New synthesis of pyrrole-2-carboxylic and ..
T1 - Synthesis and endothelin receptors binding affinity of new 1,3,5- Substituted Pyrrole-2-Carboxylic Acid Derivatives
pyrrole-2-carboxylic acid | Sigma-Aldrich
N2 - The interest of researchers for ligands of the endothelin receptors ETA and ETB is due to their extensive therapeutic potential. In particular, receptor antagonists are useful in a number of diseases such as pulmonary hypertension, acute myocardial infarction, congestive heart failure, renal failure, and atherosclerosis. In the context of our research program aimed to the development of new endothelin receptor ligands, in this paper we describe the synthesis and structure- activity relationships of a new series of 1,3,5-substituted pyrrole-2-carboxylic acid derivatives 27-40 possessing the structural features for ET receptors binding. New synthesized compounds were tested on ETA and ETB receptors stably expressed in CHO cells and some of them showed interesting affinity and selectivity towards ETA receptors.
The first one-step, continuous flow synthesis of pyrrole-3-carboxylic acids directly from -butyl acetoacetates, amines, and 2-bromoketones is reported. The HBr generated as a byproduct in the Hantzsch reaction was utilized in the flow method to hydrolyze the -butyl esters in situ to provide the corresponding acids in a single microreactor. The protocol was used in the multistep synthesis of pyrrole-3-carboxamides, including two CB1 inverse agonists, directly from commercially available starting materials in a single continuous process.
Search results for pyrrole-2-carboxylic acid at Sigma-Aldrich
While investigating the chemistry of the newly available porphyrin system the group discovered another new phlorin – and a remarkable reaction. It was found that when the porphyrin was heated under nitrogen in acetic acid for just one hour then two hydrogen atoms from the meso-propionic acid sidechain migrated to give the phlorin acrylate ester shown (bottom left). Although this wasn’t planned, and certainly hadn’t featured in the group’s retrosynthesis (if such a term was in use at the outset of this project), it did open up possibilities for the synthetic route. Further investigation found that if the reaction was conducted under air or oxygen then oxidation of the phlorin took place to give the porphyrin acrylate ester in excellent yield. This compound, when isolated and heated for much longer, with acid but under nitrogen, underwent an unusual cyclisation. Finally, the acetamide was hydrolysed under acidic conditions and the rather unstable resulting amine was subjected to Hofmann elimination by treatment with dimethyl sulfate and aqueous sodium hydroxide.
With all four pyrrole subunits in hand, the time had come to investigate conditions for their union. First the lefthand (AD) component was synthesised by simple condensation of the A and D pyrroles under acidic conditions to give the pyrromethene dibromide shown. It was found that swift isolation of the product from the reaction mixture was crucial to obtain a high yield as, although stable when pure, such salts were generally unstable in solution (and difficult to extract). For this reason, the reaction was carefully performed at -25 °C in methanol containing a small amount of water (100:1), conditions under which the desired compound simple crystallised out and could be obtained by filtration.
• Acid chloride formation from carboxylic acid-PCl 5
Comparison of this oxidation product with chlorin e6 trimethyl ester reveals that only three transformations were now required to react the target: excision of the methoxalyl group, resolution and homologation of the aldehyde to the longer chain ester. The first of these operations, a retro-Claisen condensation, was performed in fairly low yield by treatment with methanolic KOH (followed by regeneration of the other esters with diazomethane), to give the trans disposed D-ring ring isomer. These conditions also caused cyclisation of the C-ring ester onto the nearby aldehyde to give the methoxylactone. This slightly unexpected transformation was explained by the fact that cyclisation at this position had the effect of reducing the afore mentioned peripheral overcrowding at this part of the ring. In any case, the this compound was treated with aqueous sodium hydroxide in dioxane to hydrolyse the one remaining methyl ester (and incidentally convert the methoxylactone to the hydroxylactone), in order to provide a handle for resolution. Unfortunately, although resolution (via the quinine salt) could be successfully carried out (under entirely non-obvious conditions), it proved exceptionally difficult and the yield of optically pure material obtained was only 4% from the acid. Finally, treatment of this compound with yet more diazomethane gave the corresponding purpurin dimethyl ester in a surprisingly poor yield for this step. Crucially for the group, the disappointment of the resolution could now be put behind them because this compound could easily be derived from natural material (methyl pheophorbide a). Thus, a relay point had been reached and they were able to replenish their supply of material before pushing on for the finish. Comparison of various synthetic compounds at this points showed identity with naturally derived material, confirming the success of the route so far.
