- Preparation method of L-prolinamide
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The invention provides a preparation method of L-prolinamide. The preparation method comprises the following steps: by using L-proline as an initial raw material, firstly forming L-proline methyl ester hydrochloride, then carrying out ammonolysis to obtain a synthetic solution containing L-prolinamide, and dissociating the residual L-prolinamide hydrochloride in the synthetic solution into L-prolinamide through inorganic alkali in a non-aqueous environment, and removing by-products through a non-aqueous solvent system. According to the preparation method, the L-prolinamide hydrochloride can befully dissociated, the by-products and the impurities can be effectively removed, the yield and purity of the target product can be remarkably improved, the preparation method is simple and convenient in process, mild in condition and easy to control, expensive reagents are not needed, the production efficiency of the L-prolinamide can be improved, and the preparation method is suitable for large-scale industrial production and has important economic and social values.
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Paragraph 0039; 0041-0048
(2021/01/28)
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- Synthesis method of vildagliptin
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The invention discloses a synthesis method of vildagliptin. The method comprises the following steps: performing esterification reaction on L-glutamic acid and ethanol to obtain L-glutamic acid-gamma-ethyl ester; reducing the L-glutamic acid-gamma-ethyl ester under the action of potassium borohydride to obtain L-proline; mixing L-proline with ethyl chloroformate for reaction to obtain acid anhydride; further reacting the acid anhydride with amine to obtain amide; dehydrating the amide under the action of phosphorus pentoxide to obtain an intermediate 1; performing substitution reaction on theintermediate 1 and chloroacetyl chloride to obtain an intermediate 2; and further reacting the intermediate 2 with 3-amino-1-adamantanol to obtain vildagliptin. The method has the advantages that fewimpurities are generated in the vildagliptin preparation process, the yield of the prepared vildagliptin is high, and compared with the prior art, the process is simpler, and the vildagliptin preparation cost is greatly reduced.
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- Synthesis method of L-prolinamide
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The invention belongs to the field of organic synthesis, and discloses a synthesis method of L-prolinamide. The method comprises steps of S1, dissolving an initial material, L-proline, in water and then reacting with acetic anhydride, after reaction, extracting and drying to prepare N-acetyl-L-proline; S2, in a solvent system, performing a reaction on a raw material, N-acetyl-L-proline prepared inS1 and thionyl chloride, then concentrating and drying to obtain a compound; S3, dripping aqueous ammonia in the compound prepared in S2 as a raw material so as to react, filtering and preparing 1-acetyl-2-pyrrolidinecarboxamide; and S4, dripping HC1 into the 1-acetyl-2-pyrrolidinecarboxamide prepared in S3 as a raw material, so as to react, then concentrating, filtering and drying to prepare L-prolinamide. In the reaction process of the synthesis method provided by the invention, common reagent raw materials are used, the costs are low, the reaction conditions are mild, the chiral purity ishigh, the yield is high, the environment pressure is low, and the synthesis method is suitable for large-scale production.
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Paragraph 0030; 0034; 0035; 0039; 0040; 0044; 0045; 0049
(2019/01/16)
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- HEMIAMINAL-TAG FOR PROTEIN LABELING AND PURIFICATION
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The invention pertains to the synthesis, isolation, and characterization of hemiaminal for selective labeling of peptides, proteins, antibodies, and organic fragments with -C(=0) CH2NH2 and derivatives with -CH2NH2 group over -C(=0) CHRNH2 group (where R≠H). The invention also pertains to the method of single-site immobilization of proteins through N-terminus Gly on solid phase. The invention includes late-stage tagging of N-terminus Gly with an affinity tag, 19F NMR probe, and a fluorophore and a method for metal-free protein purification and isolation of analytically pure proteins.
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Page/Page column 22; 24
(2018/06/30)
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- Synthesis and evaluation of camphor and cytisine-based cyanopyrrolidines as DPP-IV inhibitors for the treatment of type 2 diabetes mellitus
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In this study, bornyl- and cytisine-based cyanopyrrolidines as potent dipeptidyl peptidase-IV (DPP-IV) inhibitors were synthesised. The in vitro inhibiting activities of bornyl- and cytisine derivatives towards DPP-IV were evaluated. Bornyl-based cyanopyrrolidines were shown to have moderate inhibitory activity with regard to DPP-IV (1.27–15.78 μM). A docking study was performed to elucidate the structure-activity relationship of the obtained compounds. The in vivo hypoglycemic activities of the same compounds were evaluated with the oral glucose tolerance test (OGTT) in mice. Bornyl-based cyanopyrrolidines were shown to have good hypoglycemic activity.
