- Application of the cyanurate-isocyanurate rearrangement to amine synthesis: Preparation of 2-(2-thienyl)ethylamine
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This communication describes a new method for preparation of 2-(2-thienyl)ethylamine, an important pharmaceutical intermediate. The method is based on the O-to-N migration of an alkyl group via cyanurate-isocyanurate rearrangment.
- Harrington,Sanchez
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Read Online
- Rational design of cannabinoid type-1 receptor allosteric modulators: Org27569 and PSNCBAM-1 hybrids
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Allosteric modulation offers an alternate approach to target the cannabinoid type-1 receptor (CB1) for therapeutic benefits. Examination of the two widely studied prototypic CB1 negative allosteric modulators (NAMs) Org27569 and PSNCBAM-1 revealed structural resemblance and similar structure–activity relationships (SARs). In silico docking and dynamics simulation studies using the crystal structure of CB1 co-bound with CP55,940 and Org27569 suggested that Org27569 and PSNCBAM-1 occupied the same binding pocket and several common interactions were present in both series with the CB1 receptor. A new scaffold was therefore designed by merging the key structural features from the two series and the hybrids retained these binding features in the in silico docking studies. In addition, one such hybrid displayed similar functions to Org27569 in dynamic simulations by preserving a key R2143.50-D3386.30 salt bridge and maintaining an antagonist-like Helix3-Helix6 interhelical distance. Based on these results, a series of hybrids were synthesized and assessed in calcium mobilization, [35S]GTPγS binding and cAMP assays. Several compounds displayed comparable potencies to Org27569 and PSNCBAM-1 in these assays. This work offers new insight of the SAR requirement at the allosteric site of the CB1 receptor and provides a new scaffold that can be optimized for the development of future CB1 allosteric modulators.
- Nguyen, Thuy,Gamage, Thomas F.,Decker, Ann M.,Finlay, David B.,Langston, Tiffany L.,Barrus, Daniel,Glass, Michelle,Harris, Danni L.,Zhang, Yanan
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- 1,2,5-oxadiazole derivative used as indoleamine 2,3-dioxygenase inhibitor
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The invention belongs to the technical field of 1,2,5-oxadiazole derivatives, and particularly relates to a 1,2,5-oxadiazole derivative or a pharmaceutically acceptable salt thereof which is used as an indoleamine 2,3-dioxygenase inhibitor. The structure of the 1,2,5-oxadiazole derivative or the pharmaceutically acceptable salt thereof used as the IDO inhibitor is shown in the following formula I.The invention provides a general formula compound I with a novel structure. Experimental results show that some compounds have excellent IDO inhibitory activity and permeation performance at the sametime. The compound is expected to be marketed as a tumor molecular immunotherapeutic drug for cancer treatment.
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- Generation of novel family of reductases from PCR based library for the synthesis of chiral alcohols and amines
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Biocatalysis has shown tremendous potential in the synthesis of drugs and drug intermediates in the last decade. Screening of novel biocatalysts from the natural genome space is the growing trend to replenish the harsh chemical synthetic routes, commonly used in the pharmaceutical and chemical industry. Here, we report a novel ketoreductase (KERD) and a nitrile reductase isolated from the PCR based library generated from the genome of Rhodococcus ruber and Bacillus subtilis, respectively. Both the proteins are hypothetical in nature as there is no putative homology found in the database, although both the enzymes have significant activity towards the synthesis of chiral alcohols and amines. Enzyme activity over a wide range of substrates (aromatic and aliphatic) for both the novel catalysts was observed. From the unique gene sequence to activity over a broad range of substrate and >99% conversion at higher concentrations (100 mM and above) entitles both the hypothetical enzymes as novel. The novel KERD has shown >99% selectivity for the synthesis of (S)-phenylethanol which makes it a potential candidate for industrial catalysis. The novel nitrile reductase has also shown promising activity for the synthesis of (R)-2-phenylethanolamine, which is a difficult moiety to synthesize chemically. In this report, starting from a homology based library, two highly potent whole cell biocatalysts are obtained.
- Sehajpal, Pallvi,Kirar, Seema,Ghosh, Saptarshi,Banerjee, Uttam Chand
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- Hydrogenation of Nitriles and Ketones Catalyzed by an Air-Stable Bisphosphine Mn(I) Complex
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Efficient hydrogenations of nitriles and ketones with molecular hydrogen catalyzed by a well-defined bench-stable bisphosphine Mn(I) complex are described. These reactions are environmentally benign and atomically economic, implementing an inexpensive, earth-abundant nonprecious metal catalyst. A range of aromatic and aliphatic nitriles and ketones were efficiently converted into primary amines and alcohols, respectively, in good to excellent yields. The hydrogenation of nitriles proceeds at 100 °C with catalyst loading of 2 mol % and 20 mol % base (t-BuOK), while the hydrogenation of ketones takes place already at 50 °C, with a catalyst loading of 1 mol % and 5 mol % of base. In both cases, a hydrogen pressure of 50 bar was applied.
