- PROCESS FOR THE PREPARATION OF 6-(HALOALKYL)-2-HALO-5-ACYLPYRIDINES AND INTERMEDIATES FOR THIS PROCESS
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The present invention relates to a process for preparing compounds of formula (I) (I), wherein R represents C1-C2-alkyl or C1-C2-haloalkyl, R1 represents C1-C6-alkyl, C2-C6-alkenyl, C2-C6- alkynyl, C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C4-alkyl, phenyl, phenyl-C1-C4-alkyl, phenyl-C2-C4- alkenyl or phenyl-C2-C4-alkynyl, and X represents chlorine or bromine, by reacting a compound of formula (II) (II), wherein RA represents -CN or –COOH and R is defined as in formula (I), in a first step A) with a dehydroxyhalogenation agent selected from COCl2, diphosgene, triphosgene, cyanuric chloride, SOCl2, SO2Cl2, PCl3, PCl5, POCl3, PBr3, SOBr2 and SO2Br2, to arrive at a compound of formula (III) (III), wherein RB represents -CN or –COX, and X and R are defined as in formula (I), and the compound of formula (III) is reacted in step B) with a compound of formula (IV) R1M1(lV), - 41 - wherein M1 represents Li or MgY, wherein Y represents chlorine or bromine, and R1 is defined as in formula (I), and optionally further reacting the compound of formula (I) to a triazole derivative of formula (VIII) (VIII). It further relates to a process for preparing the compound of formula (II) and to particular compounds of formula (II) and (III).
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Page/Page column 27-28
(2020/02/23)
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- Cu-Mediated Expeditious Annulation of Alkyl 3-Aminoacrylates with Aryldiazonium Salts: Access to Alkyl N2-Aryl 1,2,3-Triazole-carboxylates for Druglike Molecular Synthesis
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Alkyl N-aryl 1,2,3-triazole-carboxylates are important molecules or intermediates in medicinal chemistry, but the synthesis of N2-aryl counterparts remains elusive. Herein, we describe a Cu-mediated annulation reaction of alkyl 3-aminoacrylates with aryldiazonium salts, both of which are readily available substrates. Furthermore, alkyl 2-aminoacrylates are also viable substrates. Diverse alkyl N2-aryl 1,2,3-triazole-carboxylates and their analogues can be rapidly prepared under mild conditions. Especially, this protocol allows one to access several druglike variants of carbonic anhydrase inhibitors and celecoxib.
- Liu, Hao-Nan,Cao, Hao-Qiang,Cheung, Chi Wai,Ma, Jun-An
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supporting information
p. 1396 - 1401
(2020/02/22)
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- PREPARATION OF 6-HALO-2-(HALOALKYL)-3-ACYLPYRIDINES AND INTERMEDIATES THEREFOR
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The present invention relates to a process for preparing compounds of formula (I) wherein R represents C1-C2-alkyl and X represents chlorine or bromine, by reacting a compound of formula (II) wherein R is defined as in formula (I), in a first step A) with a dehydroxyhalogenation agent selected from COCl2, diphosgene, triphosgene, cyanuric chloride, SOCI2, SO2CI2, PCI3, PCI5, POCI3, PBr3, SOBr2 and SO2Br2 to arrive at a compound of formula (III) wherein X and R are defined as in formula (I), and the compound of formula (III) is reacted in step B) with a malonate of formula (IV) wherein R1 represents C1-C6-alkyl, C2-C6, -alkenyl. C2-C6-alkynyl, C3-C8-cycloalkyl or benzyl; in presence of a base and a magnesium compound to arrive at a compound of formula (V) wherein X and R are defined as in formula (I); and R1 is defined as in formula (IV); and decarboxylating the compound of formula (V). Optionally the resulting compound of formula (I) is further reacted to a triazole derivative of formula (VIII). It further relates to the compounds of formula (V).
