- Oxidative Rearrangement of MIDA (N-Methyliminodiacetic Acid) Boronates: Mechanistic Insights and Synthetic Applications
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Herein we report that coordinative hemilability allows the MIDA (N-methyliminodiacetic acid) nitrogen to behave as a nucleophile and intramolecularly intercept palladium π-allyl intermediates. A mechanistic investigation indicates that this rearrangement proceeds through an SN2-like displacement at tetrasubstituted boron to furnish novel DABN boronates. Oxidative addition into the N-C bond of the DABN scaffold furnishes borylated π-allyl intermediates that can then be trapped with a variety of nucleophiles, including in a three-component coupling.
- Kaldas, Sherif J.,Tien, Chieh-Hung,Gomes, Gabriel Dos Passos,Meyer, Stephanie,Sirvinskas, Martynas,Foy, Hayden,Dudding, Travis,Yudin, Andrei K.
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supporting information
p. 324 - 328
(2021/01/26)
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- Allyl coupling reaction method and application thereof
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The invention discloses a novel allyl coupling reaction method which takes an allyl thianthene salt as an allylation reagent and respectively takes a carboxylic acid compound. An allylated coupling product is obtained by reacting a substrate with a base in the presence of a base, or directly with a carboxylate compound, an aromatic hydrocarbon/heterocyclic hydrocarbon as a substrate, and at room temperature. The preparation method is mild in condition and free of transition metal participation, can efficiently realize preparation of various allyl ester, allyl substituted amine and allyl substituted aromatic hydrocarbon/heterocyclic hydrocarbon compound, and has an ideal application prospect in the fields of fine chemical engineering, material science and pharmacy.
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Paragraph 0304-0308
(2021/08/25)
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- Scalable preparation of stable and reusable silica supported palladium nanoparticles as catalysts for N-alkylation of amines with alcohols
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The development of nanoparticles-based heterogeneous catalysts continues to be of scientific and industrial interest for the advancement of sustainable chemical processes. Notably, up-scaling the production of catalysts to sustain unique structural features, activities and selectivities is highly important and remains challenging. Herein, we report the expedient synthesis of Pd-nanoparticles as amination catalysts by the reduction of simple palladium salt on commercial silica using molecular hydrogen. The resulting Pd-nanoparticles constitute stable and reusable catalysts for the synthesis of various N-alkyl amines using borrowing hydrogen technology without the use of any base or additive. By applying this Pd-based catalyst, functionalized and structurally diverse N-alkylated amines as well as some selected drug molecules were synthesized in good to excellent yields. Practical and synthetic utility of this Pd-based amination protocol has been demonstrated by upscaling catalyst preparation and amination reactions to several grams-scales as well as recycling of catalyst. Noteworthy, this Pd-catalyst preparation has been up-scaled to kilogram scale and catalysts prepared in both small (1 g) and large-scale (kg) exhibited similar structural features and activity.
- Alshammari, Ahmad S.,Natte, Kishore,Kalevaru, Narayana V.,Bagabas, Abdulaziz,Jagadeesh, Rajenahally V.
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p. 141 - 149
(2020/01/06)
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- Metal-Organic Capsules with NADH Mimics as Switchable Selectivity Regulators for Photocatalytic Transfer Hydrogenation
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Switchable selective hydrogenation among the groups in multifunctional compounds is challenging because selective hydrogenation is of great interest in the synthesis of fine chemicals and pharmaceuticals as a result of the importance of key intermediates. Herein, we report a new approach to highly selectively (>99%) reducing C=X (X = O, N) over the thermodynamically more favorable nitro groups locating the substrate in a metal-organic capsule containing NADH active sites. Within the capsule, the NADH active sites reduce the double bonds via a typical 2e- hydride transfer hydrogenation, and the formed excited-state NAD+ mimics oxidize the reductant via two consecutive 1e- processes to regenerate the NADH active sites under illumination. Outside the capsule, nitro groups are highly selectively reduced through a typical 1e- hydrogenation. By combining photoinduced 1e- transfer regeneration outside the cage, both 1e- and 2e- hydrogenation can be switched controllably by varying the concentrations of the substrates and the redox potential of electron donors. This promising alternative approach, which could proceed under mild reaction conditions and use easy-to-handle hydrogen donors with enhanced high selectivity toward different groups, is based on the localization and differentiation of the 2e- and 1e- hydrogenation pathways inside and outside the capsules, provides a deep comprehension of photocatalytic microscopic reaction processes, and will allow the design and optimization of catalysts. We demonstrate the advantage of this method over typical hydrogenation that involves specific activation via well-modified catalytic sites and present results on the high, well-controlled, and switchable selectivity for the hydrogenation of a variety of substituted and bifunctional aldehydes, ketones, and imines.
