- Selective Hydrogen Atom Abstraction through Induced Bond Polarization: Direct α-Arylation of Alcohols through Photoredox, HAT, and Nickel Catalysis
-
The combination of nickel metallaphotoredox catalysis, hydrogen atom transfer catalysis, and a Lewis acid activation mode, has led to the development of an arylation method for the selective functionalization of alcohol α-hydroxy C?H bonds. This approach employs zinc-mediated alcohol deprotonation to activate α-hydroxy C?H bonds while simultaneously suppressing C?O bond formation by inhibiting the formation of nickel alkoxide species. The use of Zn-based Lewis acids also deactivates other hydridic bonds such as α-amino and α-oxy C?H bonds. This approach facilitates rapid access to benzylic alcohols, an important motif in drug discovery. A 3-step synthesis of the drug Prozac exemplifies the utility of this new method.
- Twilton, Jack,Christensen, Melodie,DiRocco, Daniel A.,Ruck, Rebecca T.,Davies, Ian W.,MacMillan, David W. C.
-
supporting information
p. 5369 - 5373
(2018/04/09)
-
- On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system
-
Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in a compact, reconfigurable manufacturing platform. Continuous end-to-end synthesis in the refrigerator-sized [1.0 meter (width) × 0.7 meter (length) × 1.8 meter (height)] system produces sufficient quantities per day to supply hundreds to thousands of oral or topical liquid doses of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride that meet U.S. Pharmacopeia standards. Underlying this flexible plug-and-play approach are substantial enabling advances in continuous-flow synthesis, complex multistep sequence telescoping, reaction engineering equipment, and real-time formulation.
- Adamo, Andrea,Beingessner, Rachel L.,Behnam, Mohsen,Chen, Jie,Jamison, Timothy F.,Jensen, Klavs F.,Monbaliu, Jean-Christophe M.,Myerson, Allan S.,Revalor, Eve M.,Snead, David R.,Stelzer, Torsten,Weeranoppanant, Nopphon,Wong, Shin Yee,Zhang, Ping
-
-
- Controlling the exothermicity of O-arylation by evaporative cooling during the process development of fluoxetine hydrochloride
-
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
-
supporting information
p. 875 - 885
(2014/08/05)
-
- METHOD FOR THE PREPARATION OF N-METHYL-ARYLOXY-PROPANAMINE DERIVATIVES
-
The present invention is related to a method for the preparation of N-methyl-aryloxy-propanamine derivatives, which comprises reacting a suitable uretane derivative of the Formula (XXIV) with a Grignard reagent.
- -
-
Page/Page column 34-35
(2010/04/03)
-
- Efficient method for preparing 3-aryloxy-3-arylpropylamines and their optical stereoisomers
-
Provided is an efficient method for the preparation of 3-aryloxy-3-arylpropylamines, their optical stereoisomers, and pharmaceutically acceptable salts thereof. The process allows for the isolation of 3-aryloxy-3-arylpropylamines in high yield and purity. The present invention further relates to a process for producing fluoxetine, tomoxetine, norfluoxetine, duloxetine, nisoxetine, and their optically enriched (R)— and (S)-enantiomers.
- -
-
Page/Page column 7
(2008/06/13)
-
- AN EFFICIENT METHOD FOR PREPARING 3-ARYLOXY-3- ARYLPROPYLAMINES AND THEIR OPTICAL STEREOISOMERS
-
Provided is an efficient method for the preparation of 3-aryloxy-3- arylpropylamines, their optical stereoisomers, and pharmaceutically acceptable salts thereof. The process allows for the isolation of 3-aryloxy-3- arylpropylamines in high yield and purity. The present invention further relates to a process for producing fluoxetine, tomoxetine, norfluoxetine, duloxetine, nisoxetine, and their optically enriched (R)- and (S)-enantiomers.
- -
-
Page/Page column 20
(2010/11/25)
-
- CAN-mediated oxidative cleavage of 4-aryl-3,4-dihydroxypiperidines
-
A CAN-mediated oxidative cleavage of 4-aryl-3,4-dihydroxypiperidines 2Aa-Be to β-amino carbonyl compounds 3Aa-Be and 4Aa-Be in different ratios is described. This facile strategy was also used to synthesize racemic fluoxetine (5).
- Chang, Meng-Yang,Lin, Chun-Yu,Pai, Chun-Li
-
p. 2565 - 2568
(2007/10/03)
-
- Synthesis of 3-aminomethyl-1-propanol, a fluoxetine precursor
-
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.
- -
-
-
- Process for the preparation of fluoxetine hydrochloride
-
An improved and industrially advantageous process for the preparation of the antidepressant fluoxetine and its pharmaceutically acceptable salts, preferably hydrochloride.
- -
-
-
- Fluoxetine process from benzoylacetonitrile
-
A synthesis of fluoxetine is disclosed. The process begins with benzoylacetonitrile, which is reduced, optionally in the presence of a chiral ligand, to produce the corresponding aminoalcohol, and the amine is carbamoylated without isolation. The alcohol is deprotonated and reacted with 4-chloro- or 4-fluoro benzotrifluoride or with 4-trifluoromethylphenol to provide a carbamate of fluoxetine. The carbamate is reduced with a hydride or with borane to provide fluoxetine free base. The process may be employed for the synthesis of individual enantiomers of fluoxetine.
- -
-
-
- Fluoxetine process from benzoylpropionic acid
-
A synthesis of fluoxetine is disclosed. The process begins with a lower alkyl ester of 3-benzoylpropionic acid, which is reduced in the presence of a chiral ligand to produce the corresponding γ-hydroxy ester, and the ester is cleaved. The free acid is then condensed with the alcohol to form a γ-lactone, which is treated with ammonia to provide the γ-hydroxy amide. The amide undergoes a Hoffman rearrangement to provide a 2-oxo-1,3 oxazine, which is reduced to 3-(methylamino)-1-phenyl-1-propanol. The alcohol is deprotonated and reacted with a 4-chloro- or 4-fluoro benzotrifluoride to provide fluoxetine free base.
- -
-
-
- Production of fluoxetine and new intermediates
-
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.
- -
-
-