104641-59-0

Usage

Uses

Used in Pharmaceutical Industry:
(S)-(+)-1-Methyl-3-pyrrolidinol is used as a synthetic intermediate for the preparation of diaryl acylaminopyrimidines, which act as adenosine A2A antagonists. These antagonists have potential applications in the treatment of various neurological disorders, such as Parkinson's disease, by modulating the adenosine signaling pathway.
Additionally, (S)-(+)-1-Methyl-3-pyrrolidinol is utilized in the synthesis of (alkoxyamino)(pyridinylamino)pyrazinecarbonitriles, which are selective checkpoint kinase 1 (CHK1) inhibitors. These inhibitors exhibit oral antitumor activities and have potential applications in cancer therapy, particularly for the treatment of solid tumors. By targeting the CHK1 enzyme, these inhibitors can disrupt the cell cycle and induce apoptosis in cancer cells, offering a promising approach for cancer treatment.

InChI:InChI=1/C5H11NO/c1-6-3-2-5(7)4-6/h5,7H,2-4H2,1H3/t5-/m0/s1

Upstream product

• 104612-35-3 (S)-3-hydroxy-1-methyl-2,5-pyrrolidinedione 
• 50-00-0 formaldehyd 
• 122536-94-1 (S)-3-hydroxypyrrolidine hydrochloride 
• 68165-06-0 1-methylpyrrolidin-3-one 
• 1104643-24-4 (S)-3-tert-butoxy-N-methylpyrrolidine 

Downstream Products

• 616866-21-8 (2R,3'R)-3'-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1'-methylpyrrolidine 
• 1033594-21-6 3-[4-((3R)-hydroxymethyl-3,4-dihydro-1H-isoquinolin-2-yl)-6-(1-methyl-pyrrolidin-3(S)-yloxy)-[1,3,5]triazin-2-yl]-phenol 
• 207856-83-5 3'(S)-N-methyl-3'-pyrrolidinyl (R)-cyclopentylmandelate 
• 1061748-77-3 C₂₂H₂₅FN₆O₂ 
• 1061749-27-6 C₂₂H₂₆N₆O₂ 
• 1061749-62-9 N-{2-(3,5-dimethyl-pyrazol-1-yl)-6-[3-((S)-1-methyl-pyrrolidin-3-yloxymethyl)-phenyl]-pyrimidin-4-yl}-acetamide 
• 1159928-86-5 [(3S)-1-methylpyrrolidin-3-yl]-4-(4-methylphenyl)piperazine-1-carboxylate 
• 1219731-41-5 C₂₂H₂₈BrN₃O₃ 
• 1219727-20-4 (S)-1-ethyl-1-(3-methoxybenzyl)-3-(2-(1-methylpyrrolidin-3-yloxy)-4-(1H-pyrazol-4-yl)phenyl)urea 
• 207856-85-7 (3S)-1-methylpyrrolidin-3-yl (2R)-2-cyclopentyl-2-hydroxy-2-phenylacetate 
• 1610372-32-1 (S)-7-fluoro-5-((1-methylpyrrolidin-3-yl)oxy)-2-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one 
• 1428555-12-7 C₂₀H₂₂BrF₃N₂O₅S 
• 1428555-20-7 C₁₂H₁₃F₃N₂O₃ 
• 1231955-04-6 N-[(2Z)-5-tert-butyl-3-isobutyl-1,3-thiazol-2(3H)-ylidene]-2-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-5-(trifluoromethyl)benzamide 

Relevant academic research and scientific papers

Widely applicable background depletion step enables transaminase evolution through solid-phase screening

Directed evolution of transaminases is a widespread technique in the development of highly sought-after biocatalysts for industrial applications. This process, however, is challenged by the limited availability of effective high-throughput protocols to evaluate mutant libraries. Here we report a rapid, reliable, and widely applicable background depletion method for solid-phase screening of transaminase variants, which was successfully applied to a transaminase from Halomonas elongata (HEWT), evolved through rounds of random mutagenesis towards a series of diverse prochiral ketones. This approach enabled the identification of transaminase variants in viable cells with significantly improved activity towards para-substituted acetophenones (up to 60-fold), as well as tetrahydrothiophen-3-one and related substrates. Rationalisation of the mutants was assisted by determination of the high-resolution wild-type HEWT crystal structure presented herein.