- Kuranov,Tsypysheva,Khvostov,Zainullina, Liana F.,Borisevich,Vakhitova, Yu.V.,Luzina,Salakhutdinov
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p. 4402 - 4409
(2018/07/30)
-
- Synthesis method of L-prolinamide
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The invention relates to the technical field of medicines, in particular to a synthesis method of L-prolinamide. The synthesis method comprises the steps of (1) dissolving the L-prolinamide into an alcoholic solution, adding an esterification reagent for reacting, and obtaining an intermediate product II; (2) adding the product II of the step (1) into an alcoholic solution of ammonia, transferringto a high pressure reactor, and carrying out ammonia-feeding reaction; (3) decompressing and concentrating a reaction liquid in the step (2), and filtering to obtain a primary filter liquor; (4) desalinizing the primary filter liquor in the step (3), and filtering to obtain a secondary filter liquor; (5) decompressing and concentrating the secondary filter liquor of the step (4), adding a solventfor dissolving and crystalizing, cooling for suction filtration, and obtaining a product I. The synthesis method provided by the invention is simple to operate, less in waste water and waste gas, clean and environmentally-friendly. The total yield of the L-prolinamide is 78 percent, the product HPLC (High Performance Liquid Chromatography) purity is 99.6 percent, the maximum individual impurity is less than or equal to 0.3 percent, and a D type isomer is less than or equal to 0.3 percent.
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Paragraph 0023; 0024; 0025
(2018/03/26)
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- Synthetic method for chiral alpha-aminoamide compounds
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The invention provides a synthetic method for chiral alpha-aminoamide compounds, belongs to the technical field of organic synthetic methodology, and concretely relates to a synthetic method for chiral alpha-aminoamide compounds, wherein the method has a simple process, low costs and good economy. The method comprises the following steps: 1, performing ammonolysis: adding substituted chiral alpha-aminocarboxylate hydrochloride into concentrated ammonia water, performing stirring for 4-12h under a room temperature, wherein each 1mmol substituted chiral alpha-aminocarboxylate hydrochloride is corresponding to 2-8mL the concentrated ammonia water; 2, after a reaction is finished, performing distillation for removing ammonia water after the reaction to obtain crude products chiral alpha-aminoamide compounds; and 3, performing filtration on the obtained crude products chiral alpha-aminoamide compounds by adopting a manner of adding a solvent or performing purification on the obtained crude products chiral alpha-aminoamide compounds through a manner of column chromatography which uses ammonia water as a mobile phase to obtain the products chiral alpha-aminoamide compounds. Compared with the prior art, a large number of an ammonia gas for ammonolysis is not needed in the method, the process and post-treatment are simple, costs are low and reaction time is short.
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Paragraph 0045; 0046; 0047; 0066; 0067
(2018/01/11)
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- Corresponding amine nitrile and method of manufacturing thereof
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The invention relates to a manufacturing method of nitrile. Compared with the prior art, the manufacturing method has the characteristics of significantly reduced using amount of an ammonia source, low environmental pressure, low energy consumption, low production cost, high purity and yield of a nitrile product and the like, and nitrile with a more complex structure can be obtained. The invention also relates to a method for manufacturing corresponding amine from nitrile.
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Paragraph 0133; 0140; 0165-0167; 0172; 0173; 0199; 0206
(2017/10/22)
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- A method of refining prolinamides
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The invention relates to a method for refining prolinamide, which includes the following steps: (a) dissolving prolinamide coarse product in an organic solvent, wherein the prolinamide coarse product contains ammonium chloride, prolinamide hydrochloride or mixture thereof; (b) adding inorganic alkali for treatment; and (c) separating to obtain the prolinamide. The method for refining prolinamide is simple, the content and optical purity of the obtained product are high, and the method is very suitable for industrial production.
