- A [...] intermediate 2 - methyl - 4 - N - (2 - methyl benzoyl) benzoic acid
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The invention relates to a [...] intermediate 2 - methyl - 4 - N - (2 - methyl benzoyl) benzoic acid for the preparation of the new method, the method to 3 - methylaniline as the starting material, acetate acylation, cyano, cyano hydrolysis, the amidation reaction to obtain the intermediate 2 - methyl - 4 - N - (2 - methyl benzoyl) benzoic acid. The material of the invention is easy to obtain, mild reaction conditions, high yield, does not need special equipment, without the use of highly toxic or an expensive reagent, low cost, convenient to industrial production.
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- Ex situ generation of stoichiometric HCN and its application in the Pd-catalysed cyanation of aryl bromides: Evidence for a transmetallation step between two oxidative addition Pd-complexes
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A protocol for the Pd-catalysed cyanation of aryl bromides using near stoichiometric and gaseous hydrogen cyanide is reported for the first time. A two-chamber reactor was adopted for the safe liberation of ex situ generated HCN in a closed environment, which proved highly efficient in the Ni-catalysed hydrocyanation as the test reaction. Subsequently, this setup was exploited for converting a range of aryl and heteroaryl bromides (28 examples) directly into the corresponding benzonitriles in high yields, without the need for cyanide salts. Cyanation was achieved employing the Pd(0) precatalyst, P(tBu)3-Pd-G3 and a weak base, potassium acetate, in a dioxane-water solvent mixture. The methodology was also suitable for the synthesis of 13C-labelled benzonitriles with ex situ generated 13C-hydrogen cyanide. Stoichiometric studies with the metal complexes were undertaken to delineate the mechanism for this catalytic transformation. Treatment of Pd(P(tBu)3)2 with H13CN in THF provided two Pd-hydride complexes, (P(tBu)3)2Pd(H)(13CN), and [(P(tBu)3)Pd(H)]2Pd(13CN)4, both of which were isolated and characterised by NMR spectroscopy and X-ray crystal structure analysis. When the same reaction was performed in a THF : water mixture in the presence of KOAc, only (P(tBu)3)2Pd(H)(13CN) was formed. Subjection of this cyano hydride metal complex with the oxidative addition complex (P(tBu)3)Pd(Ph)(Br) in a 1 : 1 ratio in THF led to a transmetallation step with the formation of (P(tBu)3)2Pd(H)(Br) and 13C-benzonitrile from a reductive elimination step. These experiments suggest the possibility of a catalytic cycle involving initially the formation of two Pd(ii)-species from the oxidative addition of LnPd(0) into HCN and an aryl bromide followed by a transmetallation step to LnPd(Ar)(CN) and LnPd(H)(Br), which both reductively eliminate, the latter in the presence of KOAc, to generate the benzonitrile and LnPd(0).
- Kristensen, Steffan K.,Eikeland, Espen Z.,Taarning, Esben,Lindhardt, Anders T.,Skrydstrup, Troels
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p. 8094 - 8105
(2017/11/27)
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- Efficient indoles and anilines syntheses employing tert-butyl sulfinamide as ammonia surrogate
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tert-Butyl sulfinamide is an ammonia equivalent for the palladium-catalyzed amination of aryl bromides and aryl chlorides. Using these amine derivatives, it has been observed that indoles and anilines with sensitive functional groups can be readily prepared. This surrogate has also been used for the synthesis of indoles from 2-halophenols using palladium catalyzed cross coupling reaction as the key step.
- Prakash, Anjanappa,Dibakar, Mullick,Selvakumar, Kumaravel,Ruckmani, Kandasamy,Sivakumar, Manickam
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p. 5625 - 5628
(2011/11/06)
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- Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, process for preparing them, medicaments comprising these compounds, and their use
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This invention relates to arylaminoaryl-alkyl-substituted imidazolidone-2,4-diones of formula (I) and also to their physiologically tolerated salts: Wherein R, R′, R1 to R10, A, D, E, G, L and p are as defined herein. The invention also relates to processes for preparing them, pharmaceutical compositions comprising them and their therapeutic use. The compounds are suitable, for example, as anti-obesity drugs and for treating cardiometabolic syndrome.
