- Method for synthesizing α - isopropyl -3 and 4 -methoxyacetonitrile
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The invention belongs to the technical field of organic synthesis, and particularly discloses a synthesis method α - isopropyl -3 and 4 -methoxyacetonitrile. To 3, 4 - dimethoxyphenyl acetic acid as a raw material, 2 - (3, 4 - dimethoxyphenyl) acetamide is formed through acylation reaction, and 3, 4 -methoxyphenyl acetonitrile are obtained by dehydration, and α - isopropyl -3 and 4 -methoxyacetonitrile are formed by alkylation reaction. The starting materials are cheap and easily available. The method avoids the use of highly toxic crisis reagents, is mild in reaction conditions, simple in post-treatment, short in synthetic route and high in yield.
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Paragraph 0005-0006; 0020; 0025-0026; 0027; 0032-0033...
(2021/09/29)
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- Enantioselective synthesis of nitriles containing a quaternary carbon center by michael reactions of silyl ketene imines with 1-acrylpyrazoles
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The enantioselective construction of quaternary carbon centers is a marked challenge in asymmetric catalysis research. It is extremely difficult when a chiral catalyst can not distinguish the facial selectivity of the substrate through bond interactions. Here we realized an enantioselective Michael reaction of silyl ketene imines to 1-acrylpyrazoles using a chiral N,N′-dioxide-Co(II) complex. The protocol is highly efficient for the construction of nitrile-, aryl-, and dialkyl-bearing carbon centers and has been successful applied in the divergent synthesis of pharmaceuticals and natural products. The through-space dispersion interactions between unbound silyl ketene imines and the 1-acrylpyrazole-bonded catalyst play a key role in facilitating the reactivity and the enantioselectivity of this process.
- Chen, Long,Pu, Maoping,Li, Shiyang,Sang, Xinpeng,Liu, Xiaohua,Wu, Yun-Dong,Feng, Xiaoming
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p. 19091 - 19098
(2021/11/22)
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- A Concise and Modular Three-Step Synthesis of (S)-Verapamil using an Enantioselective Rhodium-Catalyzed Allylic Alkylation Reaction
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A concise and modular asymmetric synthesis of the calcium channel blocker (S)-verapamil is described. This approach employs an enantioselective rhodium-catalyzed allylic alkylation reaction between an α-isopropyl-substituted benzylic nitrile and allyl benzoate to construct the challenging acyclic quaternary stereocenter. The terminal olefin then serves as a convenient synthetic handle for a hydroamination to introduce the phenethylamine moiety, furnishing (S)-verapamil in three steps and 55% overall yield, thus providing the most efficient synthesis of this important pharmaceutical reported to date. Furthermore, given the modular nature of the synthesis, it can be readily modified to prepare structurally related bioactive agents.
- Evans, P. Andrew,Tom, Mai-Jan,Turnbull, Ben W. H.
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p. 2185 - 2189
(2020/08/26)
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- Synthesis of Nitrile-Bearing Quaternary Centers by an Equilibrium-Driven Transnitrilation and Anion-Relay Strategy
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The efficient preparation of nitrile-containing building blocks is of interest due to their utility as synthetic intermediates and their prevalence in pharmaceuticals. As a result, significant efforts have been made to develop methods to access these motifs which rely on safer and non-toxic sources of CN. Herein, we report that 2-methyl-2-phenylpropanenitrile is an efficient, non-toxic, electrophilic CN source for the synthesis of nitrile-bearing quaternary centers by a thermodynamic transnitrilation and anion-relay strategy. This one-pot process leads to nitrile products resulting from the gem-difunctionalization of alkyl lithium reagents.
- Alazet, Sébastien,West, Michael S.,Patel, Purvish,Rousseaux, Sophie A. L.
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supporting information
p. 10300 - 10304
(2019/07/04)
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- HIGHLY WATER-SOLUBLE SALTS OF A SHORT ACTING PHENYLALKYLAMINE CALCIUM CHANNEL BLOCKER AND USES THEREOF
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The present invention includes surprisingly water-soluble salts of a phenylalkylamine compound that are potent antagonists of L-type calcium channels. Aqueous solutions including salts of the instant invention are formulated for nasal administration and provide a novel therapeutic platform for the treatment of stable angina, migraine, and cardiac arrhythmia, such as paroxysmal supraventricular tachycardia.
