- Divergent Synthesis of γ-Amino Acid and γ-Lactam Derivatives from meso-Glutaric Anhydrides
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The first divergent synthesis of both γ-amino acid and γ-lactam derivatives from meso-glutaric anhydrides is described. The organocatalytic desymmetrisation with TMSN3 relies on controlled generation of a nucleophilic ammonium azide species mediated by a polystyrene-bound base to promote efficient silylazidation. After Curtius rearrangement of the acyl azide intermediate to access the corresponding isocyanate, hydrolysis/alcoholysis provided uniformly high yields of γ-amino acids and their N-protected counterparts. The same intermediates were shown to undergo an unprecedented decarboxylation–cyclisation cascade in situ to provide synthetically useful yields of γ-lactam derivatives without using any further activating agents. Mechanistic insights invoke the intermediacy of an unconventional γ-N-carboxyanhydride (γ-NCA) in the latter process. Among the examples prepared using this transformation are 8 APIs/molecules of considerable medicinal interest.
- Connon, Stephen J.,Craig, Ryan,Smith, Simon N.
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supporting information
p. 13378 - 13382
(2020/10/02)
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- Preparation method for synthesizing 4-amino-3-phenylbutyric acid hydrochloride by one-pot method and product prepared by preparation method
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The invention discloses a preparation method for synthesizing 4-amino-3-phenylbutyric acid hydrochloride by a one-pot method. The 4-amino-3-phenylbutyric acid hydrochloride is prepared from nitromethane and benzaldehyde as initial raw materials through condensation reaction, addition reaction, hydrogenation reaction and hydrolysis reaction. Ethanol is introduced into the condensation reaction andthe addition reaction as a medium and is neutralized with anhydrous acid, one-pot reaction is adopted and carried out in an anhydrous system, adverse effects caused by separation of intermediates in the reaction process in the prior art are avoided, and the production process is safe and environmentally friendly while the production process is simplified and the production efficiency is improved,so that the method is suitable for industrial actual production.
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Paragraph 0031-0060
(2020/07/21)
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- Assembling of medium/long chain-based β-arylated unnatural amino acid derivatives via the Pd(II)-catalyzed sp3 β-C-H arylation and a short route for rolipram-type derivatives
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In this paper, we report the assembling of libraries of β-arylated short/medium/long chain-based non-α-amino acid (aminoalkanoic acid) derivatives via the Pd(II)-catalyzed, bidentate directing group 8-aminoquinoline-aided sp3 β-C-H activation/arylation method. Short/medium chain-based unnatural amino acid derivatives containing an aryl group at the β-position are promising small molecules with therapeutic properties. Thus, it is necessary to enrich the libraries of short/medium/long chain-based unnatural amino acid derivatives containing an aryl group at the β-position. Considering the importance of β-arylated short/medium/long chain-based non-α-amino acid derivatives, an inclusive attention was paid to explore the Pd(II)-catalyzed sp3 β-C-H arylation of short/medium/long chain-based non-α-amino acids. Representative synthetic transformations including a short route for the assembling of rolipram and related compounds and 3-arylated GABA derivatives such as, baclofen, phenibut and tolibut were shown using selected β-C-H arylated non-α-amino acid derivatives.
- Tomar, Radha,Bhattacharya, Debabrata,Babu, Srinivasarao Arulananda
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p. 2447 - 2465
(2019/03/26)
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- A novel method for the synthesis of racemic pregabalin, baclofen and 3-phenibut involving lossen rearrangement
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Pregabalin,baclofen,and3-phenibutareγ-aminobutyricacid receptorsusedasanticonvulsant agents. The racemic forms of these anticonvulsants have been prepared by Lossen rearrangement. This procedure also provides an easy method to prepare carbamates useful intermediates to prepare anticonvulsants. This process is economical and easy to scale-up and yields are good.
- Ponnusamy, Kannan,Davis Presley,Nagapillai, Prakash,Deivanayagam, Eswaramoorthy
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p. 275 - 278
(2018/09/14)
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- Organic photocatalysis for the radical couplings of boronic acid derivatives in batch and flow
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We report an acridium-based organic photocatalyst as an efficient replacement for iridium-based photocatalysts to oxidise boronic acid derivatives by a single electron process. Furthermore, we applied the developed catalytic system to the synthesis of four active pharmaceutical ingredients (APIs). A straightforward scale up approach using continuous flow photoreactors is also reported affording gram an hour throughput.
- Lima, Fabio,Grunenberg, Lars,Rahman, Husaini B. A.,Labes, Ricardo,Sedelmeier, Joerg,Ley, Steven V.
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supporting information
p. 5606 - 5609
(2018/06/04)
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- Method for synthesizing 4-amino-3-phenylbutyric acid hydrochloride
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The invention provides a method for synthesizing 4-amino-3-phenylbutyric acid hydrochloride. The synthetic method comprises the following steps: preparing methyl 4-nitro-3-phenyl butyrate, preparing methyl 4-amino-3-phenyl butyrate, and treating to obtain the product. According to the synthetic method disclosed by the invention, a complete process for synthesizing 4-amino-3-phenylbutyric acid hydrochloride is created, the synthetic method is simple in process, high in yield and low in cost, and the main problems that the initial raw materials used in the conventional process are high in price, the operation steps are onerous and pollution in the production process is severe are solved.