- Weber, Stefan,St?ger, Berthold,Kirchner, Karl
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supporting information
p. 7212 - 7215
(2018/11/25)
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- Benzhydrylamine: An effective aminating agent for the synthesis of primary amines
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Aldehydes, ketones, alkyl toluene-p-sulfonates and halides are converted into the corresponding primary amines with benzhydrylamine as a valuable ammonia synthon in moderate to excellent yields.
- Sun, Quan-Wei,Xing, Jun-De,Qin, Yu-Hong,Yin, Xu-Wen,Zhou, Yi
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p. 181 - 183
(2018/05/26)
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- Industrial preparation method of 2-ethylamine-heterocyclic derivative
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The invention provides an industrial preparation method of a 2-ethylamine-heterocyclic derivative. The method is characterized in that a heteroaryl derivative and 2-substituent ethylene react to produce a 2-(2-cyanoethyl)-heterocyclic derivative, a 2-acetate-heterocyclic derivative and a 2-(3-butyl ketone)-heterocyclic derivative separately. The production method is simple and different from complicated production modes and harsh production conditions in the prior art. By means of the industrial preparation method, synthesis of a target product can be achieved by one step. As the production technology and synthetic route are optimized through the preparation method, in the production process, few side reactions occur, the aftertreatment is convenient, the production condition is mild, and the preparation method is suitable for an industrialized production mode.
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Paragraph 0057-0059
(2017/06/02)
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- An industrial preparation method for 2-substituted-thiophene derivatives
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An industrial preparation method for 2-substituted-thiophene derivatives is provided. The method is characterized in that thiophene derivatives and nitroethylene are reacted to generate 2-(2-nitroethyl)-thiophene derivatives, the 2-(2-nitroethyl)-thiophene derivatives are oxidized to obtain 2-(2-carboxylic acid)-thiophene derivatives, and then the 2-ethylamine-thiophene derivatives can be obtained through reduction. The method is simple. Different from complex production manners and harsh production conditions in the prior art, synthesis of target products can be achieved by one step by the method. A production process and a synthesis route are optimized in the method, and therefore side reactions are less, after-treatment is convenient, and production conditions are mild in a production process, and the method is suitable for industrial production modes.
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Paragraph 0039; 0040; 0041
(2017/08/28)
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- Drug application for benzene [g] ceteroary [a, g] quinazine compound and preparation method thereof
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The invention relates to a new application of a benzene [g] ceteroary [a, g] quinazine compound and a preparation method thereof. Specifically, the invention relates to the application of the benzene [g] ceteroary [a, g] quinazine compound in preparing the drug for treating and/or preventing the metabolic diseases caused by AMPK route, especially, the diabetes, adiposis, fatty liver and complication thereof caused by insulin resistance.
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- ORGANIC METAL COMPOUND AND ORGANIC LIGHT-EMITTING DEVICE EMPLOYING THE SAME
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Organic metal compounds and organic electroluminescence devices employing the same are provided. The organic metal compound has a chemical structure represented below: wherein R1, R2, R3, R4, and R5 are independent and can be hydrogen, halogen, C1-8 alkyl or C1-8alkoxy; L can be acetylacetone ligand, picolinic acid ligand, N,N′-diisopropylbenzamidinate, or N,N′-diisopropyl-diisopropyl-guanidinate.
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- D1-like receptors distinguishing thieno-azecine regioisomers
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Designing ligands with D1/D5 subtype selectivity is a challenge because of the high identity within the receptor helices. Based on the lead compounds 1-3, the thieno-benzazecine regioisomers 4 and 5 were synthesized and biologically evaluated for their affinity towards the five dopamine receptor subtypes utilizing a radioligand binding affinity technique. Within the D1-like family, compound 4 showed 20 fold selectivity for the D5 subtype over D1 subtype (Ki = 3 nM, D1: 60 nM), while its regioisomer, compound 5 with a reversed thiophene position, prefers the D1 subtype over the D5 subtype (Ki = 4 nM, D5: 15 nM). The benzothieno-benzazecine analog 6 was shown to be one of the few azecine derivatives with high affinity for both the D1- and the D2-like family members in the same order of magnitude (Ki = 1.5 nM for D2 and 1.9 nM for D5). Thorough analysis of the amino acid residues constituting the binding pockets of the target dopamine receptor subtypes revealed that at the D5 receptor, either serine S 6.62 and threonine T 7.33 residues or a water network, stabilized by anionic amino acids could contribute to the selectivity pattern of the synthesized compounds.
