in the catalyst. This implies that the rate determining step of the reaction was the activation of hydrogen. New ligand systems with varying donor strength were studied and it was possible to make the hydrogen activation significantly more efficient; a catalyst displaying around a 3-fold increase in initial turn-over frequencies for the hydrogenation of acetophenone relative to the parent system was discovered as a result of these kinetic investigations. Ester hydrogenations and ketone transfer hydrogenation (isopropanol as reductant) are first order for both the substrate and catalysts. Kinetic studies also gained insight into catalyst stability and identified a working range in which the catalyst is stable throughout the catalytic reaction (and a larger working range where high yields can still be achieved). The new more active catalyst, combining an electron-rich phosphine with an electron-rich pyridine is capable of hydrogenating acetophenone using as little as 0.01 mol% catalyst at 65 °C. In all, protocols for reduction of 21 ketones and 15 esters are described.
Widegren, Magnus B.,Clarke, Matthew L.
p. 6047 - 6058
(2019/11/14)

Synthesis process of crizotinib intermediate
The invention discloses a synthesis process of a crizotinib intermediate. The synthesis process comprises the following steps: with 2,6-dichloro-3-fluoroacetophenone as the raw material in an alkali and solvent environment and hydrogen as a reducing agent
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Paragraph 0031-0036

(2018/05/01)

A Highly Active Manganese Catalyst for Enantioselective Ketone and Ester Hydrogenation
A new hydrogenation catalyst based on a manganese complex of a chiral P,N,N ligand has been found to be especially active for the hydrogenation of esters down to 0.1 mol % catalyst loading, and gives up to 97 % ee in the hydrogenation of pro-chiral deactivated ketones at 30–50 °C.
Widegren, Magnus B.,Harkness, Gavin J.,Slawin, Alexandra M. Z.,Cordes, David B.,Clarke, Matthew L.
supporting information
p. 5825 - 5828
(2017/05/12)

Synthesis method of crizotinib and preparation method of crizotinib intermediate compound
The invention provides a synthesis method of crizotinib and a preparation method of a crizotinib intermediate compound. The synthesis method of the crizotinib comprises the following steps: reacting N-protected 4-(3-(5-fluoro-6-nitropyridine-3-yl)-1H-pyrazole-1-yl)piperidine (9) used as a raw material and a chiral intermediate compound (3) to obtain a key chiral intermediate compound; and performing reduction on the chiral intermediate compound, and performing deprotection to obtain the target compound crizotinib (1). According to the invention, the advantages of accessible raw materials, mild reaction conditions and simple operation process are achieved; and a catalyst has favorable stability and activity, and is easy to recover and use indiscriminately, thereby facilitating the large-scale preparation and production of the crizotinib.
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Paragraph 0018;

(2018/03/13)

CRIZOTINIB FOR USE IN THE TREATMENT OF CANCER
The present invention relates to the use of ROS kinase inhibitors for treating abnormal cell growth in mammals. In particular, the invention provides methods of treating mammals suffering from cancer mediated by at least one genetically altered ROS. In particular, the invention provides methods of treating mammals suffering from cancer mediated by at least one genetically altered ROS by administration of crizotinib.
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(2016/08/17)

Preferential crystallization preparation method of chiral alpha-phenylethyl alcohol
The invention discloses a method for preparing chiral alpha-phenylethyl alcohol. The method is a preferential crystallization method implemented by taking petroleum ether as a solved, is simple and convenient to operate, is high in product yield and purit
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Paragraph 0062; 0063; 0064; 0065; 0066; 0067; 0068-0069

(2016/10/10)

Synthesis process for compound crizotinib
The invention provides a new synthesis method for crizotinib. An atomic economic reaction is adopted to reduce environmental pollution. A high-optical purity raw material is obtained by chiral prolinol induced chiral reduction; a chiral centre is constructed through an SN2 substitution reaction; post-processing and purification difficulties caused by Mitsunobu reaction are overcome. Malononitrile derivative is constructed by adopting a coupling reaction of malononitrile and bromo-pyridinium derivative; N,N-dicarboamide derivatives are obtained by performing aminolysis on N,N-dimethylamine hydrochloride; in the N,N-dicarboamide derivatives, N,N-dimethylamine serving as an easy-to-leave group and hydrazine perform a ring closing reaction to construct a pyrazolone ring, so that an expected final product, namely crizotinib, is obtained. According to the method, though continuous steps are used, the reaction of each step is high, the optical purity is high, and the total yield is also high. In addition, raw materials used in the synthesis method are low in cost and easily obtained; the using amount of a catalyst is small; total cost is easy to control. An operating process is simple and convenient and easy to control, and is suitable for industrial production.
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Paragraph 0039; 0040; 0041; 0042; 0043

(2016/10/20)

