- Manganese-Catalyzed Anti-Markovnikov Hydroamination of Allyl Alcohols via Hydrogen-Borrowing Catalysis
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Controlling the selectivity in a hydroamination reaction is an extremely challenging yet highly desirable task for the diversification of amines. In this article, a selective formal anti-Markovnikov hydroamination of allyl alcohols is presented. It enables the versatile synthesis of valuable γ-amino alcohol building blocks. A phosphine-free Earth's abundant manganese(I) complex catalyzed the reaction under hydrogen-borrowing conditions. A vast range of aliphatic, aromatic amines, drug molecules, and natural product derivatives underwent successful hydroamination with primary and secondary allylic alcohols with excellent functional group tolerance (57 examples). The catalysis could be performed on a gram scale and has been applied for the synthesis of drug molecules. The mechanistic studies revealed the metal-ligand bifunctionality as well as hemilability of the ligand backbone as the key design principle for the success of this catalysis.
- Das, Kuhali,Sarkar, Koushik,Maji, Biplab
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p. 7060 - 7069
(2021/06/30)
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- Convenient Continuous Flow Synthesis of N-Methyl Secondary Amines from Alkyl Mesylates and Epoxides
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The first continuous flow process was developed to synthesize N-methyl secondary amines from alkyl mesylates and epoxides via a nucleophilic substitution using aqueous methylamine. A variety of N-methyl secondary amines were produced in good to excellent yields, including a number of bioactive compounds or their precursors. Up to 10.6 g (88% yield) of an N-methyl secondary amine was produced in 140 min process time. The amination procedure included an in-line workup, and the starting mesylate material was also produced in continuous flow from the corresponding alcohol. Finally, an in-line process combining the mesylate synthesis and nucleophilic substitution was developed.
- Lebel, Hélène,Mathieu, Gary,Patel, Heena
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p. 2157 - 2168
(2020/11/23)
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- Systems and methods for synthesizing chemical products, including active pharmaceutical ingredients
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Systems and methods for synthesizing chemical products, including active pharmaceutical ingredients, are provided. Certain of the systems and methods described herein are capable of manufacturing multiple chemical products without the need to fluidically connect or disconnect unit operations when switching from one making chemical product to making another chemical product.
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- R-(-)-atomoxetine hydrochloride preparation method
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The invention provides an R-(-)-atomoxetine hydrochloride preparation method, which comprises: preparing 3-methylamino-1-phenyl-1-propanol by using 1-phenyl-2-propenyl-1-one as a starting raw material, carrying out etherification on the 3-methylamino-1-phenyl-1-propanol and o-halo toluene in an inorganic alkali environment, splitting with L-(+)-mandelic acid to obtain R-(-)-tomoxetine-S-(+)-mandelate, refining the R-(-)-tomoxetine-S-(+)-mandelate, and carrying out hydrochloride forming to obtain the R-(-)-atomoxetine hydrochloride. According to the present invention, the method eliminates theoxalate refining step so as to reduce the reaction step, has advantages of cheap and easily available raw materials, less side reactions, low toxicity of the reaction solvent, high yield, high purity,low cost and the like, and is suitable for industrial production.
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Paragraph 0087-0088; 0093-0094; 0099-0100
(2019/09/14)
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- A model target anti-tumor medicament and its preparation method and application (by machine translation)
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This invention relates to the targeting of antineoplastic eEF2K of a small molecule inhibitor, its formula (I), formula (II) the structure of the formula (III): Formula (I), formula (II) compound of the formula (III) structure and its pharmaceutically acceptable salt thereof can kill cancer cells, the healthy organism cells are not affected, to various tumor is markedly inhibited, in particular breast cancer, glioma, stomach cancer, liver cancer cells is markedly inhibited. (by machine translation)
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- Controlling the exothermicity of O-arylation by evaporative cooling during the process development of fluoxetine hydrochloride
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This study illustrates the optimization of the O-arylation step of fluoxetine hydrochloride (1) synthesis. In the entire process, this is the most critical step that dictates the yield and quality of the product. The highlight of the process is the concept of evaporative cooling that was employed in manipulating the above highly exothermic reaction by introducing toluene as the cosolvent. The evaporative cooling not only aided in getting an efficient procedure but also increased the yield of 1 and simplified the work-up procedure. This was a protective approach adopted for process safety, considering the worst-case scenario in the plant.