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Page/Page column 66
(2009/09/07)
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- 2-ARYL- AND 2-HETEROARYLTHIAZOLYL COMPOUNDS, METHODS FOR THEIR PREPARATION AND USE THEREOF
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The present invention discloses fused bicyclic 2-aryl- or 2-heteroarylthiazolyl compounds and their pharmaceutically acceptable salts and esters thereof, which are useful for inhibiting the growth of cancerous cells, inhibiting human breast carcinoma tumo
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Page/Page column 113
(2009/10/22)
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- Carboxylic acid bioisosteres acylsulfonamides, acylsulfamides, and sulfonylureas as novel antagonists of the CXCR2 receptor
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A series of novel acylsulfonamide, acylsulfamide, and sulfonylurea bioisosteres of carboxylic acids were prepared as CXCR2 antagonists. Structure-activity relationships are reported for these series. One potent orally bioavailable inhibitor had excellent PK properties and was active in a lung injury model in hyperoxia-exposed newborn rats.
- Winters, Michael P.,Crysler, Carl,Subasinghe, Nalin,Ryan, Declan,Leong, Lynette,Zhao, Shuyuan,Donatelli, Robert,Yurkow, Edward,Mazzulla, Marie,Boczon, Lisa,Manthey, Carl L.,Molloy, Christopher,Raymond, Holly,Murray, Lynne,McAlonan, Laura,Tomczuk, Bruce
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p. 1926 - 1930
(2008/12/22)
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- BENZAMIDE DERIVATIVES
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A compound represented by formula (1): wherein X is a single bond or a substituted or unsubstituted lower alkylene group; Z is a saturated or unsaturated monocyclic hydrocarbon ring group or the like; and each of R1, R2, R3 and R4, which may be the same or different, is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a carboxyl group, a substituted or unsubstituted alkyl group, or the like, a prodrug of said compound, or a pharmaceutically acceptable salt of said compound or prodrug has inhibitory effect on Rho kinase and hence is useful for treating diseases which are such that morbidity due to them is expected to be improved by inhibition of Rho kinase and secondary effects such as inhibition of the Na+/H+ exchange transport system caused by the Rho kinase inhibition, for example, hypertension.
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- PROPIONAMIDE DERIVATIVES USEFUL AS ANDROGEN RECEPTOR MODULATORS
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Compounds of formula (I) wherein R1 to R4, X and A are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds of formula (I) possess utility as tissue-selective androgen receptor modulators (SARM) and are useful in hormonal therapy, e.g. in the treatment or prevention of male hypogonadism and age-related conditions such as andropause.
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- Exploiting subsite S1 of trypsin-like serine proteases for selectivity: Potent and selective inhibitors of urokinase-type plasminogen activator
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A nonselective inhibitor of trypsin-like serine proteases, 2-(2-hydroxybiphenyl-3-yl)-lH-indole-5-carboxamidine (1) (Verner, E.; Katz, B. A.; Spencer, J.; Allen, D.; Hataye, J.; Hruzewicz, W.; Hui, H. C.; Kolesnikov, A.; Li, Y.; Luong, C.; Martelli, A.; Radika. K.; Rai, R.; She, M.; Shrader, W.; Sprengeler, P. A.; Trapp, S.; Wang, J.; Young, W. B.; Mackman, R. L. J. Med. Chem. 2001, 44, 2753-2771) has been optimized through minor structural changes on the S1 binding group to afford remarkably selective and potent inhibitors of urokinase-type plasminogen activator (uPA). The trypsin-like serine proteases1 that comprise drug targets can be broadly categorized into two subfamilies, those with Ser190 and those with Ala190. A single-atom modification, for example, replacement of hydrogen for chlorine at the 6-position of the 5-amidinoindole P1 group on 1, generated up to 6700-fold selectivity toward the Ser190 enzymes and against the Alal90 enzymes. The larger chlorine atom displaces a water molecule (H2O1s1) that binds near residue 190 in all the complexes of 1, and related inhibitors, in uPA, thrombin, and trypsin. The water molecule, H2O1s1, in both the Ser190 or Ala190 enzymes, hydrogen bonds with the amidine N1 nitrogen of the inhibitor. When it is displaced, a reduction in affinity toward the Ala190 enzymes is observed due to the amidine N1 nitrogen of the bound inhibitor being deprived of a key hydrogen-bonding partner. In the Ser190 enzymes the affinity is maintained since the serine hydroxyl oxygen Oγser190 compensates for the displaced water molecule. Highresolution crystallography provided evidence for the displacement of the water molecule and validated the design rationale. In summation, a novel and powerful method for engineering selectivity toward Ser190 proteases and against Ala190 proteases without substantially increasing molecular weight is described.
- Mackman,Katz,Breitenbucher,Hui,Verner,Luong,Liu,Sprengeler
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p. 3856 - 3871
(2007/10/03)
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