- Wei, Jianwei,Zhao, Liang,He, Cheng,Zheng, Sijia,Reek, Joost N. H.,Duan, Chunying
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p. 12707 - 12716
(2019/09/04)
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- Preparation method and application of adjustable metal organic cage compound for efficiently selective catalytic reduction of nitrobenzaldehyde
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The invention belongs to the technical field of fine chemical engineering. The invention relates to a preparation method and application of an adjustable metal organic cage compound for efficient selective catalytic reduction of nitrobenzaldehyde. According to the preparation method, M in a transition metal salt is used as a node and L is used as a ligand for reaction to prepare the metal organic cage compound, and the synthetic route is as follows: M + L- to M-L; wherein the ligand L is selected from H2FPB; the transition metal salt is selected from one of ferrous perchlorate, cobalttetrafluoroborate, nickel perchlorate or zinc tetrafluoroborate. The metal organic cage compound prepared by the method is low in raw material price and high in yield, and the obtained compound is stable in chemical property and easy to put into practical application. As a target compound M-FPB, the adjustable metal organic cage compound shows that the selectivity of the compound M-FPB can reach 99% in the aspects of reduction of p-nitrobenzaldehyde to prepare p-nitrobenzyl alcohol, one-step synthesis of cinnarizine by reduction catalysis of cinnamyl aldehyde and reduction of p-nitrobenzaldehyde to prepare p-aminobenzaldehyde.
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Paragraph 0039-0040
(2019/12/02)
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- Palladium-Based Hydroamination Catalysts Employing Sterically Demanding 3-Iminophosphines: Branched Kinetic Products by Prevention of Allylamine Isomerization
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A new allylpalladium triflate catalyst with a dimesitylphosphine moiety was synthesized, isolated, and characterized. The greatly increased steric bulk on the phosphine of this palladium catalyst inhibited product isomerization, which is often observed after hydroamination of terminal allenes with secondary amines. The considerably reduced rate of isomerization facilitated the isolation of many previously unknown branched allylamines, products that were inaccessible when using other, more active 3-iminophosphine palladium catalysts.
- Thakuri, Rajendr S.,Schmidt, Joseph A. R.
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p. 1917 - 1927
(2019/05/21)
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- Practical regio- and stereoselective azidation and amination of terminal alkenes
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There is significant interest in developing more rapid and efficient production of nitrogen-containing allylic compounds, as widely used in various syntheses. This work reports a variety of allylic azides and allylic amines synthesized by an efficient, new one-pot protocol that employs readily available terminal alkenes as starting materials. This method is highly regio- and stereoselective, affording the linear (E)-isomer, under metal-free conditions. This process tolerates several functional groups including halogen-containing molecules; it is general for azides and amine nucleophiles; and, adducts were obtained in good yields.
- Ojo, Olatunji S.,Miranda, Octavio,Baumgardner, Kyle C.,Bugarin, Alejandro
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supporting information
p. 9354 - 9358
(2019/01/03)
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- Mitsunobu Reaction Using Basic Amines as Pronucleophiles
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A novel protocol for extending the scope of the Mitsunobu reaction to include amine nucleophiles to form C-N bonds through the utilization of N-heterocyclic phosphine-butane (NHP-butane) has been developed. Both aliphatic alcohols and benzyl alcohols are suitable substrates for C-N bond construction. Various acidic nucleophiles such as benzoic acids, phenols, thiophenol, and secondary sulfonamide also provide the desired products of esters, ethers, thioether, and tertiary sulfonamide with 43-93% yields. Importantly, C-N bond-containing pharmaceuticals, Piribedil and Cinnarizine, have been synthesized in one step from the commercial amines under this Mitsunobu reaction system.
- Huang, Hai,Kang, Jun Yong
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p. 6604 - 6614
(2017/07/15)
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- Tertiary amine synthesis: Via reductive coupling of amides with Grignard reagents
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A new iridium catalyzed reductive coupling reaction of Grignard reagents and tertiary amides affording functionalised tertiary amine products via an efficient and technically-simple one-pot, two-stage experimental protocol, is reported. The reaction-which can be carried out on gram-scale using as little as 1 mol% Vaska's complex [IrCl(CO)(PPh3)2] and TMDS as the terminal reductant for the initial reductive activation step-tolerates a broad range of tertiary amides from (hetero)aromatic to aliphatic (branched, unbranched and formyl) and a wide variety of alkyl (linear, branched), vinyl, alkynyl and (hetero)aryl Grignard reagents. The new methodology has been applied directly to bioactive molecule synthesis and the high chemoselectivity of the reductive coupling of amide has been exploited in late stage functionalization of drug molecules. This reductive functionalisation of tertiary amides provides a new and practical solution to tertiary amine synthesis.
- Xie, Lan-Gui,Dixon, Darren J.