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Page/Page column 21-22
(2016/11/02)
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- Indium Tribromide Catalyzed Coupling Reaction of Enol Ethers with Silyl Ketene Imines toward the Synthesis of β,γ-Unsaturated Nitriles
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Herein, a coupling reaction of enol ethers with silyl ketene imines in the presence of catalytic amounts of InBr3 and Me3SiBr is described. Kinetic studies have revealed that an indium catalyst and Me3SiBr accelerated the coupling process and the regeneration of the catalyst, respectively. Various types of enol ethers and silyl ketene imines are applicable. In addition, a formal synthesis of verapamil was achieved by using this novel coupling reaction. Let's get together: The coupling reaction of enol ethers with silyl ketene imines in the presence of a catalytic amount of InBr3 and Me3SiBr is shown (see scheme, TBS=tert-butyl dimethylsilyl). Kinetic studies revealed that an indium salt and Me3SiBr accelerated the coupling process and the regeneration of the catalyst. Several enol ethers and silyl ketene imines are applicable to this strategy.
- Nishimoto, Yoshihiro,Nishimura, Takashi,Yasuda, Makoto
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supporting information
p. 18301 - 18308
(2015/12/24)
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- Rational Design and Synthesis of Thioridazine Analogues as Enhancers of the Antituberculosis Therapy
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Tuberculosis, caused by Mycobacterium tuberculosis, is still one of the leading infectious diseases globally. Therefore, novel approaches are needed to face this disease. Efflux pumps are known to contribute to the emergence of M. tuberculosis drug resistance. Thioridazine has shown good anti-TB properties both in vitro and in vivo, likely due to its capacity to inhibit efflux mechanisms. Here we report the design and synthesis of a number of putative efflux inhibitors inspired by the structure of thioridazine. Compounds were evaluated for their in vitro and ex vivo activity against M. tuberculosis H37Rv. Compared to the parent molecule, some of the compounds synthesized showed higher efflux inhibitory capacity, less cytotoxicity, and a remarkable synergistic effect with anti-TB drugs both in vitro and in human macrophages, demonstrating their potential to be used as coadjuvants for the treatment of tuberculosis.
- Pieroni, Marco,Machado, Diana,Azzali, Elisa,Santos Costa, Sofia,Couto, Isabel,Costantino, Gabriele,Viveiros, Miguel
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supporting information
p. 5842 - 5853
(2015/08/24)
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- Design, synthesis and evaluation of 9-hydroxy-7H-furo [3,2-g]chromen-7-one derivatives as new potential vasodilatory agents
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Two new 9-hydroxy-7H-furo[3,2-g]chromen-7-one derivatives were designed, synthesized and evaluated for their in vitro vasodilatory activity. The structures of two compounds were elucidated by infrared, 1H NMR, and mass spectral data. The invitro pharmacological evaluation indicated that both of them possessed well vasodilatory activity compared with imperatorin. The molecule docking also showed two target compounds docked well with L-calcium channel (PDB code: 3G43). The result suggested that they would be potential vasodilatory agents for hypertension.
- Wang, Cheng,Wang, Tao,Zhou, Nan,Pan, Xiao-Yan,He, Huai-Zhen
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p. 304 - 311
(2014/02/14)
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- Synthesis of new verapamil analogues and their evaluation in combination with rifampicin against Mycobacterium tuberculosis and molecular docking studies in the binding site of efflux protein Rv1258c
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New verapamil analogues were synthesized and their inhibitory activities against Mycobacterium tuberculosis H37Rv determined in vitro alone and in combination with rifampicin (RIF). Some analogues showed comparable activity to verapamil and exhibited better synergies with RIF. Molecular docking studies of the binding sites of Rv1258c, a M. tuberculosis efflux protein previously implicated in intrinsic resistance to RIF, suggested a potential rationale for the superior synergistic interactions observed with some analogues.
