- A 2 - (3, 5 - double - trifluoromethyl - phenyl) -2 - methyl - propionic acid preparation method
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The invention provides a 2 - (3, 5 - double - trifluoromethyl - phenyl) - 2 - methyl - propionic acid preparation method. In particular, the use of 3, 5 - trifluoro - methyl-bromobenzene as raw materials, through Grignard - sediment reaction, Suzuki coupling reaction, to obtain 2 - (3, 5 - double - trifluoromethyl - phenyl) - 2 - methyl - propionic acid. The method of short synthetic route, raw materials are easy and the cost is low, mild reaction conditions, easy purification of products, and have high yield, is suitable for industrial mass production.
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Paragraph 0092-0096
(2019/07/08)
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- Synthesis method of netupitant intermediate (2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propionic acid)
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The invention discloses a synthesis method of a netupitant intermediate (2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propionic acid). The method includes the following steps of adding a compound III and trimethylcyanosilane to an organic solvent, cooling the organic solvent to 0 DEG C, dropwise adding an acid catalyst, heating reaction liquid to the room temperature after dropwise adding is completed, conducting quenching, extracting, organic phase drying, filtering, filtrate concentrating, recrystallizing, filtering and drying on reaction liquid after reaction ends to obtain a compound II, adding water to the compound II, dropwise adding concentrated sulfuric acid for reflux reaction, and conducting quenching, extracting, organic phase drying, filtering, concentrating, filtering and drying on the reaction liquid after reaction ends. The method has the advantages that the adopted synthesis method is simple in step, a highly-toxic product (methyl iodide) or a metal palladium catalyst is avoided, the reaction route is short, the raw materials are low in price and easy to obtain, the reaction conditions are mild, the production process is simple in operation, the product yield is high, and thus the method is suitable for large-scale production.
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Paragraph 0036; 0040-0041; 0045-0046; 0050-0051; 0055
(2019/10/10)
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- Preparation method of synthetic 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propioric acid
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The invention discloses a preparation method of synthetic 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propioric acid. S1: 3,5-bis(trifluoromethyl)bromobenzene is dissolved in an organic solvent, the solution is added dropwisely into isopropylmagnesium chloride, and a Grignard reagent is obtained; mafosfamide is dissolved in an organic solvent, the solution is added dropwisely into the Grignard reagent, in order to obtain 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propyl-1-ketone; S2: 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propyl-1-ketone obtained in the step S1 is dissolved in an organicsolvent, and 2-(3,5-bis(trifluoromethyl)phenyl)-2-bromo-methyl propyl-1-ketone is obtained; S3: 2-(3,5-bis(trifluoromethyl)phenyl)-2-bromo-2-methyl propyl-1-ketone obtained in the step S2 is dissolved in an organic solvent, zinc bromide is added, in order to obtain 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl methacrylate; S4: 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl methacrylate obtained in the step S3 is dissolved in an organic solvent, the solution is added into an aqueous solution of alkali, and 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propioric acid is obtained.
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Paragraph 0039; 0041; 0051; 0053; 0055; 0065; 0069; 0079
(2018/04/03)
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- Synthesis method of netupitant intermediates
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The invention discloses a synthesis method of netupitant intermediates. The method includes the steps of dissolving cyano-acetate and 3,5-bis(trifluoromethylphenyl halide) in solvent, conducting decarboxylation and cyanomethylation reaction under the effect of a palladium catalyst and organophosphorus ligand to obtain 2-(3,5-bistrifluoromethylphenyl)acetonitrile, converting a cyano group into a carboxy group through alkali to obtain 2-(3,5-bistrifluoromethylphenyl)acetic acid, and making 2-(3,5-bistrifluoromethylphenyl)acetic acid react with a methylating agent to obtain a target product. The method is easy to operate, free of side reaction and high in yield, and raw materials are low in price, easy to obtain and easy to synthesize.