- -
-
Paragraph 0037-0038
(2017/01/12)
-
- A method for synthesizing allah Geleg sandbank (by machine translation)
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The invention relates to a method for preparing anti-II type diabetes drug allah Geleg sandbank method for the synthesis of bulk drug (Anagliptin). The lack of commercial synthetic allah Geleg sandbank solve the technical problems of the method. Synthetic method comprises the following steps : (1) with vinyl ether and trichloro acetyl chloride as the raw material, passes through the three-step reaction to obtain the aldehyde protected intermediates 4 ; The 3-amino-5-methyl pyrazole condensation for dehydrating and gets pyrazolo pyrimidine mother nucleus; Carboxy b ester hydrolysis to obtain 2-methyl-pyrazolo [1,5-a] pyrimidin 6-carboxylic acid 6 ; (2) to L-proline as a raw material, passes through the methyl esterification, ammoniation, acetylation, Carbonitride reaction to obtain the chiral cyano pyrrolizinone intermediate 11 ; Chiral cyano pyrrolizinone intermediate 11 And diamine fragment 12 In alkaline conditions to obtain intermediate affinity substituted 13 ; Finally, intermediate 13 Under the conditions of the hydrochloric acid removal protection Boc base namely obtain cyanopentanoyl Azolylamine intermediate 14 ; (3) 2-methyl-pyrazolo [1,5-a] pyrimidine-6-carboxylic acid 6 The cyano Azolylamine intermediate 14 The condensation conditions to obtain the bulk drug allah Geleg sandbank coupled. (by machine translation)
- -
-
Paragraph 0016
(2016/10/10)
-
- Towards novel 5-HT7 versus 5-HT1A receptor ligands among LCAPs with cyclic amino acid amide fragments: Design, synthesis, and antidepressant properties. Part II
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A 26-membered library of novel long-chain arylpiperazines, which contained primary and tertiary amides of cyclic amino acids (proline and 1,2,3,4-tetrahydroisoquinoline-3-carboxamide) in the terminal fragment was synthesized and biologically evaluated for binding affinity for 5-HT7 and 5-HT1A receptors. Docking studies confirmed advantages of Tic-amide over Pro-amide fragment for interaction with 5-HT7 receptors. Selected compounds 32 and 28, which behaved as 5-HT7Rs antagonist and 5-HT1A partial agonist, respectively, produced antidepressant-like effects in the forced swim test in mice after acute treatment in doses of 10 mg/kg (32) and 1.25 mg/kg (28). Compound 32 reduced immobility in a manner similar to the selective 5-HT7 antagonist SB-269970.
- Canale, Vittorio,Kurczab, Rafa?,Partyka, Anna,Sata?a, Grzegorz,Witek, Jagna,Jastrz?bska-Wi?sek, Magdalena,Paw?owski, Maciej,Bojarski, Andrzej J.,Weso?owska, Anna,Zajdel, Pawe?
-
supporting information
p. 202 - 211
(2015/03/18)
-
- AN ADVANCED AND COST-EFFECTIVE PROCESS FOR PREPARING HIGHLY PURE VILDAGLIPTIN
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The present invention describes an improved process for preparing highly pure (S)-1-[N- (3-hydroxy-l-adamantyl) glycyl] pyrrolidine-2-carbonitrile known as Vildagliptin. Also the present invention discloses a novel insitu process for preparing an intermediate (2S)- l-(chloroacetyl)pyrrolidine-2-carbonitrile. Further, the present invention discloses a method of preparing undesired dimer impurity.
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- Diverted total synthesis of falcitidin acyl tetrapeptides as new antimalarial leads
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We report not only the convergent total synthesis of falcitidin, a natural inhibitor of falcipain-2 from myxobacterium Chitinophaga, but also its diversification into a new antimalarial class of N-acyl tetrapeptides (Acyl-His-Ile-Val-Pro-NH2). Despite the lack of whole-cell activity of falcitidin itself, our study led to the identification of a trifluoromethyl (CF3) analogue displaying sub-micromolar IC50 activity against Plasmodium falciparum 3D7 in a standard blood-cell assay, but only when N-tritylated on its histidine (imidazole) residue.
- Kotturi, Santosh R.,Somanadhan, Brinda,Ch'Ng, Jun-Hong,Tan, Kevin S.-W.,Butler, Mark S.,Lear, Martin J.
