The present invention relates to Form IV of fenofibrate and its preparation methods thereof. Its X-ray powder diffraction pattern expressed as 2θ angle has characteristic peaks at 14.15±0.2°, 15.94±0.2°, 16.49±0.2°, 17.45±0.2°, 20.21±0.2°, and 22.87±0.2°. The present invention also provides preparation methods of Form IV. The preparation methods are simple, easy to operate, short, and have good repeatability. The methods are also non-toxic and non-polluting by using water as a medium and using a pharmaceutically accepted excipient, such as polyvinylpyrrolidone or polyvinyl alcohol as an inducer. The results of stability experiments (light exposure, high humidity and grinding) and solubility tests show that Form IV is stable and has a higher solubility than the prior art crystal form.

The present invention relates to Form IV of fenofibrate and its preparation methods thereof. Its X-ray powder diffraction pattern expressed as 2θ angle has characteristic peaks at 14.15±0.2°, 15.94±0.2°, 16.49±0.2°, 17.45±0.2°, 20.21±0.2°, and 22.87±0.2°. The present invention also provides preparation methods of Form IV. The preparation methods are simple, easy to operate, short, and have good repeatability. The methods are also non-toxic and non-polluting by using water as a medium and using a pharmaceutically accepted excipient, such as polyvinylpyrrolidone or polyvinyl alcohol as an inducer. The results of stability experiments (light exposure, high humidity and grinding) and solubility tests show that Form IV is stable and has a higher solubility than the prior art crystal form.

The radiation-sensitive resin composition contains: a polymer having a structural unit that includes an acid-labile group; and a compound represented by formula (1). In the formula (1), Ar.sup.1 represents a group obtained by removing (m+n+2) hydrogen atoms from an aromatic ring of an arene having 6 to 30 carbon atoms; —OH and —COO— are bonded at ortho positions to each other on a same benzene ring on Ar.sup.1; and R.sup.G represents a group represented by formula (V-1), a group represented by formula (V-2), a group including a lactone structure, a group including a cyclic carbonate structure, a group including a sultone structure, a group including a ketonic carbonyl group, a group including a thiocarbonate group, or a group including a group represented by formula (V-3), or the like. ##STR00001##

The radiation-sensitive resin composition contains: a polymer having a structural unit that includes an acid-labile group; and a compound represented by formula (1). In the formula (1), Ar.sup.1 represents a group obtained by removing (m+n+2) hydrogen atoms from an aromatic ring of an arene having 6 to 30 carbon atoms; —OH and —COO— are bonded at ortho positions to each other on a same benzene ring on Ar.sup.1; and R.sup.G represents a group represented by formula (V-1), a group represented by formula (V-2), a group including a lactone structure, a group including a cyclic carbonate structure, a group including a sultone structure, a group including a ketonic carbonyl group, a group including a thiocarbonate group, or a group including a group represented by formula (V-3), or the like. ##STR00001##

A method for producing a purified peptide from a supported crude peptide having a support and a first peptide chain bonded to the support at the C-terminus. The method includes: introducing a linker and a hydrophilic unit to an amino group of the first peptide chain of the supported crude peptide; cleaving a bond between the first peptide chain and the support before or after at least one of the linker and the hydrophilic unit is introduced to the amino group of the first peptide chain such that a support-free hydrophilized peptide is obtained; treating the support-free hydrophilized peptide by liquid chromatography; and cleaving a bond between the linker and the first peptide chain in the support-free hydrophilized peptide by chemical treatment after the liquid chromatography treatment such that a peptide including the first peptide chain is obtained.

A method for producing a purified peptide from a supported crude peptide having a support and a first peptide chain bonded to the support at the C-terminus. The method includes: introducing a linker and a hydrophilic unit to an amino group of the first peptide chain of the supported crude peptide; cleaving a bond between the first peptide chain and the support before or after at least one of the linker and the hydrophilic unit is introduced to the amino group of the first peptide chain such that a support-free hydrophilized peptide is obtained; treating the support-free hydrophilized peptide by liquid chromatography; and cleaving a bond between the linker and the first peptide chain in the support-free hydrophilized peptide by chemical treatment after the liquid chromatography treatment such that a peptide including the first peptide chain is obtained.

Methods for making prodrugs of trepreostinil and treprostinil derivatives are provided. Specifically, methods are provided herein for producing prostacyclin compounds comprising treprostinil covalently linked to a linear C.sub.5-C.sub.18 alkyl, branched C.sub.5-C.sub.18 alkyl, linear C.sub.2-C.sub.18 alkenyl, branched C.sub.3-C.sub.18 alkenyl, aryl, aryl-C.sub.1-C.sub.18 alkyl or an amino acid or a peptide (e.g., dipeptide, tripeptide, tetrapeptide). The linkage, in one embodiment, is via an amide or ester bond. Prostacyclin compounds provided herein can also include at least one hydrogen atom substituted with at least one deuterium atom. The compounds provided herein can be used to treat pulmonary hypertension (e.g., pulmonary arterial hypertension) and portopulmonary hypertension.

Methods for making prodrugs of trepreostinil and treprostinil derivatives are provided. Specifically, methods are provided herein for producing prostacyclin compounds comprising treprostinil covalently linked to a linear C.sub.5-C.sub.18 alkyl, branched C.sub.5-C.sub.18 alkyl, linear C.sub.2-C.sub.18 alkenyl, branched C.sub.3-C.sub.18 alkenyl, aryl, aryl-C.sub.1-C.sub.18 alkyl or an amino acid or a peptide (e.g., dipeptide, tripeptide, tetrapeptide). The linkage, in one embodiment, is via an amide or ester bond. Prostacyclin compounds provided herein can also include at least one hydrogen atom substituted with at least one deuterium atom. The compounds provided herein can be used to treat pulmonary hypertension (e.g., pulmonary arterial hypertension) and portopulmonary hypertension.

Provided are methods of carbonylating cyclic substrates to produce carbonylated cyclic products. The cyclic substrates may be 2, 2-di substituted epoxides and the cyclic products may be β,β-di substituted lactones. The method may be carried out by forming and pressurizing a reaction mixture of the cyclic substrate, a solvent, carbon monoxide, and a [LA.sup.+][CO(CO)4.sup.−] catalyst, where [LA.sup.+] is a Lewis acid capable of coordinating to the cyclic substrate. The method may proceed with a regio selectivity of 90:10 or greater. The resulting carbonylated cyclic products may be converted to ketone aldol products that retain the stereochemistry and enantiomeric ratio of the carbonylated cyclic products.

Provided are methods of carbonylating cyclic substrates to produce carbonylated cyclic products. The cyclic substrates may be 2, 2-di substituted epoxides and the cyclic products may be β,β-di substituted lactones. The method may be carried out by forming and pressurizing a reaction mixture of the cyclic substrate, a solvent, carbon monoxide, and a [LA.sup.+][CO(CO)4.sup.−] catalyst, where [LA.sup.+] is a Lewis acid capable of coordinating to the cyclic substrate. The method may proceed with a regio selectivity of 90:10 or greater. The resulting carbonylated cyclic products may be converted to ketone aldol products that retain the stereochemistry and enantiomeric ratio of the carbonylated cyclic products.