- Mohanty, Sandeep,Roy, Amrendra Kumar,Kiran, S. Phani,Rafael, G. Eduardo,Kumar, K. P. Vinay,Karmakar, A. Chandra
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p. 875 - 885
(2014/08/05)
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- Total synthesis of fluoxetine and duloxetine through an in situ imine formation/borylation/transimination and reduction approach
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We report efficient, catalytic, asymmetric total syntheses of both (R)-fluoxetine and (S)-duloxetine from α,β-unsaturated aldehydes conducting five sequential one-pot steps (imine formation/copper mediated β-borylation/transimination/reduction/oxidation) followed by the specific ether group formation which deliver the desired products (R)-fluoxetine in 45% yield (96% ee) and (S)-duloxetine in 47% yield (94% ee). This journal is the Partner Organisations 2014.
- Calow, Adam D. J.,Fernandez, Elena,Whiting, Andrew
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p. 6121 - 6127
(2014/08/05)
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- SUBSTITUTED 3-HETEROARYLOXY-3-(HETERO)ARYL-PROPYLAMINES AS SEROTONIN TRANSPORTER AND SEROTONIN HT2C RECEPTOR MODULATORS
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The present invention relates to compounds compound according to Formula (1): and pharmaceutically acceptable salts, hydrates and solvates thereof. These compounds have serotonin (5-HT) transporter inhibitory effects and 5-HT 2C receptor antagonist or inverse agonist effects. The present invention also relates to pharmaceutical compositions comprising these compounds, and methods of using them for application in the prophylaxis or treatment of CNS disorders.
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Page/Page column 12-13; 23
(2014/04/04)
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- Preparation of fluoxetine by multiple flow processing steps
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Microflow technology is established as a modern and fashionable tool in synthetic organic chemistry, bringing great improvement and potential, on account of a series of advantages over flask methods. The study presented here focuses on the application of flow chemistry process in performing an efficient multiple step syntheses of (±)-fluoxetine as an alternative to conventional synthetic methods, and one of the few examples of total synthesis accomplished by flow technique.
- Ahmed-Omer, Batoul,Sanderson, Adam J.
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experimental part
p. 3854 - 3862
(2011/06/23)
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- Design, synthesis and evaluation of substituted N-(3-arylpropyl)-9,10- dihydro-9-oxoacridine-4-carboxamides as potent MDR reversal agents in cancer
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A novel class of molecules with structure N-(3-arylpropyl)-9,10-dihydro-9- oxoacridine-4-carboxamides (20-29) were designed by generating a pharmacophore for potent MDR reversal activity using phase drug design software. The designed molecules were synthesized by a novel synthesis route and evaluated for their inhibitory effects on the transport activity of P-glycoprotein (P-gp) by standard Hoechst 33342 assay method. Based on the pIC50 values of ten title compounds screened, three compounds exhibited better activity as compared to Verapamil used as standard.
- Velingkar,Dandekar
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experimental part
p. 504 - 510
(2012/01/06)
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- Microwave-assisted synthesis and evaluation of substituted aryl propyl acridone-4-carboxamides as potential chemosensitizing agents for cancer
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A novel class of compounds with structure Aryl propyl acridone-4- carboxamides were synthesized by conventional and microwave (MW) irradiation methods and evaluated for their inhibitory effects on the transport activity of P- glycoprotein (P-gp) by standard Hoechst 33342 assay method. The title compounds with phenoxy substitution exhibited better activity.
- Velingkar, Vinaykumar S.,Dandekar, Vikrant D.
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p. 268 - 275
(2013/01/10)
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- Novel synthetic route to fluoxetine
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Racemic fluoxetine was synthesized from 3-benzoylpropionic acid in five steps in 54% overall yield. Copyright
- Schulze, Matthias
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experimental part
p. 3415 - 3422
(2011/01/12)
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- SYNTHESIS OF ATOMOXETINE HYDROCHLORIDE
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(±)-Atomoxetine oxalate having crystalline Form II and a solid (±)-atomoxetine free base are useful in preparing atomoxetine hydrochloride.
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Page/Page column 21-22
(2010/10/20)
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- Novel carbon-carbon bond formation between N-methyl-3-phenyl-3- hydroxypropylamine and cresols catalyzed by p-toluenesulphonic acid
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The p-toluenesulphonic acid-catalyzed reaction between appropriate cresols and N-methyl-3-phenyl-3-hydroxypropylamine in refluxing toluene resulted in the formation of o -substituted phenol derivatives by an aromatic nucleophilic substitution reaction. Copyright Taylor & Francis Group, LLC.