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supporting information
p. 1949 - 1951
(2014/03/21)
-
- Development and evaluation of novel phosphotyrosine mimetic inhibitors targeting the Src homology 2 domain of signaling lymphocytic activation molecule (SLAM) associated protein
-
Specific interactions between Src homology 2 (SH2) domain-containing proteins and the phosphotyrosine-containing counterparts play significant role in cellular protein tyrosine kinase (PTK) signaling pathways. The SH2 domain inhibitors could potentially serve as drug candidates in treating human diseases. Here we have incorporated a novel phosphotyrosine mimetic, which is an unusual amino acid carrying a cyclosaligenyl (cycloSal) phosphodiester moiety, into dipeptides to investigate the inhibitory effect on SH2 domain-containing proteins. A plate-based assay was also established to screen for inhibitors that disrupt the interaction between a phosphopeptide of SLAM (signaling lymphocytic activation molecule) and its interacting protein SAP (SLAM-associated protein). We identified a number of inhibitors with IC50 values in the range of 17-35 μM, implying that the cycloSal phosphodiester-carrying amino acid could mimic the phosphotyrosyl residue. Our results also raise the possibility of integrating the newly developed phosphotyrosine mimetic moiety into inhibitors designed for other SH2 domain-containing proteins.
- Chu, Chi-Yuan,Chang, Chun-Ping,Chou, Yun-Ting,Handoko,Hu, Yi-Ling,Lo, Lee-Chiang,Lin, Jing-Jer
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p. 2841 - 2849
(2013/06/04)
-
- A cost-effective method to prepare pure vildagliptin
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A cost-effective synthetic approach to prepare vildagliptin under gentle experimental conditions has been reported with good yield and high purity. It was initiated with L-proline via successful reaction with chloroacetyl chloride in THF (Tetrahydrofuran) to give the 1-(2-chloroacetyl)-pyrrolidine-2-carboxylic acid, which was then treated by TCT (2, 4, 6-trichloro-1, 3, 5-triazine) in DCM (dichloromethane), and converted into 1-(2-chloroacetyl)-pyrrolidine-2- carboxamide, then further converted into 1-(2-chloroacetyl)-pyrrolidine-2- carbonitrile after dehydrated by TCT in DMF (N, N- dimethylformamide), the latter product was reacted with 3-Aminoadamantanol to get vildagliptin. The total yield of vildagliptin was about 48%, the purity was about 99%.
- Peng, Jun,Feng, Yue,Tao, Zhu,Chen, Yingjie,Hu, Xiangnan
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p. 159 - 163
(2013/07/26)
-
- Effects of dendritic interface on enantioselective catalysis by polymer-bound prolines
-
Dendritic effects have been observed in the past for a number of metal-based catalysts, but only rarely for organocatalysts, and particularly chiral organocatalysts. In the current study, l-proline was immobilized as an ester or amide on polyether dendritic spacers attached to polystyrene. The ester-including catalysts showed a remarkable positive dendritic effect on yield, but even more so on enantioselectivity, in the aldol reaction of acetone with aromatic aldehydes. The positive dendritic effect of the aforementioned catalytic systems on the yield, diastereo- and enantioselectivity of a three-component Mannich reaction was of an even greater magnitude. A series of experiments marked the possibility of catalysis by homogenous l-proline, detached from the resin during the reaction, highly unlikely. Model comparative studies with catalysts equipped with linear or only partially dendritic spacers emphasized the superiority of the fully dendritic spacer architecture.
- Kehat, Tzofit,Goren, Kerem,Portnoy, Moshe
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experimental part
p. 394 - 401
(2012/03/22)
-
- Amino acid derived amides and hydroxamic acids as ligands for asymmetric transfer hydrogenation in aqueous media
-
Amides and hydroxamic acids derived from α-amino acids were evaluated as ligands in combination with rhodium and iridium half-sandwich complexes in asymmetric transfer hydrogenation (ATH) of ketones. The reactions were performed in aqueous media using lithium formate as hydride source. The catalyst systems turned out to be highly efficient and ee's up to 90% were obtained.
- Ahlford, Katrin,Adolfsson, Hans
-
scheme or table
p. 1118 - 1121
(2012/01/15)
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- Inhibition of imidazolidinone intermediate formation in the aldol reactions catalyzed by zinc-prolinamide complexes
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The use of zinc salts as cocatalysts in aldol condensations catalyzed by single prolinamide (and in the extension by other more complex prolinamides) can prevent the formation of the parasitic intermediate imidazolidinone, with faster and also more stereoselective reactions than those catalyzed by the free amine. This new finding, together with this ion's already known properties, make zinc salts highly suitable additives for aldol reactions catalyzed for prolinamide derivatives.