- Abdel-Fattah, Mohamed A. O.,Abadi, Ashraf H.,Lehmann, Jochen,Schweikert, Peter M.,Enzensperger, Christoph
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p. 1679 - 1686
(2015/09/21)
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- DIARYL[A, G]QUINOLIZIDINE COMPOUND, PREPARATION METHOD THEREFOR, PHARMACEUTICAL COMPOSITION, AND USES THEREOF
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The present invention relates to a diarylo[a,g]quinolizidine compound of formula (I), enantiomer, diastereoisomer, racemate, mixture, pharmaceutically acceptable salt, crystalline hydrate or solvate thereof; the preparation method thereof, and uses thereof in preparing an experimental model drugs related to dopamine receptors and 5-HT receptors or a medicament for treating or preventing a disease related to dopamine receptors and 5-HT receptors.
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- DIARYL[A, G]QUINOLIZIDINE COMPOUND, PREPARATION METHOD THEREFOR, PHARMACEUTICAL COMPOSITION, AND USES THEREOF
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The present invention relates to a diarylo[a,g]quinolizidine compound of formula (I), enantiomer, diastereoisomer, racemate, mixture, pharmaceutically acceptable salt, crystalline hydrate or solvate thereof; the preparation method thereof, and uses thereof in preparing an experimental model drugs related to dopamine receptors and 5-HT receptors or a medicament for treating or preventing a disease related to dopamine receptors and 5-HT receptors.
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- 17a-HYDROXYLASE/C17,20-LYASE INHIBITORS
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The present invention provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, R6, A and n are as defined herein. A deuteriated derivative of the compound of Formula (I) is also provided.
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Paragraph 0256
(2014/03/21)
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- 17α-HYDROXYLASE/C17,20-LYASE INHIBITORS
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The present invention provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, R6, A and n are as defined herein. A deuteriated derivative of the compound of Formula (I) is also provided.
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Page/Page column 46
(2012/04/04)
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- Reaction of InCl3 with various reducing agents: InCl 3-NaBH4-mediated reduction of aromatic and aliphatic nitriles to primary amines
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While alternative methods of preparing dichloroindium hydride (HInCl 2) via the in situ reduction of InCl3 using lithium amino borohydride (LAB) were explored, generation of HInCl2 from the reduction of InCl3 by sodium borohydride (NaBH4) was also re-evaluated for comparison. The reductive capability of the InCl 3/NaBH4 system was found to be highly dependent on the solvent used. Investigation by 11B NMR spectroscopic analyses indicated that the reaction of InCl3 with NaBH4 in THF generates HInCl2 along with borane-tetrahydrofuran (BH 3?THF) in situ. Nitriles underwent reduction to primary amines under optimized conditions at 25 °C using 1 equiv of anhydrous InCl 3 with 3 equiv of NaBH4 in THF. A variety of aromatic, heteroaromatic, and aliphatic nitriles were reduced to their corresponding primary amine in 70-99% isolated yields. Alkyl halide and nitrile functional groups were reduced in tandem by utilizing the reductive capabilities of both HInCl2 and BH3?THF in a one-pot reaction. Finally, the selective reduction of the carbon bromine bond in the presence of nitriles was achieved by generating HInCl2 via the reduction InCl3 with NaBH4 in CH3CN or with lithium dimethylaminoborohydride (MeLAB) in THF.
- Saavedra, Jaime Z.,Resendez, Angel,Rovira, Alexander,Eagon, Scott,Haddenham, Dustin,Singaram, Bakthan
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experimental part
p. 221 - 228
(2012/02/05)
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- Regioselective Heck reaction of N-vinylphthalimide: A general strategy for the synthesis of (E)-N-styrylphthalimides and phenethylamines
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The arylation of N-vinylphthalimide takes place at the β-position with aryl iodides, bromides and chlorides using palladium acetate [Pd(OAc) 2] or phenone oxime-derived palladacycles as catalysts under phosphine-free conditions. The reaction is succesfully carried out in organic solvents, such as DMF, in the presence of an organic base, such as dicyclohexylmethylamine, and with TBAB as additive at 120°C under conventional or microwave heating. (E)-N-Styrylphthalimides are mainly obtained using a rather low palladium loading (0.05-1 mol%). Similar catalytic efficiency is observed using a Kaiser oxime resin-derived palladacycle, which allows reuse of the polymeric complex for three cycles. The high regioselectivity observed supports that these palladacycles work as a source of Pd(0)spec ies operating mainly through a neutral mechanism. The syntheses of 2-thienylphenethylamine and mescaline have been performed by subsequent hydrogenation with Wilkinson's catalyst and hydrazinolysis.
