Carboxamides reduced

Ge Z-D, Peart JN, Kreckler LM, Wan TC, Jacobson MA, Gross GJ, Auchampach JA (2006) (Cl-IB-MECA (2-chloro-((lV5-(3-iodobenzyl)adenosine)-5 - /V-methyl carboxamide) reduces ischemia/reperfusion injury in mice by activating the Aj adenosine receptor. J Pharmacol Exp Ther 319 1200-1210... 

The effect of replacing the carboxamide iV-piperidinyl group of (470) was also investigated. Reducing the ring of the piperidinyl group by one carbon... 

Secondary amines, such as pyrrolidine, must be alkylated with care too polar a solvent leads to participation of a second nearby polymer-bound alkylant in the formation of a quaternary ammonium salt, along with the desired immobilized trialkyl amine. The exception, as seen above, is diisopropylamine, which refuses to displace tosylate even in the refluxing pure amine, or in hot dimethyl-formamide or other polar solvent, while metal diisopropylamide is notorious as a powerful non-nucleophilic base. However, carboxamide is not difficult to form from (carboxymethyl)polystyrene, again using toluenesulfonyl chloride as condensing agent this can then be reduced to (diisopropyl-ethylaminoethyl)polystyrene, which is of interest as a polymer-bound non-nucleophilic base. ... 

Fig. 14.1 Cellular pathway of methotrexate. ABCBl, ABCCl-4, ABC transporters ADA, adenosine deaminase ADP, adenosine diphosphate AICAR, aminoimidazole carboxamide ribonucleotide AMP, adenosine monophosphate ATIC, AICAR transformylase ATP, adenosine triphosphate SjlO-CH -THF, 5,10-methylene tetrahydrofolate 5-CHj-THF, 5-methyl tetrahydro-folate DHFR, dihydrofolate reductase dTMP, deoxythymidine monophosphate dUMP, deoxy-uridine monophosphate FAICAR, 10-formyl AICAR FH, dihydrofolate FPGS, folylpolyglutamyl synthase GGH, y-glutamyl hydrolase IMP, inosine monophosphate MTHFR, methylene tetrahydrofolate reductase MTR, methyl tetrahydrofolate reductase MTX-PG, methotrexate polyglutamate RFCl, reduced folate carrier 1 TYMS, thymidylate synthase. Italicized genes have been targets of pharmacogenetic analyses in studies published so far. (Reproduced from ref. 73 by permission of John Wiley and Sons Inc.)...

Dervieux, T., Eurst, D., Lein, D. O., et al. (2004) Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis and Rheumatism. 50, 2766-2774. 

Table 2 Ratio of Isomers 1 and 2 in the Oxidative Folding Reaction of Reduced Endothelin-1, KR-ET-1 and Carboxamide Analogues of KR-ET-1 in the Presence or Absence of Redox Reagents 58 ...

The reduced basicity of phenothiazine nitrogen requires that even acylation proceed via the anion. The amide (34-2) from the methyl thioether (34-1) can be prepared, for example, by sequential reaction with sodium amide and acetic anhydride. Oxidation of that intermediate with peracid proceeds preferentially on the more electron-rich alkyl thioether to give the sulfone this affords the phenothiazine (34-3) on hydrolysis of the amide. Complex side chains are most conveniently incorporated in a stepwise fashion. The first step in the present sequence involves reaction of (34-3) as its anion with l-bromo-3-chloropropane to give (34-4). The use of that halide with alkylate piperidine-4-carboxamide (34-5) affords the antipsychotic agent metopimazine (34-6) [35]. 

Chemical reduction of pyrroles by hydriodic acid and phosphorus leads to the formation of pyrrolidines (B-77MI30507) except when the 2-position is substituted by electron-withdrawing groups, which reduce the ease of protonation at the 3-position and, consequently, promote the formation of 2-substituted A3-pyrrolines (cf. Scheme 54) (B-74MI30500, 79MI30504). The analogous reduction of indole-2-carboxamide yields indoline-2-carboxamide (72HC(25-l)l). 