- Andreu, Cecilia,Varea, Teresa,Asensio, Gregorio
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body text
p. 8705 - 8709
(2011/12/01)
-
- Synthesis and anticonvulsant activity of novel 2,6-diketopiperazine derivatives. Part 1: Perhydropyrrole[1,2-a]pyrazines
-
A number of novel pyrrole[1,2-a]pyrazine derivatives were synthesized and evaluated in in vivo animal models of epilepsy. Among them, several compounds displayed promising seizure protection in the maximal electroshock seizure (MES), subcutaneous metrazol seizure (scMET), 6 Hz and pilocarpine-induced status prevention (PISP) tests, with ED50 values comparable to the reference anticonvulsant drugs (AEDs). A critical influence of the stereochemistry and conformational preferences of the pyrrole[1,2-a]pyrazine core on in vivo pharmacological activity was observed. The mechanism of the anticonvulsant action of the agents synthesized is most probably not via inhibition of the voltage-dependent sodium (Na+) currents.
- Dawidowski, MacIej,Herold, Franciszek,Chodkowski, Andrzej,Kleps, Jerzy,Szulczyk, Pawel,Wilczek, Marcin
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scheme or table
p. 4859 - 4869
(2011/11/30)
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- PROCESS FOR PREPARATION OF DPP-IV INHIBITORS
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Process for the preparation of DPP-IV inhibitors, such as 1-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine are disclosed.
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Page/Page column 18
(2011/09/19)
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- Synthesis, characterisation and in vitro cytotoxicity studies of a series of chiral platinum(II) complexes based on the 2-aminomethylpyrrolidine ligand: X-ray crystal structure of [PtCl2(R-dimepyrr)] (R-dimepyrr = N-dimethyl-2(R)-aminomethylpyrrolidine)
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A series of platinum(II) complexes were synthesised based on the enantiomerically pure amino acid proline. Novel synthetic pathways were developed, adapted from standard peptide chemistry, to produce the 2-aminomethylpyrrolidine (pyrr) ligand and its derivatives with differing arrangements of methyl substituents at the exocyclic amine sites. The crystal structure of [PtCl2(R-dimepyrr)] (R-dimepyrr = N,N-dimethyl-2(R)-aminomethylpyrrolidine) is reported and the five-membered ligand ring has been shown to be in an envelope conformation. Cytotoxicity studies were carried out on the ovarian cancer A2780 tumour cell line and its cisplatin-resistant variant, A2780cisR. Remarkably good activity was seen for several of the drugs when compared to cisplatin despite the addition of substantial steric bulk to the amine groups, and there was a lack of cross-resistance with cisplatin seen for some compounds.
- Diakos, Connie I.,Zhang, Mei,Beale, Philip J.,Fenton, Ronald R.,Hambley, Trevor W.
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experimental part
p. 2807 - 2814
(2009/10/10)
-
- An efficient synthesis of enantiomerically pure (R)-pipecolic acid, (S)-proline, and their N-alkylated derivatives
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Enantiomerically pure (R)-(+)-pipecolic acid was synthesized in four steps and 42% overall yield starting from dihydropyran and (R)-α- methylbenzylamine. A general short strategy is also described for preparing (S)-proline (47.5% overall yield) and derivatives.
- Fadel, Antoine,Lahrache, Nabil
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p. 1780 - 1784
(2007/10/03)
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- The synthesis of new diastereomers of (4S,8aS)- and (4R,8aS)-4-phenyl-perhydropyrrole[1,2-a]pyrazine-1,3-dione
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The synthesis of new (4S,8aS)- and (4R,8aS)-4-phenyl-perhydropyrrole[1,2-a]pyrazine-1,3-diones in the cyclocondensation reaction of the respective derivatives of l-prolineamide is described. The effect of the amount of NaOEt, temperature, and reaction time on the proportions of diastereomers formed in the cyclocondensation reaction was examined. The structures of the diastereomers were confirmed by GC/MS, HRMS, HPLC, XRD, and 1H and 13C NMR investigations.