- Singh, Kawaljit,Kumar, Malkeet,Pavadai, Elumalai,Naran, Krupa,Warner, Digby F.,Ruminski, Peter G.,Chibale, Kelly
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supporting information
p. 2985 - 2990
(2014/06/24)
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- SHORT ACTING PHENYLALKYLAMINE CALCIUM CHANNEL BLOCKERS AND USES THEREOF
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The present invention relates to the use of a pharmaceutically effective amount of an short-acting calcium channel blocking compound to treat ischemic heart conditions, cardiac arrhythmias, hypertensive crisis in an emergency room setting, hypertension before, during, or after surgery, no- reflow phenomenon following reperfusion, and diseases associated with decreased skeletal muscle blood flow. The invention also relates to pharmaceutical compositions formulated for use in such methods and to kits for such methods.
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Page/Page column 51
(2009/01/23)
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- Facile preparation of α-aryl nitriles by direct cyanation of alcohols with TMSCN under the catalysis of InX3
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(Chemical Equation Presented) A convenient and efficient synthesis of α-aryl nitrites was developed by direct cyanation of alcohols with TMSCN under the catalysis of Lewis acid. Using 5-10 mol % of InBr3 as the catalyst, a variety of benzylic alcohols can be converted to the corresponding nitriles in 5-30 min with yields of 46-99%.
- Chen, Gang,Wang, Zheng,Wu, Jiang,Ding, Kuiling
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supporting information; experimental part
p. 4573 - 4576
(2009/05/07)
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- PHENYLACETONITRILE DERIVATIVES AND HAIR TONICS AND EXTERNAL PREPARATIONS FOR SKIN CONTAINING THE DERIVATIVES
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A hair growth promoting composition comprising, as an effective ingredient, a phenylacetonitrile derivative or a pharmacologically acceptable salt thereof expressed by the following Formula (I): wherein each of R1 and R2 is hydrogen atom, a C1-10 alkyl group, a C2-10 alkenyl group or C2-10 acyl group, or NR1R2 may be a heterocycle having 3-7 members; R3 is a C1-5 alkyl group; and each of R4, R5 and R6 is hydrogen atom or a C1-4 alkoxy group. The present invention provides a hair growth promoting composition having excellent effects on promoting hair regrowth, preventing or inhibiting hair loss, and the like in human by compounding above-specified phenylacetonitrile derivative as a effective ingredient thereto.
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- Enzyme-catalysed improved resolution of (RS)-4-cyano-4-(3,4- dimethoxyphenyl)-4-isopropyl-1-butanol
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Resolutions of (RS)-4-cyano-4-(3,4-dimethoxyphenyl)-4-isopropyl-1- butanol 1 using various enzymes were performed. Among them, Pseudomonas fluorescens resolved it with moderate stereoselectivity (E=13) and reacted faster with the (S)-enantiomer. To optimize enzyme-catalysed reaction conditions for the resolution, the effect of solvents and additives was studied. In n-hexane:ethyl acetate (9:1), both reaction rate and selectivity were high. When pyridine, potassium carbonate and molecular sieves were used as additives, the enantiomeric excess of the (R)-enantiomer was 99, 99 and 98% at 52-60% conversion, respectively. However, in diisopropyl ether, the enantiomeric excess of unreacted alcohol (R)-1 was up to 99% at 70% conversion without additives.
- Im, Dai Sig,Cheong, Chan Seong,Lee, So Ha,Park, Hokoon,Youn, Byoung Hee
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p. 3759 - 3767
(2007/10/03)
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- Ethylamine derivatives and antihypertensives containing the same
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An ethylamine derivative of formula (I): STR1 wherein A represents a carbon atom or a nitrogen atom; B represents a substituted or unsubstituted aralkyl or aryl group; C represents hydrogen, alkyl, aralkyl, or aryl, each of which may optionally be substituted or C may optionally be bonded to A to form an alkylene bridge which is optionally substituted, Q represents a substituted or unsubstituted aryl group, said group optionally being substituted by hetero atom(s) or substituent(s) optionally containing hetero atom(s); and X represents an alkylene bridge having from 2 to 20 carbon atoms and is optionally substituted with groups which include hetero atoms with the non-hetero atom substituents optionally containing hetero atoms.