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Paragraph 0018; 0019
(2017/10/07)
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- New multicomponent reaction for the direct synthesis of β-aryl-γ-nitroesters promoted by hydrotalcite-derived mixed oxides as heterogeneous catalyst
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A new approach based on multicomponent/domino combined reactions for the synthesis of γ-nitroesters promoted by a mixed aluminium-magnesium oxides derived from hydrotalcite-like material was developed. Different γ-nitroesters were synthesized in 15-95percent yield using Meldrum's acid, aromatic aldehydes, nitromethane and different alcohols as reagents and solvents. The γ-aminobutyric acid derivatives, Phenibut and Baclofen, were prepared in 63 and 61percent overall yield, respectively, through a two steps synthetic strategy. A mechanistic pathway was proposed based on the gas chromatography mass spectrometry (GC-MS) and electrospray ionization mass spectrometry (ESI-MS) experiments.
- D'Oca, Caroline R. M.,Naciuk, Fabricio F.,Silva, Jéssica C.,Guedes, Esthéfani P.,Moro, Celso C.,D'Oca, Marcelo G. M.,Santos, Leonardo S.,Natchigall, Fabiane M.,Russowsky, Dennis
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p. 285 - 298
(2016/12/18)
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- A 4-amino-3-phenyl-butyric acid hydrochloride method for the synthesis of
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A provided synthetic method for 4-amino-3-phenylbutyric acid hydrochloride comprises the steps: preparing ethyl benzoylacetate, preparing nitroethenylbenzene, preparing an addition product, and processing to obtain the product. The synthetic method is an integral technology for synthesizing 4-amino-3-phenylbutyric acid hydrochloride. The method is simple in technology, high in yield and relatively low in cost, and mainly solves the problems that an initial raw material used in the prior art is high in price, operation steps are tedious and a production process is large in pollution.
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Paragraph 0031-0034
(2017/02/24)
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- Palladium-catalyzed Cs2CO3-promoted arylation of unactivated C(sp3)-H bonds by (diacetoxyiodo)arenes: Shifting the reactivity of (diacetoxyiodo)arenes from acetoxylation to arylation
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PdCl2(CH3CN)2-catalyzed arylation of unactivated C(sp3)-H bonds using (diacetoxyiodo)arenes as arylation reagents is reported. The reactivity of (diacetoxyiodo)arenes as arylation reagents is enabled in the presence of Cs2CO3 under the reaction conditions. This arylation method is highly efficient and occurs without the use of silver salt. The reaction tolerates a broad substrate scope that was not demonstrated by other silver salt-free C(sp3)-H bond arylation conditions. The synthetic utility of the method is further illustrated in the synthesis of the psychotropic drug phenibut. A detailed mechanism study has been conducted to understand the reaction pathway.
- Gou, Quan,Zhang, Zhao-Fu,Liu, Zhi-Cheng,Qin, Jun
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p. 3176 - 3186
(2015/03/30)
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- One pot domino reaction accessing γ-nitroesters: Synthesis of GABA derivatives
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Michael addition of 1,3-dicarbonyl compounds to nitrostyrenes is efficiently promoted by hydrotalcite [Mg-Al] to afford the respective γ-nitrodicarbonyl adducts. Differently, the addition of Meldrum's acid leads to a direct access of γ-nitroesters through a one pot domino process. GABA derivatives (+/-)-phenibut and (+/-)-baclofen were readily synthesized from the respective nitro adducts.
- Naciuk, Fabricio F.,Vargas, Debora Z.,D'oca, Caroline R. M.,Moro, Celso C.,Russowsky, Dennis
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p. 1643 - 1653
(2015/03/18)
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- β-Substituted γ-butyrolactams from mucochloric acid: Synthesis of (±)-baclofen and other γ-aminobutyric acids and useful building blocks
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In the course of our exploration of the application of mucohalic acids in organic synthesis, we reported the synthesis of α,β-dihalo-α, β-unsaturated γ-butyrolactams by reductive amination of a suitable mucohalic acid and a suitable amine. However, the functionalization of the α- and/or β-halogen was found to be elusive under Suzuki conditions that worked well with the corresponding γ-lactones. Although the corresponding β-aryl derivative was obtained under some of the modified Suzuki conditions tried, the yields were found to be very low. Next, the Suzuki coupling was performed on mucochloric acid prior to the reductive amination step. By careful control of the reaction conditions, only β-substitution was achieved to yield the corresponding β-aryl mucochloric acid. This could then be converted to the corresponding β-substituted γ-butyrolactam by reductive amination with 2,4-dimethoxybenzylamine (DMB-NH2) followed by reduction by nickel boride and subsequent deprotection of the DMB group. The resulting γ-butyrolactam could either be alkylated or hydrolyzed resulting in the corresponding β-substituted γ-aminobutyric acid. This methodology was extended to synthesize (±)-baclofen in five steps starting from mucochloric acid.
- Biswas, Kallolmay,Gholap, Rajesh,Srinivas, Padakanti,Kanyal, Sachin,Sarma, Koushik Das
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p. 2538 - 2545
(2014/01/06)
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- Process for producing β-phenyl-γ-amino butyric acid hydrochloride
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The invention relates to a new substance, namely the hydrochloride of β-phenyl- γ-aminobutyric acid of the following formula: EQU1 and to the process for its production which comprises condensing malonic ester with β-nitrostyrene resulting in the separation of an ester of γ-carbomethoxy-β-phenyl-γ-nitrobutyric acid at a temperature ranging from 0° to 14°C, reducing the ester thus obtained with hydrogen in the presence of the Raney nickel under a pressure of 6 to 30 atm, treating 3-carbomethoxy-4-phenyl-2-pyrrolidone, as formed by the reduction, with hydrochloric acid, and separating the desired product.
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