- Herold, Franciszek,Dawidowski, Maciej,Wolska, Irena,Chodkowski, Andrzej,Kleps, Jerzy,Turlo, Jadwiga,Zimniak, Andrzej
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p. 2091 - 2098
(2008/02/11)
-
- Comparison of the inhibition of human and Trypanosoma cruzi prolyl endopeptidases
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Prolyl endopeptidases (PEPs) have been found in numerous species. Inhibitors of human enzyme could correct cognitive deficits in Alzheimer patients while inhibition of Trypanosoma cruzi PEP could prevent invasion phase in Chagas disease. A structure-activity relationship study carried out in a tetrahydroisoquinoline series allowed to obtain potent competitive inhibitors superior to SUAM-1221. Besides, inhibitors expected to act according to an irreversible mechanism revealed to be superior to JPT-4819, for applications linked to human enzyme inhibition.
- Vendeville, Sandrine,Goossens, Filip,Debreu-Fontaine, Marie-Ange,Landry, Valérie,Davioud-Charvet, Elisabeth,Grellier, Philippe,Scharpe, Simon,Sergheraert, Christian
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p. 1719 - 1729
(2007/10/03)
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- Solid and solution phase syntheses of the 2-cyanopyrrolidide DPP-IV inhibitor NVP-DPP728
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DPP-IV inhibitors have been suggested as potential new treatments for type-II diabetes and 2-cyanopyrrolidides have been reported as potent DPP-IV inhibitors. Alternative synthetic approaches to one such compound, NVP-DPP728, are investigated here. One strategy is based in solution phase and is amenable to scale-up. The other is based on solid phase and is appropriate for the rapid analoging of the structural series.
- Willand, Nicolas,Joossens, Jurgen,Gesquière, Jean-Claude,Tartar, André L,Evans, D.Michael,Roe, Michael B
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p. 5741 - 5746
(2007/10/03)
-
- Synthesis and properties of aminoacylamido-AMP: Chemical optimization for the construction of an N-acyl phosphoramidate linkage
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This paper describes the design and synthesis of a new type of aminoacyl-adenylate analogue (aa-AMPN) having an N-acyl phosphoramidate linkage where the oxygen atom of the mixed anhydride bond of aminoacyl-adenylate (aa-AMP) is replaced by an amino group. This new type of aa-AMP analogue is expected to be useful as material for studies on the recognition mechanism of the aminoacylation of tRNA and other biochemical reactions. The condensation of phosphoramidite derivatives of carboxamides with nucleoside derivatives failed, because the activated phosphoramidite derivatives reacted with not only the hydroxyl groups but also another reactive species. An alternative approach was examined by the reaction of 5'-O-phosphoramidite adenosine derivatives with carboxamide derivatives. The TBTr and TSE groups were chosen for protection of the amino group of amino acid amides and the phosphate group, respectively. Detailed studies revealed that the use of 5-(3,5-dinitrophenyl)-1H-tetrazole as an activating catalyst of phosphoramidites resulted in rapid condensation within 10 min to give fully protected aa-AMPN derivatives. No side reaction occurred. Deprotection of these products via a two-step procedure gave aa-AMPN derivatives in good yields. It also turned out that aa-AMPNs thus obtained are stable under both acidic and basic conditions, such as 0.1 M HCl (pH 1.0) and 0.1 M NaOH (pH 13.0).
- Moriguchi,Yanagi,Kunimori,Wada,Sekine
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p. 8229 - 8238
(2007/10/03)
-
- Conformational Studies in Solid State and Solution of Protected C-terminal Dipeptide Fragment (Boc-Phe-Pro-NH2) of Morphiceptin
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The crystal structure of the protected C-terminal dipeptide fragment (Boc-Phe-Pro-NH2) of the μ-opioid receptor highly selective agonist, morphiceptin (Tyr-Pro-Phe-Pro-NH2), was determined; the crystals are monoclinic with space group P21 and unit cell dimensions: α = 11.5731(5), b = 6.4490(3), c = 15.4082(5) A, β = 100.359(5)° and Z = 2. To examine the influence of proline on the conformation of peptide bond, the molecular conformation was studied in solid state and solution (using 1H and 13C NMR data). The X-ray analysis revealed the following conformations of peptide backbone: φ1 = -63.2(5)°, ψ1 = 156.1(4)°, ω1 = -174.3(4)°, φ2 = -66.0(5)° and ψ2 = 152.0(4)°. The conformation of the Boc group is trans-trans. Experimental data revealed the trans conformation about the Phe-Pro amide bond, both in solid state and solution (DMSO). The possibility of cis/trans isomerization about the peptide bond (ω1) was examined by theoretical calculations using BIOSYM software. Molecular modelling, including molecular dynamics simulations of the title dipeptide, is in favour of trans peptide bond.