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Page/Page column 30; 31
(2020/07/07)
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- Identification of 5-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)thiophene-2-Carboxamides as Novel and Selective Monoamine Oxidase B Inhibitors Used to Improve Memory and Cognition
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Initial work in Drosophila and mice demonstrated that the transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) is a master control gene for memory formation. The relationship between CREB and memory has also been found to be true in other species, including aplysia and rats. It is thus well-established that CREB activation plays a central role in memory enhancement and that CREB is activated during memory formation. On the basis of these findings, a phenotypic high-throughput screening campaign utilizing a CRE-luciferase (CRE-Luci) SK-N-MC cell line was performed to identify compounds that enhance transcriptional activation of the CRE promoter with a suboptimal dose of forskolin. A number of small-molecule hits of unknown mechanisms of action were identified in the screening campaign, including HT-0411. Follow-up studies suggested that the CREB activation by HT-0411 is attributed to its specific and selective inhibition of monoamine oxidase B (MAO-B). Further, HT-0411 was shown to improve 24 h memory in rodents in a contextual fear conditioning model. This report describes the lead optimization of a series of 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl) thiophene-2-carboxamides that were identified as novel, potent, and selective inhibitors of MAO-B. Extensive SAR studies and in vivo behavioral evaluations of this and other related analogue series identified a number of potential clinical development candidates; ultimately, compound 8f was identified as a candidate molecule with high selectivity toward MAO-B (29-56 nM) over MAO-A (19% inhibition at a screening concentration of 50 μM), an excellent profile against a panel of other enzymes and receptors, good pharmacokinetic properties in rodents and dogs, and efficacy in multiple rodent memory models.
- Kaplan, Alan P.,Keenan, Terence,Scott, Roderick,Zhou, Xianbo,Bourchouladze, Rusiko,McRiner, Andrew J.,Wilson, Mark E.,Romashko, Darlene,Miller, Regina,Bletsch, Matthew,Anderson, Gary,Stanley, Jennifer,Zhang, Adia,Lee, Dong,Nikpur, John
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p. 2746 - 2758
(2017/12/26)
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- Method for preparing 3-amino-4,4,4-trifluorocrotonate
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The invention discloses a method for preparing 3-amino-4,4,4-trifluorocrotonate with high raw material utilization rate. According to the invention, 4,4,4-trifluoroacetyl ethyl acetate and excessive ammonium acetate are subjected to an amination reaction to obtain a reaction solution, then the reaction solution is separated to an organic phase and an aqueous phase, ammoniacal liquor is added in the aqueous phase to obtain ammonium acetate, and finally ammonium acetate is cycled to continuous reaction.
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Paragraph 0012; 0022
(2017/01/31)
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- Synthesis, Herbicidal Activity, and QSAR of Novel N-Benzothiazolyl- pyrimidine-2,4-diones as Protoporphyrinogen Oxidase Inhibitors
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Protoporphyrinogen oxidase (PPO, E.C. 1.3.3.4) is known as a key action target for several structurally diverse herbicides. As a continuation of our research work on the development of new PPO-inhibiting herbicides, a series of novel 3-(2′-halo-5′-substituted-benzothiazol-1′-yl)-1-methyl-6-(trifluoromethyl)pyrimidine-2,4-diones 9 were designed and synthesized. The bioassay results indicated that a number of the newly synthesized compounds exhibited higher inhibition activity against tobacco PPO (mtPPO) than the controls, saflufenacil and sulfentrazone. Compound 9F-5 was identified as the most potent inhibitor with a Ki value of 0.0072 ΜM against mtPPO, showing about 4.2-fold and 1.4-fold higher potency than sulfentrazone (Ki = 0.03 ΜM) and saflufenacil (Ki = 0.01 ΜM), respectively. An additional green house assay demonstrated that compound 9F-6 (Ki = 0.012 ΜM) displayed the most promising postemergence herbicidal activity with a broad spectrum even at a concentration as low as 37.5 g of active ingredient (ai)/ha. Maize exhibits relative tolerance against compound 9F-6 at the dosage of 150 g ai/ha, but it is susceptible to saflufenacil even at 75 g ai/ha. Thus, compound 9F-6 exhibits the potential to be a new herbicide for weed control in maize fields.
