- Preparation method of tyrosine kinase inhibitor AZD3759
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The invention provides a preparation method of a tyrosine kinase inhibitor AZD3759, and relates to the field of medicinal chemistry. The preparation method comprises the following steps: by taking 3,4-dihydro-7-methoxy-4-oxoquinazoline-6-alcohol acetate as a raw material, carrying out a chlorination reaction and a hydrolysis reaction to obtain 4-chloro-7-methoxyquinazoline-6-alcohol (a compound 3); taking (R)-(-)-2-methylpiperazine as a raw material, and obtaining (R)-4-chlorocarbonyl-3-tert-butyl formate (compound 6) through a nucleophilic addition-elimination reaction and a chloroformylation reaction; carrying out an esterification reaction on the compound 3 and the compound 6 to obtain a compound 7; carrying out a Boc removal reaction and a methylation reaction on the compound 7 to obtain a compound 9; and carrying out alkylation reaction on the compound 9 and 2-fluoro-3-chloroaniline to obtain AZD3759. The method has the advantages of cheap and accessible raw materials and lower cost; sodium cyanoborohydride is not used in the reaction process, so that the method is more environment-friendly and is beneficial to industrial large-scale production.
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Paragraph 0047; 0072-0073; 0076; 0082-0083; 0086
(2020/09/23)
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- Preparation method of novel anti-cancer drug AZD3759
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The invention provides a preparation method of a novel anticancer drug AZD3759, and relates to the technical field of medicinal chemistry. The preparation method comprises the following steps: hydrolyzing 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-alcohol acetate to obtain a compound 2, by (R)-(-)-2-methylpiperazine as a raw material, carrying out nucleophilic addition-elimination to obtain a compound 4, carrying out chloroformylation on the compound 4 to obtain a compound 5, carrying out esterification reaction on the compound 2 and the compound 5 to obtain a compound 6, carrying out Boc removal reaction on the compound 6 to obtain a compound 7, carrying out methylation reaction on the compound 7 to obtain a compound 8, carrying out chlorination reaction on the compound 8 to obtain a compound 9, and finally, carrying out an alkylation reaction process on the compound 9 and 2-fluoro-3-chloroaniline so that AZD3759 is obtained. The preparation method provided by the invention has the advantages of cheap and accessible raw materials and lower cost, sodium cyanoborohydride is not used in the reaction process, so that the method is more environment-friendly, the product yield is high, and industrial large-scale production is facilitated.
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Paragraph 0073; 0076; 0083; 0086
(2020/09/30)
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- 1,4-Palladium Shift/C(sp3)-H Activation Strategy for the Remote Construction of Five-Membered Rings
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1,n-Metal shift is an elegant alternative approach enabling the functionalization of remote C-H bonds from simple precursors. In this work, we report a novel and simple Pd0-catalyzed domino reaction involving 1,4-palladium shift and C(sp3)-H activation and leading to (fused) five-membered rings. This method allowed access to a broad range of valuable arylidene γ-lactams and indanones and was applied to the formal synthesis of (-)-pyrrolam.
- Rocaboy, Ronan,Baudoin, Olivier
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supporting information
p. 1434 - 1437
(2019/02/19)
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- Novel method of synthetic process of lung cancer targeted compound AZD-3759
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The invention discloses a novel method of a synthetic process of a lung cancer targeted compound AZD-3759. The novel method comprises the following specific steps: carrying out chlorination on 3,4-dihydro-7-methoxyl-4-oxyquinazoline-6-farnesyl acetate to obtain a compound 2; reacting the compound 2, a compound 3 and an organic solvent to obtain a compound 4, and carrying out hydrolysis reaction toobtain a compound 5; reacting a compound 6, dichloromethane and Boc-anhydride to obtain a compound 7; reacting the compound 7 and pyridine with triphosgene by taking dichloromethane as a solvent to obtain a compound 8; and reacting the compound 5, the compound 8, organic alkali and DMF to obtain a compound 9, desorbing Boc from an acidic system, regulating pH to obtain a compound 10, carrying outmethylation, adjusting pH and separating out, and refining to obtain AZD-3759. The novel method of the synthetic process of the lung cancer targeted compound AZD-3759 has the beneficial effects thatthe raw materials for the novel method are easily obtained, the price is low, the yield is high, the cost is low, the method is environmentally friendly, and industrialized enlarged production can berealized.
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Paragraph 0034; 0039; 0044; 0051; 0064
(2019/04/09)
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- CHEMOKINE RECEPTOR ANTAGONISTS AND METHODS OF USE THEREOF
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Disclosed are novel compounds and a method of treating a disease associated with aberrant leukocyte recruitment and/or activation. The method comprises administering to a subject in need an effective amount of a compound represented by: or physiologically acceptable salt thereof.
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Paragraph 1671; 1672
(2016/02/21)
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- KINETIC RESOLUTION OF CHIRAL AMINES
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The present invention refers to a method for the kinetic resolution of a chiral primary or secondary amine by treating the amine with a chiral, hydroxamic acid derived reagent of the formula (I). These chiral reagents are particularly useful for the kinetic resolution of cyclic amines and may be generated in situ in the presence of an N-heterocyclic carbene, thus allowing for a catalytic reaction.