- Kojic-Prodic, Biserka,Antolic, Snjezana,Kveder, Marina,Zigrovic, Ivanka,Kidric, Jurka,Horvat, Stefica
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p. 259 - 277
(2007/10/03)
-
- Scavenger assisted combinatorial process for preparing libraries of amides, carbamates and sulfonamides
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This invention relates to a novel solution phase process for the preparation of amide, carbamate, and sulfonamide combinatorial libraries. These libraries have utility for drug discovery and are used to form wellplate components of novel assay kits.
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- Catalytic epoxidation of unfunctionalized alkenes by dinuclear nickel(II) complexes
-
The synthesis, crystal and molecular structure and catalytic activity in epoxidation reactions of new dinuclear nickel(II)-complexes, octahedral μ-diacetato-μ-[2,6-bis[N-2-2'-pyridylethyl)formimidoyl]phenolato]bis nickel(II)·perchlorate·methanol (6) and square planar (μ-hydroxo-μ-[2,6-bis[N-((S)-1-benzyl-2-yl-pyrrolidine)formimidoyl]p henolato]bisnickel(II)·bisperchlorate (7), are described. For the preparation of 7 a new 5-step route for homochiral bisamine (S)-benzyl-2-aminomethyl-pyrrolidine (19) was developed starting from (S)-proline. Epoxidation of unfunctionalized alkenes with sodium hypochlorite and tert-butyl hydroperoxide as terminal oxidants was effectively catalyzed with bisnickel(II)-complexes 6 and 7, and a turnover of 165 was reached using trans-β-methylstyrene (34). The epoxidations probably proceed via a radical intermediate (such as OCl·) and no enantioselectivity is obtained under phase transfer conditions. In epoxidation reactions employing tert-butyl hydroperoxide as terminal oxidant a turnover of 43 was obtained with trans-stilbene (30) as substrate. Unexpectedly in the case of styrene (29) 1,2-bis-(tert-butylperoxy)ethylbenzene (59) was isolated as the major product.
- Rispens, Minze T.,Gelling, Onko Jan,De Vries, Andre H.M.,Meetsma, Auke,Van Bolhuis, Fre,Feringa, Ben L.
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p. 3521 - 3546
(2007/10/03)
-
- Amino acids and peptides. XVI. Synthesis of N-terminal tetrapeptide analogs of fibrin α-chain and their inhibitory effects on fibrinogen/thrombin clotting
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N-Terminal tetrapeptide analogs of fibrin α-chain were synthesized by the solution method using a new active ester, the ester of the oxime of p-nitroacetophenone, and by the solid-phase method. Their inhibitory effects on fibrinogen/thrombin clotting were examined. Of the synthetic peptides, amide analogs of Gly-Pro-Arg-Pro exhibited a more potent inhibitory effect.
- Kawasaki,Hirase,Miyano,Tsuji,Iwamoto
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p. 3253 - 3260
(2007/10/02)
-
- Synthesis, antitumor activity, and nephrotoxicity of the optical isomers of 2-aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato) platinum(II)
-
The optical isomers of 2-aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato)platinum(II) (DWA2114, 1), which has potent antitumor activity against various tumors, were synthesized. They were examined for antitumor activity against Colon 26 carcinoma in a sc-iv system, and changes in urinary protein and sugar levels in drug-treated mice were used as an index of nephrotoxicity. In their effect on tumors, (+)-(S)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato) platinum(II) (6b) was more potent than the enantiomer 6a in that the effective dose of 6b was smaller than that of 6a; but, both drugs exhibited potent antitumor activity. On the other hand, a distinct difference between 6a and 6b was shown in their nephrotoxicity. Isomer 6b induced a great increase in urinary protein and sugar levels in mice, whereas 6a caused no increase in these levels.