- Zuo, Yang,Wu, Qiongyou,Su, Sun-Wen,Niu, Cong-Wei,Xi, Zhen,Yang, Guang-Fu
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p. 552 - 562
(2016/02/05)
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- Pyrimidine diketone compounds containing benzoxazine ring and application thereof
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The invention discloses a kind of pyrimidine diketone compounds containing a benzoxazine ring and application thereof. The pyrimidine diketone compounds containing the benzoxazine ring are compounds with the structure shown as a general formula (1) in the specification, and in the formula (1), R1 is selected from hydrogen or an alkyl with the carbon atom number of 1-6, R2 is an ester with the carbon atom number of 2-10, and X is selected from halogen. The pyrimidine diketone compounds containing the benzoxazine ring possess high weeding activity.
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Paragraph 0098; 0101; 0102
(2016/10/07)
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- Pyrimidinedione compound and application thereof
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The present invention discloses a pyrimidinedione compound and an application thereof. The pyrimidinedione compound is a compound of the structure shown in the formula (1), wherein in the formula (1), R is selected from an alkyl group with 1 to 6 carbon atoms, an alkenyl group with 2 to 6 carbon atoms, an alkynyl group with 2 to 6 carbon atoms or an ester group with 2 to 10 carbon atoms; X is selected from halogen; and Y is selected from O or S. The pyrimidindione compound disclosed by the present invention has high herbicidal activity .
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Paragraph 0114; 0117; 0118
(2016/10/08)
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- Facile synthesis of pyrido[2,3-d]pyrimidines via cyclocondensation of 4,6-dichloro-2-methylsulfanylpyrimidine-5-carbaldehyde with β-substituted β-aminoacrylic esters
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Abstract A new facile synthesis of pyrido[2,3-d]pyrimidin-4-ones via cyclocondensation of 4,6-dichloro-2-methylsulfanylpyrimidine-5-carbaldehyde with β-alkyl and β-aryl-β-aminoacrylic esters followed by hydrolysis of chlorine atom at position 4 of pyridopyrimidine ring has been developed. The cyclocondensation was found to be accelerated by acid.
- Chizhova, Maria E.,Bakulina, Olga Yu.,Ivanov, Alexander Yu.,Lobanov, Pavel S.,Dar'in, Dmitrii V.
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supporting information
p. 6196 - 6203
(2015/08/03)
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- The Hemetsberger-Knittel synthesis of substituted 5-, 6-, and 7-azaindoles
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A series of substituted 5-, 6-, and 7-azaindoles were prepared via the Hemetsberger-Knittel reaction. In general, better yields were obtained at higher temperatures and shorter reaction times than required for the formation of the analogous indoles, and in some cases, only decomposition occurred below a minimum temperature. The resulting templates offer up to five sites for subsequent functionalization to allow a wide range of chemical diversity. Georg Thieme Verlag Stuttgart.
- Roy, Patrick J.,Dufresne, Claude,Lachance, Nicolas,Leclerc, Jean-Philippe,Boisvert, Michel,Wang, Zhaoyin,Leblanc, Yves
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p. 2751 - 2757
(2007/10/03)
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- METHOD FOR PRODUCING 3-AMINO-4,4,4-TRIFLUOROCROTONIC ACID ESTERS
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The invention relates to a method for producing 3-amino-4,4,4-trifluorocrotonic acid esters of formula (I) or their E/Z isomers or tautomeric forms, whereby R1 and R2, independent of one another, represent hydrogen, an optionally substituted linear C1-C4 alkyl radical or an optionally substituted benzyl radical, and R3 represents methyl or ethyl. The inventive method is characterized in that: a) an alkyl trifluoroacetate is reacted with an alkyl acetate of formula CH3-CO-OR3 and with an alkali metal alcoholate to form an enolate of a trifluoroacetoacetic acid ester of formula (II), whereby M represents sodium or potassium, and R3 has the aforementioned meaning, and afterwards; b) the alkali enolate of the trifluoroacetoacetic acid ester from step a) can, without further purification, directly react with an amine of formula NHR1R2 in the presence of an acid to form 3-amino-4,4,4-trifluorocrotonic acid esters. This two-step method enables the production of 3-amino-4,4,4- trifluorocrotonic acid esters in high yields without resulting in the formation of significant byproducts.