PROCESSES FOR MAKING, AND METHODS OF USING, GLYCOPYRRONIUM COMPOUNDS

Provided herein are processes for making and methods of using salts of glycopyrronium, including solid forms and forms suitable for use as topicals. Disclosed here are processes for making salts of glycopyrronium, also processes for making compositions comprising salts of glycopyrronium, and methods of treating hyperhidrosis with salts of glycopyrronium as well as with compositions comprising salts of glycopyrronium such as, but not limited to, topical compositions. Disclosed herein are methods of treating hyperhidrosis including administering salts of glycopyrronium to subjects in need thereof.

PROCESS FOR THE EFFICIENT PREPARATION OF 3-HYDROXY PYRROLIDINE AND DERIVATIVES THEREOF

The present invention relates to an effective process for the preparation of 3-hydroxypyrrolidine or derivatives thereof. The process comprises (a) protecting a hydroxyl group of 4-halo-3-hydroxybutyric acid, (b) reducing an ester group of the compound obtained from the step (a) to obtain a corresponding alcohol compound, (c) reacting the compound obtained from the step (b) with sulfonyl halide to produce a corresponding sulfonate compound, (d) reacting the compound obtained from the step (c) with an amine to obtain 3-hydroxy-protected pyrrolidine compound, and (e) deprotecting the compound obtained from the step (d) to produce the targeted 3-hydroxypyrrolidine or derivatives thereof. The process provides 3-hydroxypyrrolidine or derivatives thereof with high optical purity, because optical purity of the starting material is substantially retained. In the process, each of the steps is carried out in a mild condition and does not require any special purification. This means that the process is useful and adequate for industrial mass production of 3-hydroxypyrrolidine and derivatives thereof having high optical purity.

Stereoisomers of N-substituted soft anticholinergics and their zwitterionic metabolite based on glycopyrrolate - Syntheses and pharmacological evaluations

Purpose. In this study, isomers of two N-substituted soft anticholinergics based on glycopyrrolate, SGM (PcPOAGP_NA.Me) and SGE (PcPOAGP_NA.Et) [3′-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1′-methyl-1′- alkoxycarbonylpyrrolidinium bromide] and their zwitterionic metabolite, SGa (PcPOAGP_NA.H) [3′-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1′- methyl-1′-carboxymethylpyrrolidinium inner salt] were synthesized and their pharmacological activities were evaluated in vitro and in vivo. Methods. The isomers of SGM and SGE were synthesized with both optically pure methyl-cyclopentylmandelate and 3-hydroxy-N-methylpyrrolidine. Trans-esterification followed by quarternization with alkyl bromoacetate gave four isomers of SGM or SGE with the nitrogen chiral center unresolved (2R3′S-SGM, 2R3′R-SGM, 2S3′S-SGM, 2S3′R-SGM or 2R3′S-SGE, 2R3′R-SGE, 2S3′S-SGE, 2S3′R-SGE). The hydrolysis of these four isomers followed by HPLC separation resulted in eight fully resolved isomers of SGa (2R3′R1′R, 2R3′S1′R, 2R3′R1′S, 2R3′S1′S, 2S3′R1′R, 2S3′S1′R, 2S3′R1′S, and 2S3′S1′S). Pharmacological activities were assessed by using in vitro receptor-binding assay and guinea pig ileum pA2-assay, and by evaluating the in vivo rabbit mydriatic effects. Results were compared to those obtained with conventional anticholinergic agents, such as glycopyrrolate, N-meythylscopolamine, and tropicamide, as well as those obtained with previously prepared racemic mixtures and 2R isomers. Results. Receptor binding pK i values at cloned human muscarinic receptors (M1-M 4 subtypes) were in the 6.0-9.5 range for the newly synthesized SGM and SGE isomers, and in the 5.0-8.6 range for the SGa isomers. In all cases, 2R isomers were significantly more active than 2S isomers (27 to 447 times for SGM isomers, and 6 to 4467 times for SGa isomers). Among the four SGM isomers with unresolved 1′ (N) chiral center, the 3′R isomers were more active than the corresponding 3′S isomers (1.5-12.9 times), whereas, among the SGa isomers, the 3′S isomers were not always more active than the corresponding 3′R isomers indicating that activity determined based on configuration at chiral center 3′ is significantly affected by the configuration of the other two chiral centers, 2 and 1′. Among the completely resolved eight SGa isomers (all three chiral centers resolved), 1′S isomers were always more active than the corresponding 1′R isomers (1.8-22.4 times). Results also indicate that some isomers showed good M3/M2 muscarinic-receptor subtype-selectivity (about 3-5 times), and 2R and 3′S were the determining configurations for this property. Guinea pig ileum assays and rabbit mydriasis tests on SGa isomers further confirmed the stereospecificity. In rabbit eyes, some 2R-SGa isomers showed mydriatic potencies similar to glycopyrrolate and exceeded tropicamide, but their mydriatic effects lasted considerably shorter, and they did not induce dilation of the pupil in the contralateral, water-treated eye. These results indicate that these compounds are locally active, but safe and have a low potential to cause systemic side effects. The pharmacological potency of the eight SGa isomers was estimated as 2R3′S1′S ≈ 2R3′R1′S ≈ 2R3′S1′R > 2R3′R1′R > 2S3′R1′S > 2S3′S1′S ≈ 2S3′R1′R > 2S3′S1′R (p 3/M2 muscarinic-receptor subtype-selectivity of soft anticholinergics, SGM, SGE, and SGa have been demonstrated. In agreement with previous results, the potential for their effective and safe use has been confirmed.