- Morikawa,Honda,Endoh -i.,Matsumoto,Akamatsu -i.,Mitsui,Koizumi
-
p. 837 - 842
(2007/10/02)
-
- N-heterocyclic platinum complexes
-
Novel platinum complexes represented by the formula: STR1 wherein A is alkylene having carbon atoms of from 1 to 3; R1, R2, R3 and R4 are the same or different and are hydrogen or alkyl having carbon atoms of from 1 to 4; X and Y are independently a halogen atom, or combined together to form STR2 and l, m and n are independently 0 or 1, and a process for preparing the same are disclosed. These platinum complexes have high antitumor activity and low toxicity, and are easily soluble in water. Therefore, they are very useful as an antitumor agent.
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- Electrochemical Decarboxylation of L-Threonine and Oligopeptide Derivatives with Formation of N-Acyl-N,O-acetals: Preparation of Oligopeptides with Amide or Phosphonate C-Terminus
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Derivatives of α-amino acids with two stereogenic centers (cf.L-threonine) and di-, tri- and tetrapeptides are electrolyzed in MeOH or AcOH, with formation of N-acyl-N,O-acetals (1b - 15b, 20b), in an anodic oxidative substitution of the COOH by an OR group.The amine ends of the oligopeptides may be benzyloxycarbonyl(Z)- or (tert-butoxy)carbonyl(Boc)-protected.With unprotected dipeptides, an electrolytic decarboxylative cyclization to imidazolidinones (18c, 19c) may also occur (in H2O/NH4OAc).The electrolyses are carried out in simple flasks with cooling jackets ('undivided cell'), using constant current conditions and anodes of Pt or glassy C.The electrolyte is generated in situ by adding 10 - 20 mol-percent of a tertiary amine.Mild acidic hydrolysis of electrolysis products thus obtained may lead to amino-acid amides or peptide amides (10c, 11c, 12c, 17c) with one amino acid less than the starting material.The N,O-acetals from L-threonine and the oligopeptides also react with organometallic nucleophiles such as Grignard compounds (->21 - 26, 29), with formation of products in which the original COOH group has been replaced by alkyl or allyl (sometimes even with moderate stereoselectivity).By treatment of the peptide-derived (open-chain) N,O-acetals with trialkyl or triaryl phosphites/TiCl4, the RO group is replaced by a phosphodiester group in a (non-diastereoselective) Michaelis-Arbuzov-type reaction (1d, 1e, 2d - 9d, 5e).Thus, the two-step sequence of electrolysis and phosphonation converts an oligopeptide derivative to an analogue with a phosphonic-acid end group.The diastereoisomeric N-protected dimethyl and diethyl dipeptidephosphonates (also prepared from the corresponding diaryl esters by Ti(OR)4-mediated transesterification) could be separated by preparative HPLC (SiO2, Lichrosorb Si 60, 10 μm); the dextrorotatory isomers of 1d - 3d were assigned L,D-, the laevorotatory ones L,L-configuration by hydrolysis to and identification of the known amino and aminophosphonic acids.The results described demonstrate a new simple route leading, from a give oligopeptide, to pure peptide analogues of known configuration.
- Seebach, Dieter,Charczuk, Roland,Gerber, Christian,Renaud, Philippe,Berner, Heinz,Schneider, Helmut
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p. 401 - 425
(2007/10/02)
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- PHOTOLABILE p-METHOXYPHENACYLOXYCARBONYL GROUP FOR THE PROTECTION OF AMINES
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P-Methoxyphenacyloxycarbonyl (Phenoc) is a new photolabile protective group for amines.Various phenacyl urethanes, i.e.Phenoc protected amines, have been prepared.An application of the group in peptide synthesis is reported.
- Church, George,Ferland, Jean-Marie,Gauthier, Jean
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p. 1901 - 1904
(2007/10/02)
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- >metal Tetrachlorometallate Complexes. The Detection of Polynuclear Complex Formation in Solution by Circular Dichroism
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The CuII, NiII, PdII, and CoII complexes of tetradentate chiral ligand, glyoxal bis(gpmi) have been prepared.Circular dichroism spectra show strong peaks in the absorption range of the free (2-) (M'=Cu, Ni or Co) ions which indicate the polynuclear structures achieved by chloro-bridging between M and M' (M=Cu, Ni and Co) persist in solution at concentrations > 3 mmol dm-3.
- Nakamura, Akira,Mori, Yoshihiko,Oguni, Nobuki
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p. 2359 - 2362
(2007/10/02)
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