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Paragraph 0044; 0045
(2016/12/01)
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- Method for synthetizing Netupitant midbody impurity 2-(3,5-Bis-trifluoromethyl-phenyl) propionic acid
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The invention discloses a method for synthetizing a Netupitant midbody impurity 2-(3,5-bis-trifluoromethyl-phenyl) propionic acid, comprising the following steps: dissolving 2-cyano propionate and 3,5-bis-trifluoromethyl halogeno benzene into a first solvent, and performing a decarboxylation cyanomethylation reaction under the effects of a palladium catalyst and phosphorus ligands to obtain 2-(3,5-bis-trifluoromethyl-phenyl) propionitrile; adding the 2-(3,5-bis-trifluoromethyl-phenyl) propionitrile and alkali into a second solvent to generate 2-(3,5-bis-trifluoromethyl-phenyl) propionate, and then acidizing to obtain the 2-(3,5-bis-trifluoromethyl-phenyl) propionic acid. According to the method for synthetizing the Netupitant midbody impurity 2-(3,5-bis-trifluoromethyl-phenyl) propionic acid, the raw materials are cheap and easy to get, the operation is simple, the synthesis is easy, a side reaction cannot occur, and higher yield is achieved.
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Paragraph 0036; 0033; 0034; 0037
(2016/11/28)
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- A intermediate [...] 2 - (3,5-bis-trifluoromethyl-phenyl) - 2-methyl-propionic acid synthetic method (by machine translation)
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The invention discloses a intermediate [...] 2 - (3,5-bis-trifluoromethyl-phenyl) - 2-methyl-propionic acid synthetic method, comprising the following steps: in order to compound 3.5-bis (trifluoromethyl) bromobenzene as raw materials, the presence of the alkali reagent 1st the 1st diethyl malonate in a solvent in the reaction, a generating compound, then the compound in the solvent 2nd, through the 2nd alkali reagent to carry out saponification, decarboxylation reaction, and the second generating compound, the final compound II in the presence of the alkali reagent 3rd the 3rd with methylation reagent in the reaction in the solvent to obtain 2 - (3,5-bis-trifluoromethyl-phenyl) - 2-methyl-propionic acid. The invention uses the one-pot synthesis preparation [...] intermediate, not only the easily obtained raw material used, the cost is low, and the reaction flow is short, the operation is simple, the production cost is low, is convenient for industrial production and application. (by machine translation)
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Paragraph 0027
(2016/10/20)
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- Method for synthesizing drug intermediate
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The invention discloses a method for synthesizing a drug intermediate. Cyano-acetate and 3,5-bis(trifluoromethyl) halogenobenzene are dissolved in a solvent and have a decarboxylation cyanomethylation reaction under the action of a palladium catalyst and an organic phosphorus ligand to obtain 2-(3,5-bis(trifluoromethyl phenyl) acetonitrile, then 2-(3,5-bis(trifluoromethyl phenyl) acetonitrile reacts with a methylation reagent to obtain 2-(3,5-bis(trifluoromethyl phenyl)-2-methyl propanenitrile, and finally cyano groups are converted into carboxyl groups with alkali to obtain the target product. The method for synthesizing the drug intermediate is easy to operate, raw materials are cheap and easy to obtain, synthesis is easy, side reactions do not happen, and the yield is high.
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- Synthetic method for netupitant intermediate 2-(3,5-bistrifluoromethylphenyl)-2-methyl propionate
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The invention discloses a synthetic method for a netupitant intermediate 2-(3,5-bistrifluoromethylphenyl)-2-methyl propionate. According to the synthetic method, 2-cyano-2-methyl propionate and 3,5-bistrifluoromethyl halogeno benzene are dissolved in a solvent for a decarboxylation cyanomethylation reaction under the action of a palladium catalyst and an organophosphorus ligand to obtain 2-(3,5-bistrifluoromethylphenyl)-2-methyl propionitrile, and then the cyano group is converted into the carboxy group through alkali to obtain a target product. Through the synthetic method for the intermediate, operation is easy, raw materials are cheap and easy to get, synthesis is easy, a side reaction will not happen, and a high yield is achieved.
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Paragraph 0039; 0040; 0041; 0046; 0047; 0054; 0055
(2016/10/17)
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- Pyrrolidine-carboxamides and oxadiazoles as potent hNK1 antagonists
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The preparation and structure-activity-relationships of novel pyrrolidine-carboxamides and oxadiazoles are described. Compounds in this series were found to be potent hNK1 antagonists in vitro and efficacious in vivo with minimal interactions with P450 liver enzymes. Oxadiazole analog 22 was determined to have excellent hNK1 binding affinity, functional activity, and a good PD response in vivo.