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Page/Page column 69; 70; 71; 80; 81; 82
(2013/03/26)
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- Expanded substrate scope and catalyst optimization for the catalytic kinetic resolution of N-heterocycles
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The scope, reactivity, and selectivity of the chiral hydroxamic acid-catalyzed kinetic resolution of chiral amines are improved by a new catalyst structure and a more environmentally friendly reaction protocol. In addition to increasing selectivity across all substrates, these conditions make possible the resolution of N-heterocycles containing lactams or other basic functional groups that can inhibit the catalyst.
- Hsieh, Sheng-Ying,Binanzer, Michael,Kreituss, Imants,Bode, Jeffrey W.
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supporting information
p. 8892 - 8894
(2012/11/07)
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- Solid Forms Comprising A Cyclopropyl Amide Derivative
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This disclosure relates to at least one solid form of 4-{(1S, 2S)-2-[((R)-4-cyclobutyl-2-methylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide. This disclosure also relates to at least one pharmaceutical composition comprising at least one solid form described herein, methods of using the solid forms and pharmaceutical compositions comprised thereof, and processes of manufacturing the solid forms.
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Page/Page column 14
(2011/09/14)
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- Cyclopropyl Amide Derivatives
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Disclosed herein is at least one cyclopropyl amide derivative, at least one pharmaceutical composition comprising at least one cyclopropyl amide derivative disclosed herein, and at least one method of using at least one cyclopropyl amide derivative disclosed herein for treating at least one histamine H3 receptor associated condition therewith.
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Page/Page column 45
(2010/09/05)
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- ALPHA-UNSUBSTITUTED ARYLMETHYL PIPERAZINE PYRAZOLO[1,5-A] PYRIMIDINE AMIDE DERIVATIVES
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Methods of preventing, treating or delaying the onset of HIV in a subject by administering to the subject novel pharmaceutically active arylmethyl pyrazolo[1,5-α ]pyrimidine amide derivatives, or pharmaceutical compositions containing the same are described. Additionally, compounds of novel pharmaceutically active arylmethyl piperazine pyrazolo[l,5-α]pyrimidine amide derivatives and their use for the manufacture of specific medicaments are described.
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Page/Page column 123; 142
(2008/12/08)
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- PHOSPHOINOSITIDE 3-KINASE INHIBITOR COMPOUNDS AND METHODS OF USE
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Compounds of Formulas Ia-d where X is S or O, mor is a morpholine group, and R3 is a monocyclic heteroaryl group, and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for modulating the activity of lipid kinases including PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula Ia-d for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed. [Insert Formula Ic and Id]
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Page/Page column 191
(2008/12/06)
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- Novel ORL1-selective antagonists with oral bioavailability and brain penetrability
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Following the discovery of 5-chloro-6-[piperazin-1-yl]-1H-benzimidazole as a novel pharmacophore for potent and selective ORL1 antagonist activity, optimization of this new lead by introduction of a methyl substitution on the piperazine ring resulted in a highly potent and selective, orally available, and brain penetrable ORL1 antagonist, 2-(tert-butylthio)-5-chloro-6-[(2R)-4-(2-hydroxyethyl)-2-methylpiperazin-1-yl]-1H-benzimidazole. Stereochemistry of the methyl substituent on the piperazine ring to control the functional activity of other opioid receptors is also described.
- Okamoto, Osamu,Kobayashi, Kensuke,Kawamoto, Hiroshi,Ito, Satoru,Yoshizumi, Takashi,Yamamoto, Izumi,Hashimoto, Masaya,Shimizu, Atsushi,Takahashi, Hiroyuki,Ishii, Yasuyuki,Ozaki, Satoshi,Ohta, Hisashi
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scheme or table
p. 3282 - 3285
(2009/04/06)
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- CERTAIN CHEMICAL ENTITIES, COMPOSITIONS AND METHODS
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Certain substituted urea derivatives selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.
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Page/Page column 108
(2010/11/27)
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- PYRIMIDINE SULPHONAMIDE DERIVATIVES AS CHEMOKINE RECEPTOR MODULATORS
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A compound of formula (1), or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof and pharmaceutical compositions comprising these, all for use in the treatment of chemokine mediated diseases and disorders.
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Page/Page column 159
(2010/10/20)
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- CYCLOALKANOPYRIDINE DERIVATIVE
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Provided are cycloalkanopyridine derivatives of formula [I]: [wherein the symbols are the same as those stated in the description]. The compounds act as a nociceptin receptor antagonist, and are useful as medicines for diseases associated with a nociceptin receptor, for example, as a reliever against tolerance to a narcotic analgesic; a reliever against dependence on or addiction to a narcotic analgesic; an analgesic enhancer; an antiobesitic or appetite suppressor; a treating or prophylactic agent for cognitive impairment and dementia/amnesia; an agent for treating developmental cognitive abnormality; a remedy for schizophrenia; an agent for treating neurodegenerative diseases; an anti-depressant or treating agent for affective disorder; a treating or prophylactic agent for diabetes insipidus; a treating or prophylactic agent for polyuria; or a remedy for hypotension.
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Page/Page column 80
(2010/11/24)
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- Chemokine receptor antagonists and methods of use thereof
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Disclosed are novel compounds and a method of treating a disease associated with aberrant leukocyte recruitment and/or activation. The method comprises administering to a subject in need an effective amount of a compound represented by: formula (1) or physiologically acceptable salt thereof.
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- PIPERAZINE AND HOMOPIPERAZINE COMPOUNDS
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Compounds are provided having a piperazine or homopiperazine ring which are useful in the treatment of thrombosis.
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