A soln of the crude acid in THF (14 mL) was cooled to — 20 °C and treated with TEA (686 pL, 4.92 mmol) and ethyl chloroformate (470 pL, 4.92 mmol) and stirred for 30 min. A mixture of coned NHtOH (2mL) and THF (lOmL) was added and the mixture was stirred at -20°C for 30min and left standing at 5 °C for 18 h. The mixture was then poured into ice-cold 3 M HC1 and extracted with EtOAc. The combined organic extracts were dried (MgS04) and concentrated under reduced pressure. Partial purification of the residue by flash chromatography (silica gel, 3 x 20 cm, CHCl3/MeOH/AcOH 96 4 0.1) gave carboxamide (553 mg) as a mixture of diastereomers contaminated with ethyl carbamate. 

The carboxamide was dissolved in a mixture of 80% TFA/CH2C12 (12 mL) and stirred at rt for 1 h. The reaction was then concentrated under reduced pressure, re-concentrated from toluene, and then dried in vacuo. This acid was dissolved in DMF (5mL) and the pH of the resulting soln adjusted to -7 with TEA. This soln was then treated with H-Val-OMe (520 mg, 3.96 mmol), HOBt (250 mg, 1.85 mmol), and DCC (279 mg, 1.35 mmol). After stirring for 44 h, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 3 x 20 cm, CHCI /MeOH 98 2) to give 39 as an inseparable mixture of diastereomers yield 486mg (84%). 

When 2//-chromene-3-carboxamide (208) is treated with LAH, the amide and the pyran double bond are reduced (68BRP1043857). The ester group of the chromene (209) is similarly reduced by diborane during hydroboration (73SC231). 

The reduced form of the respiratory coenzyme diphosphopyridine nucleotide (DPNH), which is vitally important for all cellular metabolism, is changed by dilute acid to a substance that, in the light of the following model experiments, may be a covalent hydrate. The 1,4-and 1,6-dihydro derivatives of l-benzylpyridine-3-carboxamide furnish a single substance when dissolved in dilute acid at 20° and the solution is basified. The stable yellow product, which has a prominent peak at 292 nm, was assigned the constitution 1-benzyl-6-hydroxy-1,4,5,6-tetra-hydropyridine-3-carboxamide61 (see Scheme 2). 3-Acetyl-1 -benzyl- 1,4-... 

Full details42 have been published on the conversion of enynes into iminocyclopentenes using a titanium precatalyst in the presence of BuLi and TESCN (equation 9) the resulting iminocyclopentenes can be hydrolysed to cyclopentenones or reduced to allylic silyl-amines. In a related protocol43, the tandem insertion of TMSCN and alkenes, alkynes, ketones or isocyanates into zirconacyclo-pentanes or -pentenes leads to cyclopentylamines carrying an a-alkyl, -alkenyl, -1-hydroxyalkyl or -carboxamide substituent, respectively (equation 9). 

Carboxamides can be cathodically reduced to amines or alcohols, depending on the reaction conditions the reaction is carried out industrially. One example is the reduction of pyridine carboxamides at Reilly 543) ... 

To a stirred solution of [4-(2-pyrimidinyl)piperazino]ethylamine (2.0 g, 0.01 mol) in 50 ml of methylene chloride, adamantane-l-carboxylic acid chloride (3.6 g, 0.018 mol) and triethylamine (2.9 g, 0.015 mol) were added. Stirring was continued at room temperature overnight. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The remaining residue was subjected to preparative HPLC. The residue was dissolved in ethyl acetate (10 ml) and subjected to flash chromatography using a 9 inch column of silica gel and ethyl acetate as the eluent. The N-[2-[4-(2-pyrimidinyl)-l-piperazinyl]ethyl]tricyclo[3.3.1.1(3,7)] decane-l-carboxamide was separated. 

A solution of 195 mg of 2-[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenyl butyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide in 20 ml of ethanol was hydrogenated at room temperature and atmospheric pressure for 18 h over 10 mg of 10% palladium-on-charcoal. The catalyst was filtered off and the filtrate was evaporated under reduced pressure to give 154 mg of 2-[3(S)-[(L-asparaginyl)amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide. 

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