The present disclosure provides regioselective methods for synthesizing intermediates useful in making prostacyclin derivatives, such as treprostinil.

The invention relates to improved method of synthesis for Treprostinil comprising condensation reaction of the carbonyl compound having allyl, alkyl, crotyl or MEM-protected phenolic hydroxyl group, compound (4) with a hydroxyl-protected alkynol (5) to give the condensation product, compound (6). Subjecting compound (6) to oxidation, reduction, hydroxyl protection and carbonylation, cyclization reactions gave the tricyclic derivative (10). Further reactions comprising reduction, hydrogenation and deprotection of the phenolic and side-chain hydroxyl groups, wherein the sequence and choice of reagents was governed by protecting groups, gave the triol intermediate, compound (14). Cyanoalkylation at phenolic hydroxyl functionality and further hydrolysis yielded the prostacyclin compound, Treprostinil (1) and its pharmaceutically acceptable salts, having desired purity.

The invention relates to improved method of synthesis for Treprostinil comprising condensation reaction of the carbonyl compound having allyl, alkyl, crotyl or MEM-protected phenolic hydroxyl group, compound (4) with a hydroxyl-protected alkynol (5) to give the condensation product, compound (6). Subjecting compound (6) to oxidation, reduction, hydroxyl protection and carbonylation, cyclization reactions gave the tricyclic derivative (10). Further reactions comprising reduction, hydrogenation and deprotection of the phenolic and side-chain hydroxyl groups, wherein the sequence and choice of reagents was governed by protecting groups, gave the triol intermediate, compound (14). Cyanoalkylation at phenolic hydroxyl functionality and further hydrolysis yielded the prostacyclin compound, Treprostinil (1) and its pharmaceutically acceptable salts, having desired purity.

Provided are cycloalkyl- and cycloalkenyl-substituted benzaldehydes and heteroaldehydes of formula (I) that act as allosteric modulators of hemoglobin, methods and intermediates for their preparation, pharmaceutical compositions containing the modulators, and methods for their use in treating disorders mediated by hemoglobin and disorders that would benefit from increased tissue oxygenation. ##STR00001##

Provided are cycloalkyl- and cycloalkenyl-substituted benzaldehydes and heteroaldehydes of formula (I) that act as allosteric modulators of hemoglobin, methods and intermediates for their preparation, pharmaceutical compositions containing the modulators, and methods for their use in treating disorders mediated by hemoglobin and disorders that would benefit from increased tissue oxygenation. ##STR00001##

The present invention relates to compounds of formula I, ##STR00001##
processes for their production and their use as anti-inflammatory agents.

The present invention relates to compounds of formula I, ##STR00001##
processes for their production and their use as anti-inflammatory agents.

Disclosed herein are processes for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde (also referred to herein as Compound (I)) and intermediates used in such processes. Compound (I) binds to hemoglobin and increases it oxygen affinity and hence can be useful for the treatment of diseases such as sickle cell disease.

Disclosed herein are processes for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde (also referred to herein as Compound (I)) and intermediates used in such processes. Compound (I) binds to hemoglobin and increases it oxygen affinity and hence can be useful for the treatment of diseases such as sickle cell disease.

The invention relates to an improved method for the preparation of alkylsalicylaldehyde or its corresponding metallic salts. The invention also relates to a method for the preparation of alkylsalicylaldoxime by reacting said alkylsalicylaldehyde or its corresponding metallic salts with hydroxylamine or its salt. The invention also relates to a method for extracting a metal in an aqueous solution containing dissolved metal.