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- Process for the synthesis of the α-(-methyl-ethyl)-3,4-dimethoxybenzene-acetonitrile
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New process for the synthesis of the α-(1-m.ethylethyl)-3,4-dimethoxyacetonitrile of formula (I): STR1 which is known as an intermediate in the synthesis of the drug internationally known as verapamil. The process starts from the isobutyryl-3,4-dimethoxybenzene of formula (II): STR2 which, by means of the Darzens condensation, gives an epoxyester which, by alkaline hydrolysis and subsequent decarboxylation, gives the α-(1-methylethyl)-3,4-dimethoxybenzeneacetaldehyde. This product is reacted with hydroxylamine to obtain the corresponding oxime that, by dehydration, gives the nitrile of formula I.
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- SOME NEW ANALOGUES OF VERAPAMIL AND MEPAMIL. SYNTHESIS AND BASIC PHARMACOLOGICAL PROPERTIES
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Some new analogues of verapamil (Ia) and mepamil (Ib), calcium antagonists of arylkylamine type, were synthesized and screened for cardiovascular activities.The basic structure was modified a) on the phenyl ring, attached to the quaternary carbon, b) on the alkyl group, attached to the quaternary carbon and c) on the alkylamino group, attached in position 3 to the n-propyl fragment.Except of 2-(2-chlorophenyl)-2-isopropyl-5-(N-methylhomoveratrylamino)valeronitrile (VIa), all the synthesized compounds exhibited lower hypotensive activity, than the mother compound, verapamil.
- Butora, Gabriel,Blaha, Ludvik,Rajsner, Miroslav,Helfert, Ivan
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p. 1967 - 1981
(2007/10/02)
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- Antagonistes calciques. I. Remplacement du groupe dimethoxy-3,4- phenylethyle du verapamil
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In the verapamil structure, the 3,4-dimethoxy phenylethyl group has been replaced by several moieties belonging to α- and β-blockers or other classes of calcium channel blockers.The best derivatives, as calcium blockers, were prepared with β-blocker fragments like aryloxypropanolamines (AOPA) with an ortho substituent on the aromatic ring.
- Laguerre, M.,Boyer, C.,Carpy, A.,Panconi, E.,Cognic, F.,Vaugien, B.
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p. 351 - 359
(2007/10/02)
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- New process for the synthesis of the alpha-(1-methylethyl)-3,4-dimethoxybenzene-acetonitrile
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New process for the synthesis of the α-(1-methylethyl)--3,4-dimethoxyacetonitrile of formula intermediate in the synthesis of the drug internationally known as verapamil. The process starts from the isobutyryl--3,4-dimethoxybenzene of formula which, by means of the Darzens condensation, gives an epoxyester which, by alkaline hydrolysis and subsequent decarboxylation, gives the α-(1-methylethyl)-3,4-dimethoxybenzeneacetaldehyde. This product is reacted with hydroxylamine so obtaining the corresponding oxime that, by dehydratation, gives the nitrile of formula I.
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- Process for the preparation of basically substituted phenylacetonitriles
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A simplified process for the preparation of basically substituted phenylacetonitriles, in particular of verapamil, is described. This process is carried out with fewer stages and higher yields than the known processes according to the state of the art.
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- Bicyclo-substituted phenylacetonitrile derivatives
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The invention relates to compounds of the formula: STR1 which are useful cardiovascular agents.
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- Bicyclo-substituted phenylacetonitrile derivatives
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The invention relates to compounds of the formula: STR1 which are useful cardiovascular agents.
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- N-substituted-dihydroxyphenethylamines
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The compounds are N-substituted-dihydroxyphenethylamines which are cardiotonic agents, central nervous system depressants and analgetic agents. Representative of the compounds disclosed is N-(3,4-dihydroxyphenisobutyl)-β-isopropyl-3,4-dihydroxyphenethylamine.
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