- Young, Jonathan R.,Eid, Ronsar,Turner, Cherilyn,DeVita, Robert J.,Kurtz, Marc M.,Tsao, Kwei-Lan C.,Chicchi, Gary G.,Wheeldon, Alan,Carlson, Emma,Mills, Sander G.
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p. 5310 - 5315
(2008/03/11)
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- Efficient synthesis of novel NK1 receptor antagonists: Selective 1,4-addition of Grignard reagents to 6-chloronicotinic acid derivatives
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A new efficient synthesis of two novel classes of NK1 receptor antagonists, among them befetupitant and netupitant, starting from 6-chloronicotinic acid is described. The introduction of the o-tolyl substituent at C(4) of the pyridine ring was achieved by a one-pot selective 1,4-Grignard addition/oxidation sequence to 6-chloronicotinic acid or a derivative of it. The scope of this addition/oxidation sequence was examined. It was also shown that the carboxylic function can be converted to a methyl amino group by a Hofmann rearrangement followed by reduction. Furthermore, a new high-yielding synthesis of 2-(3,5-bistrifluoromethylphenyl)-2-methyl propionic acid based on the carbonylation of the tertiary alcohol obtained by Grignard addition of 3,5-bis(trifluoromethyl)bromobenzene to acetone was established.
- Hoffmann-Emery, Fabienne,Hilpert, Hans,Scalone, Michelangelo,Waldmeier, Pius
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p. 2000 - 2008
(2007/10/03)
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- PIPERIDINE COMPOUND AND PROCESS FOR PREPARING THE SAME
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The present invention is to provide a piperidine compound represented by the formula [I]: wherein Ring A is an optionally substituted benzene ring, Ring B is an optionally substituted benzene ring, R1 is hydrogen atom or a substituent for amino group, R2 is hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted alkyl group, a substituted carbonyl group or a halogen atom, Z is oxygen atom or -N(R3)-, R3 is hydrogen atom or an optionally substituted alkyl group, R4a and R4b may be the same or different, and each is hydrogen atom or an optionally substituted alkyl group, or a pharmaceutically acceptable salt thereof, which has an excellent tachykinin receptor antagonistic action.
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Page/Page column 55; 129
(2010/10/20)
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- Cyclohexyl derivatives and their use as therapeutic agents
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The present invention relates compounds of the formula (I): wherein ring A is a phenyl or pyridyl ring; X represents a linker selected from the group consisting of: (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l) and R1, R2, R3, R4, R5, R6, R7, R13, R14, R15, R16, R?17, R18, R19, R21a and R21b are as defined herein. The compounds are of particular use in the treatment or prevention of depression, anxiety, pain, inflammation, migraine, emesis or postherpetic neuralgia.
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- Cyclohexane derivatives and their use as therapeutic agents
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The present invention relates compounds of formula (I), wherein ring A is a phenyl or pyridyl ring; X represents a linker selected from the group consisting of formulae: (a), (b), (c), (d), and (e); and R1, R2, R3, R4, R5, R6, R7, R13, R14, R15, R16, R17, R21a and R21b are as defined herein. The compounds are of particular use in the treatment or prevention of depression, anxiety, pain, inflammation, migraine, emesis or postherpetic neuralgia.
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- Process for preparation of 2-phenyl acetic acid derivatives
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The present invention is a process for the preparation of a compound of formula The compounds of formula I are valuable intermediates for the manufacture of therapeutically active compounds.
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- 4,4-Disubstituted cyclohexylamine NK(1) receptor antagonists I.
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A series of novel 4,4-disubstituted cyclohexylamine based NK(1) antagonists is described. The effect of changes to the C(1)-C(4) relative stereochemistry on the cyclohexane ring and replacements for the flexible linker are discussed, leading to the identification of compounds with high affinity and good in vivo duration of action.
- Elliott, Jason M,Castro, Jose L,Chicchi, Gary G,Cooper, Laura C,Dinnell, Kevin,Hollingworth, Gregory J,Ridgill, Mark P,Rycroft, Wayne,Kurtz, Marc M,Shaw, Duncan E,Swain, Christopher J,Tsao, Kwei-Lan,Yang, Lihu
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p. 1755 - 1758
(2007/10/03)
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