- Alacid, Emilio,Najera, Carmen
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experimental part
p. 1316 - 1322
(2009/05/30)
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- 2-aminobenzoxazole derivatives and combinatorial libraries thereof
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The present invention relates to novel 2-aminobenzoxazole derivative compounds of the following formula: wherein R1 to R4 and Z have the meanings provided herein. The invention further relates to combinatorial libraries containing two or more such compounds, as well as methods of preparing 2-aminobenzoxazole derivative compounds.
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- Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors. 1. Synthesis and basic structure-activity relationship studies of PETT analogs
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A novel series of potent specific HIV-1 inhibitory compounds is described. The lead compound in the series, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (1), inhibits HIV-1 RT using rCdG as the template with an IC50 of 0.9 μM. In MT-4 cells, compound 1 inhibits HIV-1 with an ED50 of 1.3 μM. The 50% cytotoxic dose in cell culture is >380 μM. The chemical structure-activity relationship (SAR) was developed by notionally dividing the lead compound in four quadrants. The SAR strategy had two phases. The first phase involved optimization of antiviral activity through independent variation of quadrants 1-4. The second phase involved the preparation of hybrid structures combining the best of these substituents. Further SAR studies and pharmacokinetic considerations led to the identification of N-(2-pyridyl)-N'-(5-bromo-2- pyridyl)-thiourea (62; LY300046 · HCl) as a candidate for clinical evaluation. LY300046 · HCl inhibits HIV-1 RT with an IC50 of 15 nM and in cell culture has an ED50 of 20 nM.
- Bell,Cantrell,Hogberg,Jaskunas,Johansson,Jordan,Kinnick,Lind,Morin Jr.,Noreen,Oberg,Palkowitz,Parrish,Pranc,Sahlberg,Ternansky,Vasileff,Vrang,West,et al.
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p. 4929 - 4936
(2007/10/03)
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- Preparation of 2-(2-thienyl) ethylamine and synthesis of thieno [3,2-C] pyridine derivatives therefrom
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Compounds of the formulae:and wherein:, R1, R2, R3 and R4 are independently hydrogen, lower alkyl of one to six carbon atoms, aryl or substituted aryl;, are advantageously converted to isocyanurate compounds, 2-(2-thienyl)ethylamine compounds and thieno[3,2-c]pyridine derivatives and the pharmaceutically acceptable salts thereof, particularly ticlopidine hydrochloride.
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- (1S)-1-(Aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinoline and heterocycle-condensed tetrahydropyridine derivatives: Members of a novel class of very potent κ opioid analgesics
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The synthesis and structure-activity relationship (SAR) of a novel class of κ opioid analgesics, 1-(amino-methyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinolines and (aminomethyl)-N-(arylacetyl)-4,5,6,7-tetrahydrothienopyridines, are described. These compounds, formally derived by the condensation of a benzene or thiophene ring on the piperidine nucleus of the recently described compounds 1, are from 3 to 7 times more potent as antinociceptive agents and with a longer duration of action than the original lead compounds. A similar N2-C1-C9-N10 pharmacophore torsional angle of approximately 60° was also found for this class of compounds by using X-ray and 1H NMR analyses. The same absolute configuration (S) at the chiral center of the active (-) enantiomers was determined by X-ray crystallographic analysis. A varied degree of κ receptor selectivity was a feature of this novel class of antinociceptive agents (μ/κ ratio from 44 to 950 according to the nature of the basic moiety). A SAR analysis indicated that the presence of electron-withdrawing and lipophilic substituents in para and/or meta positions in the arylacetic moiety and the pyrrolidino or dimethylamino basic groups are required to optimize biological activity. The lead compounds 28, 30, and 48 are among the most potent antinociceptive agents (ED50 ca. 0.020 μM/kg sc) and κ ligands (K(i)(κ) ca. 0.20 nM) identified so far.
- Vecchietti,Clarke,Colle,Giardina,Petrone,Sbacchi
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p. 2624 - 2633
(2007/10/02)
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- 2-(2-nitrovinyl)thiophene reduction and synthesis of thieno[3,2-c]pyridine derivatives
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An improved process for the reduction of 2-(2-nitrovinyl)thiophene to form 2-(2-thienyl)ethylamine employs a boron-containing reducing agent, preferably diborane. The 2-(2-thienyl)ethylamine produced by this process is advantageously converted to ticlopidine.