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- Production of aminohalogencrotonates
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Lower alkyl esters of 3-amino crotonates substituted by halogen in the C-4 position, e.g. ethyl 3-amino-4,4,4-trifluoro-crotonate, in which the amino group optionally may be substituted by one or two C1 to C3 alkyl groups or by one or two aryl groups, e.g. phenyl, are synthesized by thermolysis of ammonium salts of corresponding lower alkyl esters of acetoacetic acid substituted in the C-4 position by halogen, and removal of the resulting water of reaction. The water of reaction may be removed by an entraining agent, which preferably has a specific gravity heavier than that of the aqueous phase which forms in the reaction. This minimizes yield losses due to the ammonium salt becoming dissolved in the aqueous phase and results in especially high yields. Formation of the ammonium salt and thermolysis can be carried out simultaneously. Alternatively, it is possible to start from a molten ammonium salt of the halogencrotonate, e.g. the salt of the lower alkyl ester of 4,4,4-trifluoroacetoacetic acid, or to produce the salt in situ, and to pass an inert gas through the molten salt under thermolytic conditions and in the absence of a solvent. In this way the desired product can be produced in high yield and in high purity. This alternative can be implemented as a continuous process.
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- Method for preparing 3-amino substituted crotonates
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The present invention relates to methods for preparing 3-amino-4,4,4-trihalocrotonates and their derivatives from a 4,4,4-trihaloacetoacetate derivative and an amine or ammonium salt.
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- Method for preparing 3-amino substituted crotonates
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The present invention relates to methods for preparing 3-amino-4,4,4-trihalocrotonates and their derivatives from a 4,4,4-trihaloacetoacetate derivative and an amine or ammonium salt.
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- A convenient synthesis of perfluoroalkylated enamines and vinyl phosphonates
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The reaction of fluoroalkynes with ammonia and benzylamine gave perfluoroalkylated enamines predominantly as the Z isomer, which were hydrogenated with palladium on carbon to afford perfluoroalkylated β-amino acids in good yield.The reaction of fluoroalky
- Cen, Wenbiao,Ni, Yuhua,Shen, Yanchang
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p. 161 - 164
(2007/10/02)
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- Novel Perfluoroalkyl-Substituted Pyrazoles. 1. Hydroxypyrazoles
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Addition of methylhydrazine to a variety of haloalkyl-substituted α,β-unsaturated esters gives 1,5-disubstituted 3-hydroxypyrazoles, in contrast to the more common synthesis from β-ketoesters, which gives 1,3-disubstituted 5-hydroxypyrazoles.This reaction is used to prepare several novel pyrazoles bearing haloalkyl substituents.Criteria for assignment of structures have been developed based on physical and spectroscopic properties of the isomers.The regiochemical preference in this addition is considered on the basis of steric, electronic, and mechanistic factors.
- Gaede, Bruce J.,McDermott, Lisa L.
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- Long-acting dihydropyridine calcium antagonists. 9. Structure activity relationships around amlodipine
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The preparation of a range of 1,4-dihydropyridine analogues of amlodipine has been undertaken and their calcium antagonist activities on rat aorta have been evaluated.Increasing the size of the C5 ester group dramatically reduces calcium antagonist activity, a trend which would be compatible with the carbonyl group of that ester binding to the DHP receptor.Amlodipine analogues with extended C3 ester substituents also have lower potency than amlodipine, possibly because of disruption of a favourable interaction between the protonated amino group on the 2-substituentand the DHP receptor.Replacement of the 6-methyl substituent in amlodipine by alkoxyalkyl groups or electron-withdrawing groups is also detrimental to calcium antagonist activity. amlodipine / 1,4-dihydropyridine / structure activity relationship
- Alker, D,Arrowsmith, JE,Campbell, SF,Cross, PE
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p. 907 - 913
(2007/10/02)
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