PROCESS FOR PRODUCING OPTICALLY ACTIVE SECONDARY ALCOHOL
[Object] The object of this invention is to provide a method for producing an optically active secondary alcohol at a high optical purity by hydrogenating a substrate carbonyl compound at a high efficiency using as a catalyst a ruthenium complex bearing as a ligand certain optically active diphosphine compound and a readily synthesized amine compound. [Solution] The method of producing an optically active secondary alcohol according to the present invention is characterized in that a substrate carbonyl compound (provided that 3-quinuclidinone, 3-quinuclidinone derivative having a substituent, and a ketone having an aromatic hydrocarbon group and a heterocycle are excluded) is reacted with hydrogen and/or a hydrogen donating compound in the presence of a ruthenium complex selected from the compounds expressed by following general formula (1) RuXYAB (1) [in the general formula (1), X and Y are the same or different from each other and denote a hydrogen atom or an anionic group, A denotes an optically active diphosphine expressed by the general formula (2), B denotes an amine compound expressed by following general formula (3)].
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Paragraph 0169

(2015/02/19)

PRODUCTION METHOD OF OPTICALLY ACTIVE SECONDARY ALCOHOL
PROBLEM TO BE SOLVED: To provide a chemical catalytic method allowing efficient production of a corresponding optically active secondary alcohol from an aromatic ketone having a substituent at each of two β-positions in an aromatic ring to the carbonyl site, so that both enantiomers can be separately made. SOLUTION: A production method of optically active secondary alcohol is characterized by reacting a ketone compound such as acetophenone derivatives with hydrogen in the presence of a ruthenium complex catalyst having an optically active diphosphine ligand. COPYRIGHT: (C)2015,JPO&INPIT
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Paragraph 0133

(2016/11/14)

Inhibitors of nedd8-activating enzyme
The invention relates to an administration unit comprising crystalline form I of {(1 S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl sulfamate (I-216) hydrochloride salt and to a packaging comprising the administration unit according to the invention.
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(2014/08/20)

CRIZOTINIB FOR USE IN THE TREATMENT OF CANCER
The present invention relates to the use of ROS kinase inhibitors for treating abnormal cell growth in mammals. In particular, the invention provides methods of treating mammals suffering from cancer mediated by at least one genetically altered ROS. In particular, the invention provides methods of treating mammals suffering from cancer mediated by at least one genetically altered ROS by administration of crizotinib.
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(2013/03/26)

SUBSTITUTED PYRIDAZINE CARBOXAMIDE COMPOUNDS
The new pyridazine derivatives have unexpected drug properties as inhibitors of protein kinases especially against ALK and are useful in treating disorders related to abnormal protein kinase activities such as cancer, neurological and psychiatric diseases
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Page/Page column 37

(2012/04/23)

SUBSTITUTED PYRIDAZINE CARBOXAMIDE COMPOUNDS AS KINASE INHIBITOR COMPOUNDS
The new pyridazine derivatives have unexpected drug properties as inhibitors of protein kinases especially against c-Met and are useful in treating disorders related to abnormal protein kinase activities such as cancer.
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Page/Page column 30

(2012/04/23)

Polymorphs of a C-Met/Hgfr Inhibitor
This invention relates to polymorphs of (R)-3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine that are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to compositions including such salts and polymorphs, and to methods of using such compositions in the treatment of abnormal cell growth in mammals, especially humans.
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Page/Page column 4

(2009/01/20)

PYRAZOLE-SUBSTITUTED AMINOHETEROARYL COMPOUNDS AS PROTEIN KINASE INHIBITORS
Compounds of formula (1) are provided, as well as methods for their synthesis and use. Preferred compounds are potent inhibitors of the c-Met protein kinase, and are useful in the treatment of abnormal cell growth disorders, such as cancers.
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Page/Page column 58

(2010/10/20)

ENANTIOMERICALLY PURE AMINOHETEROARYL COMPOUNDS AS PROTEIN KINASE INHIBITORS
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Page/Page column 19-20

(2010/10/20)

AMINOHETEROARYL COMPOUNDS AS PROTEIN TYROSINE KINASE INHIBITORS
Aminoheteroaryl compounds are provided, as well as methods for their synthesis and use. Preferred compounds are potent inhibitors of the c-Met protein kinase, and are useful in the treatment of abnormal cell growth disorders, such as cancers.
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Page/Page column 49-50

(2010/10/20)

Highly enantioselective reduction of achiral ketones with NaBH4/Me3SiCl catalyzed by (S)-α,α-diphenylpyrrolidinemethanol
The reducing agent prepared from sodium borohydride, trimethylsilyl chloride and a catalytic amount of (S)-α,α-diphenylpyrrolidinemethanol has been successfully applied to the enantioselective reduction of ketones. The optically active secondary alcohols were obtained in excellent enantiomeric excess and almost quantitative chemical yield. (C) 2000 Elsevier Science Ltd.
Jiang, Biao,Feng, Yan,Zheng, Jian
p. 10281 - 10283
(2007/10/03)