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- Synthese von 2-(2-Aminoethyl)thiophen ueber aktivierte Arylsulfonylaziridine
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Synthesis of 2-(2-Aminoethyl)thiophene via Activated Arylsulfonylaziridines.Activated arylsulfonylaziridines react with 2-lithiothiophene under ring cleavage to afford sulfonamides 2, reductive cleavage of which with sodium bis(2-methoxyethoxy)aluminiumhydride yields 2-(2-aminoethyl)thiophene (3).
- Fikentscher, Rolf,Brueckmann, Ralf,Betz, Rainer
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p. 113 - 114
(2007/10/02)
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- Thienopyridine derivatives useful in treating gastric ulcers
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A compound of the formula: STR1 (wherein R1 is hydrogen, C1 -C5 alkyl, C1 -C5 alkoxy, C1 -C5 alkoxycarbonyl, or trifluoromethyl; R2 is hydrogen, C1 -C5 alkoxycarbonyl, C6 -C12 aryloxycarbonyl, C1 -C5 alkanoyloxy-C1 -C5 alkyl, C1 -C5 alkoxycarbonyloxy-C1 -C5 alkyl, C1 -C5 acylamino-C1 -C5 alkyl, 2-hydroxy-1-C2 -C5 alkenyl, phthalimido-C1 -C5 alkyl, halogeno-C1 -C5 alkoxycarbonyl-C1 -C5 alkyl, hydroxy-C1 -C5 alkyl, C1 -C5 alkylthio-C1 -C5 alkyl, or C1 -C5 alkylsulfinyl-C1 -C5 alkyl; STR2 m is an integer of 0 or 1; R3 and R4 each is hydrogen, halogen, cyano, C1 -C5 alkyl, amino, C1 -C5 alkoxy, C6 -C12 aryl-C1 -C5 alkoxy, C1 -C5 alkoxycarbonyl, fluoro-C1 -C5 alkoxy, C1 -C5 alkanoylamino, or carbamoyl) or its salt, being useful as antiulcer agents, is provided.
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- Process for the preparation of 2-(2-thienyl)-ethylamine and derivatives thereof
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The present invention provides a process for the preparation of 2-(2-thienyl)-ethylamine and derivatives thereof having the general formula: STR1 wherein R1 and R2 are hydrogen or taken together form a phenyl ring.
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- A Thiophene Analogue of Praziquantel, and Related Systems, by Intramolecular Cyclisation of Acyliminium Salts
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N--succinimide (7a) and -glutarimide (7b) on reduction with sodium borohydride in methanol at -10 deg C yield the respective hydroxylactams which on treatment with formic acid cyclise via the intermediate acyliminium ions to 4,5,9,9a-tetrahydropyrrolothienopyridin-7-one (9a) and 4,5,8,9,10,10a-hexahydropyridothienopyridin-7-one (9b) respectively.In a similar manner, 4-cyclohexylcarbonyl-1-piperazine-2,6-dione (11) is converted into the thiophene isostere (2) of praziquantel (1).Likewise, formic acid induced cyclisations of the hydroxylactams derived from N-- (16) and N-succinimide (19) furnish 5,6,10,10a-tetrahydropyrrolothienothiazepin-8(9H)-one (18) and 5,6,10,10a-tetrahydropyrrolothienothiazepin-8(9H)-one (21), respectively.
- Meth-Cohn, Otto,Vij, Rup Rani,Smalley, Robert K.,Bass, Robert J.
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p. 1001 - 1018
(2007/10/02)
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- PO-Activated Olefination and Conversion of Aldehydes and Ketones to Higher Amines; II. Synthesis of Arylethylamines
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The transformation of arylcarboxaldehydes and/or - ketones 2 by three different routes into arylethylamines 3 and/or 4 is reported.According to the first route, the intermediate iminophosphonates 9 react through a classical PO-activated olefination.The second and the third involve the rearrangement of the iminophosphonates 9 into the vinylphosphoramidates 12.
- Heymes, A.,Chekroun, I.
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p. 245 - 249
(2007/10/02)
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- Nickel-Catalyzed Synthesis of Arylacetonitriles from Arylzinc Chlorides and Bromoacetonitrile
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Arylacetonitriles are synthesised by coupling arylzinc chlorides with bromoacetonitrile using Ni(acac)2/P(c-C6H11)(C6H5)2 as catalyst.The arylacetonitriles are reduced in situ with LiAlH4/AlCl3 to give the corresponding 2-aryl-1-aminoethanes.
- Frejd, Torbjoern,Klingstedt, Tomas
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