- Gopalakrishnan,Sureshkumar,Kanagarajan,Thanusu,Govindan, Shanmugam,Reddy Ghanta, Mahesh
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p. 1923 - 1926
(2007/10/03)
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- Practical synthesis of enantiopure γ-amino alcohols by rhodium-catalyzed asymmetric hydrogenation of β-secondary-amino ketones
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(Chemical Equation Presented) Another way to antidepressants: A series of β-secondary-amino ketone hydrochlorides (e.g. 1) were hydrogenated with remarkably high enantioselectivities by using a Rh complex containing P-chiral bisphospholane 2. These results establish a short and practical means for the synthesis of enantiopure N-monosubstituted γ-amino alcohols (e.g. 3), which are key intermediates in the synthesis of important antidepressants. (nbd = norbornadiene; TON = turnover number).
- Liu, Duan,Gao, Wenzhong,Wang, Chunjiang,Zhang, Xumu
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p. 1687 - 1689
(2007/10/03)
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- Synthesis of 3-aminomethyl-1-propanol, a fluoxetine precursor
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The present invention concerns a method of synthesizing fluoxetine hydrochloride. The method includes the synthesis of 3-methylamino-1-phenyl-1-propanol by reduction of 1-phenyl-3-methylamino-1-propen-1-one with sodium borohydride and acetic acid.
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- Dutch Resolution: Separation of enantiomers with families of resolving agents. A status report
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Dutch Resolution is the term given to the use of mixtures (families) of resolving agents in classical resolutions. In this status report an overview is given of the latest results and new (possible) families of resolving agents are introduced. The concept of families is discussed as well as the factors that come into play on use of families. Practical aspects of Dutch Resolution in particular and resolutions in general are discussed.
- Kellogg, Richard M.,Nieuwenhuijzen, Jose W.,Pouwer,Vries, Ton R.,Broxterman, Quirinus B.,Grimbergen, Reinier F.P.,Kaptein, Bernard,La Crois, Rene M.,De Wever, Ellen,Zwaagstra, Karen,Van Der Laan, Alexander C.
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p. 1626 - 1638
(2007/10/03)
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- Preparation and uses of N-methylnitrone
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Oxidation of secondary amines with hydrogen peroxide and sodium tungstate is reported to give good yields of nitrones. However, when using dimethylamine in this manner, a considerable amount of N,N-dimethylformamide was produced as a co-product. To more selectively produce N-methylnitrone from dimethylamine, a two-step process is used which comprises (a) mixing together dimethylamine and a peroxidic compound, and subjecting the resultant mixture to reaction conditions effective to form a reaction mixture in which N,N-dimethylhydroxylamine has been formed; and (b) mixing together (i) reaction mixture from (a), (ii) a peroxidic compound, and (iii) a transition metal-containing oxidation catalyst, and subjecting the resultant mixture to reaction conditions effective to form a reaction mixture in which N-methylnitrone has been formed. Highest yields of N-methylnitrone are achieved by conducting step (b) at a pH in the range of 7 to about 12, and at a temperature in the range of about -10° to about 100° C.
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- Preparation and uses of hydrocarbylnitrones
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Nitrones are produced by reaction of primary amine with aldehyde or ketone, in the presence of a transition metal-containing oxidation catalyst, and a peroxidic compound. The nitrone can then be reacted with a vinylaromatic compound to produce a 2-hydrocarbyl-5-arylisoxazolidine. Both such reactions can be conducted concurrently by including the vinylaromatic compound in the initial reaction mixture. Hydrogenation of the 2-hydrocarbyl-5-arylisoxazolidine, e.g., using hydrogen and a palladium-carbon catalyst, forms an N-hydrocarbyl-3-aryl-3-hydroxypropylamine. Such reactions enable, inter alia, synthesis of the racemic hydrochloride salt of N-methyl-3-phenyl-3-[4-trifluoromethyl)phenoxy]-propylamine, known generically as fluoxetine hydrochloride, a widely used antidepressant.