The first three steps to the D-ring were shared with those of the A-ring, comprising selective hydrolysis of the β-ester, decarboxylation of the acid obtained, and formylation of the free position. This aldehyde was then condensed with malonic acid in the presence of aniline to give the unsaturated diacid as the Knoevenagel-type product. Hydrogenation with Raney Nickel under a hydrogen atmosphere in aqueous sodium hydroxide solution reduced the double bond, and effected monodecarboxylation to give the β-propionic acid. The α-methyl group was oxidised to the carboxylic acid, employing slightly different conditions to those used in the synthesis of the C-ring. Treatment of this compound with sodium hydroxide solution then simultaneously caused decarboxylation of this acid, as well as hydrolysis and decarboxylation of the ethyl ester. The propionic acid sidechain was then esterified using diazomethane and a semi-regioselective Vilsmeier-Haack formylation then gave a mixture of regioisomeric aldehydes. These could be separated by hydrolysis of their methyl esters to give two regioisomeric acids with very different solubilities in water. Re-esterification with yet more diazomethane gave the D-ring pyrrole in 8 steps and around 16% overall yield.
• Acid chloride formation from carboxylic acid-SOCl 2 ..
Pyrrole-2-carboxylic Acid 634-97-9 | TCI EUROPE N.V.
T1 - Synthesis and optical resolution of 1-[(3-carboxy-1,1′-biphenyl)-2- yl]-1H-pyrrole-2-carboxylic acid
A Novel Synthesis of Pyrrole-2-carboxylic Acid …
Keywords: Aerguginosin; Octahydroindole 2-carboxylic acid; Rigid conformation; Thrombin inhibitor 1.
1H-pyrrole-2-carboxylic acid Step I: Synthesis of Ethyl ..
Compared with the reported acidic or basic conditions for polysubstituted pyrrole synthesis, ..
Get supplier listing of Pyrrole-2-carboxylic acid and equal product
The synthesis of the B-ring began with the same two steps as for the previous ring to selectively remove the β-ester, and the free position was then filled by an acetyl group, introduced by a Friedel-Crafts reaction with acetyl chloride in the presence of aluminium trichloride. This was then reduced all the way to the ethyl group using a Wolff-Kischner reduction, and the harsh conditions required for this transformation also caused hydrolysis and decarboxylation of the α-ester. Formylation of the α-position under Vilsmeier-Haack conditions gave an aldehyde that was again protected by condensation with malononitrile in essentially quantitative yield. Finally, chlorination of the α-methyl group using sulfuryl chloride in acetic acid gave the B-ring pyrrole in an excellent overall yield of 39% over 7 steps.
Chemical Synthesis and Properties of Carboxylic acids
The synthesis of the C-ring pyrrole began with the oxidation of the α-methyl group to the corresponding acid that was then removed decarboxylatively by heating neat with copper bronze. The α-ester was then selectively hydrolysed without affecting the β-ester, and removed in the same fashion to give the C-ring pyrrole in just four steps.
Carboxylic acids - Synthesis and Properties ..
The route to the A-ring pyrrole began with selective hydrolysis and decarboxylation of the β-ester group. The now free position opened up was then formylated under Vilsmeier-Haack conditions (on up to 2.5 kg at a time!), this sequence providing a neat and surprisingly high yielding solution to adjusting the oxidation level of the group at this position without affecting the α-ester. This aldehyde was then protected by condensation with malononitrile to allow oxidation of the α-methyl group to the corresponding methyl ester. A global hydrolysis of the methyl and ethyl esters, as well as the dicyanovinyl protecting group, with concentrated sodium hydroxide solution, gave the formyldiacid. The unmasked aldehyde was then condensed with nitromethane in a Henry reaction to give the nitroalkene, and this was then reduced to the nitroalkane using sodium borohydride in methanol. Both carboxylic acids were then removed by decarboxylation in sodium acetate – potassium acetate melt and final catalytic reduction of the nitroalkane to the primary amine using hydrogen and a platinum catalyst gave the required A-ring pyrrole. It was anticipated that Hofmann elimination later in the sequence could be used to convert this aminoethyl chain to the vinyl group present in the target. Although the preparation of this compound took 10 steps, the longest of any of the four pyrroles, the yields were generally good, and skilful optimisation allowed the required reactions to be performed on large scale to provide sufficient material.
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