SOFT ANTICHOLINERGIC ESTERS

Soft anticholinergic esters of the formulas: wherein R1 and R2 are both phenyl or one of R1 and R2 is phenyl and the other is cyclopentyl; R is C1-C8 alkyl, straight or branched chain; and X- is an anion with a single negative charge; and wherein each asterisk marks a chiral center; said compound having the R, S or RS stereoisomeric configuration at each chiral center unless specified otherwise, or being a mixture thereof.

NEW PYRROLIDINIUM DERIVATIVES

New pyrrolidinium derivatives having the chemical structure of general formula (I) are disclosed; as well as processes for their preparation, pharmaceutical compositions comprising them and their use in therapy as antagonists of M3 muscarinic receptors.

Optical Isomers of Rocastine and Close Analogues: Synthesis and H1 Antihistaminic Activity of Its Enantiomers and Their Structural Relationship to the Classical Antihistamines

The enantiomers of 2--3,4-dihydro-4-methylpyrido-1,4-oxazepine-5(2H)-thione (rocastine) and two of its more potent analogues were prepared with an enantiomeric purity of > 99.9percent.The antihistaminic activity of these compounds was assessed by their ability to block histamine-induced lethality in guinea pigs and to inhibit mepyramine binding to guinea pig cortex.In this series, compounds having the R configuration at the 2-position are at least 300 times more potent than the S isomers.Conformational analysis and molecular modeling suggest that rocastine can adopt a conformation in which the pyridine ring, ether oxygen, and protonated amine functions are positioned similarly to the corresponding elements of the probable binding conformers of some of the more classical antihistamines.This conformation, boatlike in the oxazepine ring with the side chain quasi-equatorial and folded back toward the ring, is the likely binding conformer at the histamine H1 receptor, and the available structure-activity relationship data is consistent with this interpretation.

Fused aromatic oxazepinones, thiazepinones, diazepinones and sulfur analogs thereof

Aromatic azepinones and thiones having the formula STR1 wherein; A is benzene, naphthalene, quinoline or pyridine; B is oxygen or sulfur; E is oxygen, sulfur or STR2 n is 1, 2 or 3; Z is an amino or a heterocyclic nitrogen-containing radical; R is hydrogen, loweralkyl, cycloalkyl or phenylloweralkyl; Y is halo, loweralkyl, loweralkoxy, diloweralkylamino, nitro, amino, loweracetylamino, trifluoromethyl, phenyl or phenyl substituted by one to three Y' radicals selected from halo, loweralkyl, loweralkoxy, diloweralkylamino, nitro, amino, loweracylamino or trifluoromethyl; and having antihistaminic utility, a process for the preparation thereof and chemical intermediates therefor are disclosed.

Fused aromatic oxazepinones, thiazepinones, diazepinones and sulfur analogs thereof

Aromatic azepinones and thiones having the formula STR1 wherein; A is benzene, naphthalene, quinoline or pyridine; B is oxygen or sulfur; E is oxygen, sulfur or STR2 n is 1, 2 or 3; Z is an amino or a heterocyclic nitrogen containing radical; R is hydrogen, loweralkyl, cycloalkyl or phenylloweralkyl; and having antihistaminic utility, a process for the preparation thereof and chemical intermediates therefor are disclosed.