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- Synthesis and characterization of fluorescent ligands for the norepinephrine transporter: Potential neuroblastoma imaging agents
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Radiolabeled m-iodobenzylguanidine (MIBG) is a tumor-seeking radioactive drug used in the diagnosis and treatment of pheochromocytomas and neuroblastomas. It is transported into the tumor cells by the neuronal norepinephrine (NE) transporter (NET) which is expressed in almost all neuroblastoma cells. Here, we describe the synthesis and some pharmacological properties of a series of fluorescent compounds structurally related to the NET substrate, MIBG, or to the NET inhibitors, (-)-(2R,3S)-cocaine and nisoxetine. Three of 10 synthesized fluorescent compounds, 1-(1- naphthylmethyl)guanidinium sulfate (1), 1-[2-(dibenz[b,f]azepin-5- yl)ethyl]guanidinium sulfate (2), and (2R,3S)-2β-ethoxycarbonyl-3β-tropanyl 5-(dimethylamino)naphthalene-1-sulfonate (6), exhibited high affinity (IC50 about 50 nM) for the NET. The nisoxetine derivatives 8 (rac-N-[(3- methylamino-1-phenyl)propyl]-5-(dimethylamino)-1-naphthalene-sulfonamide) and 9 (rac-4-[(3-methylamino-1-phenyl)propyl]amino-7-nitro-2,1,3-benzoxadiazole) and especially the guanidine derivative 4 (1-[4-(4-phenyl-l,3- butadienyl)benzyl]guanidinium sulfate) which are characterized by intermediate affinity for the NET (IC50 370-850 nM) caused significant and nisoxetine-sensitive cell fluorescence. At least the guanidine derivative 4 might represent a potentially useful agent for imaging of neuroblastoma cells.
- Hadrich, Dirk,Berthold, Frank,Steckhan, Eberhard,B?nisch, Heinz
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p. 3101 - 3108
(2007/10/03)
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- Preparation and use of 2-methyl-5-phenylisoxazolidine
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(a) An alkali metal base (hydroxide, oxide, carbonate, bicarbonate or sesquicarbonate), an acid addition salt of N-methylhydroxylamine, and (iii) water are mixed together to form a reaction mixture in which the acid of the acid addition salt has been neutralized. (b) Reaction mixture from (a) and formaldehyde or formalin are mixed together and the resultant mixture is subjected to reaction conditions that produce a reaction mixture in which N-methylnitrone has been formed. (c) Reaction mixture from (b) and styrene are mixed and the resultant mixture to subjected to reaction conditions that produce a reaction mixture in which 2-methyl-5-phenylisoxazolidine has been formed. Preferably, 2-methyl-5-phenylisoxazolidine formed in (c) is hydrogenated such that N-methyl-3-phenyl-3-hydroxypropylamine is formed, which in turn is reacted with 4-halobenzotrifluoride such that N-methyl-3-phenyl-3-?4-trifluoromethyl)phenoxy!propylamine is formed. Conversion of the N-methyl-3-phenyl-3-?4-trifluoromethyl)phenoxy!propylamine to its racemic hydrochloride salt provides fluoxetine hydrochloride, a widely used antidepressant.
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- Production of fluoxetine and new intermediates
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4-methyl-3-[(4-trifluormethyl)phenoxy]-3-phenyl propylamine (I) is prepared by reacting 3-dimethylamino-1-phenyl-1-propanol (III) with haloformate (VIII) to obtain a substituted propyl carbamate (IX) which is hydrolyzed under basic conditions to yield methylamino-1-phenyl-1-propanol (X). The methylamino-1-phenyl-1-propanol is then converted to fluoxetine (I) by reaction with 4-halobenzotrifluoride (XI). In the process certain substituted carbamates are obtained as intermediates.
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- Process for the preparation of fluoxetine
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An improved process for the preparation of fluoxetine. The invention is concerned with an improved process for the preparation of the antidepressant, fluoxetine hydrochloride, or N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine hydrochloride, by simultaneous debenzylation and catalytic hydrogenation of 2-benzoyl-1-(N-benzyl-N-methyl)ethylamine base with the aid of Pd/C, Pt/C or Pd-Pt/C at a hydrogen pressure of 5 bar at 50° C. with ethyl acetate as a solvent to obtain 1-phenyl-3-(N-methylamino)-propan-1-ol. This compound is then selectively etherified with 1-chloro-4-trifluoromethylbenzene in N-methylpyrrolidone at 80° C. in the presence of potassium t-butoxide to form N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine, or fluoxetine base, which is transformed in a known manner to fluoxetine hydrochloride, or N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine hydrochloride. The yield of fluoxetine hydrochloride is 85-87% of the theoretical.
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