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p. 7492 - 7497
(2017/10/30)
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- Direct use of allylic alcohols and allylic amines in palladium-catalyzed allylic amination
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Allylic alcohols and allylic amines were directly utilized in a Pd-catalyzed hydrogen-bond-activated allylic amination under mild reaction conditions in the absence of any additives. The cooperative action of a Pd-catalyst and a hydrogen-bonding solvent is most likely responsible for its high reactivity. The catalytic system is compatible with a variety of functional groups and can be used to prepare a wide range of linear allylic amines in good to excellent yields. Furthermore, this methodology can be easily applied to the one-step synthesis of two drugs, cinnarizine and naftifine, on a gram scale.
- Jing, Jiangyan,Huo, Xiaohong,Shen, Jiefeng,Fu, Jingke,Meng, Qinghua,Zhang, Wanbin
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supporting information
p. 5151 - 5154
(2017/07/12)
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- Continuous-Flow Multistep Synthesis of Cinnarizine, Cyclizine, and a Buclizine Derivative from Bulk Alcohols
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Cinnarizine, cyclizine, buclizine, and meclizine belong to a family of antihistamines that resemble each other in terms of a 1-diphenylmethylpiperazine moiety. We present the development of a four-step continuous process to generate the final antihistamines from bulk alcohols as the starting compounds. HCl is used to synthesize the intermediate chlorides in a short reaction time and excellent yields. This methodology offers an excellent way to synthesize intermediates to be used in drug synthesis. Inline separation allows the collection of pure products and their immediate consumption in the following steps. Overall isolated yields for cinnarizine, cyclizine, and a buclizine derivative are 82, 94, and 87 %, respectively. The total residence time for the four steps is 90 min with a productivity of 2 mmol h-1. The incredible bulk: Bulk alcohols are converted continuously into chlorides using HCl in a microflow. A reaction network that consists of four steps and two inline separations leads to the continuous preparation of cinnarizine, cyclizine, and a buclizine derivative with yields of 82, 94, and 87 %, respectively. The total residence time for the four steps is 90 min with a productivity of 2 mmol h-1.
- Borukhova, Svetlana,Nol, Timothy,Hessel, Volker
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- Iron-Catalyzed Allylic Amination Directly from Allylic Alcohols
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Allylic amination, directly from alcohols, has been demonstrated without any Lewis acid activators using an efficient and regiospecific molecular iron catalyst. Various amines and alcohols were employed and the reaction proceeded through the oxidation/reduction (redox) pathway. A direct one-step synthesis of common drugs, such as cinnarizine and nafetifine, was exhibited from cinnamyl alcohol that produced water as side product. The iron way! A direct amination of allylic alcohols has been demonstrated without the need of Lewis acid activators using an efficient and regiospecific molecular iron catalyst. A range of amines and alcohols were tolerated, and the reaction was found to procced through an oxidation/reduction (redox) pathway (see scheme).
- Emayavaramban, Balakumar,Roy, Moumita,Sundararaju, Basker
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p. 3952 - 3955
(2016/03/16)
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- ADENYLYL CYCLASE INHIBITORS FOR NEUROPATHIC AND INFLAMMATORY PAIN
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The invention generally relates to adenylyl cyclase inhibitor compounds and methods for treating neuropathic or inflammatory pain by using those compounds.
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Paragraph 0320-0321; 0344-0345
(2016/10/11)
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- Iron-catalyzed synthesis of cinnarizine
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Cinnarizine was synthesized in a high yield by iron-catalyzed cross-coupling of phenylmagnesium chloride with 1-[(2E)-3-chloroprop-2-en-1-yl]-4-(diphenylmethyl)piperazine prepared by allylation of 1-(diphenylmethyl) piperazine with (E)-1,3-dichloropropene.
- Shakhmaev,Sunagatullina, A. Sh.,Zorin
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- Palladium-catalyzed regio- and stereoselective β-arylation of tertiary allylic amines: Identification of potent adenylyl cyclase inhibitors
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Substituted allylic amines and their derivatives are key structural motifs of many drug molecules and natural products. A general, mild, and practical palladium-catalyzed β-arylation of tertiary allylic amines, one of the most challenging Heck arylation substrates, has been developed. The β-arylation products were obtained in excellent regio- and stereoselectivity. Moreover, novel and potent adenylyl cyclase inhibitors with the potential for treating neuropathic and inflammatory pain have been identified from the β-arylation products.
- Ye, Zhishi,Dai, Mingji,Brust, Tarsis F.,Watts, Val J.
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supporting information
p. 892 - 895
(2015/03/30)
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- Palladium-catalyzed direct amination of allylic alcohols at room temperature
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A palladium complex ligated with Xantphos has beenz identified as an efficient catalyst for the catalytic amination of allylic alcohols, which allows the direct amination of allylic alcohols with amines to proceed at room temperature in the absence of additives. The method is compatible with a variety of functional groups and can be used to prepare a wide range of linear allylic amines in good to excellent yields with high stereoselectivities.
- Wang, Maorong,Xie, Yinjun,Li, Jiawen,Huang, Hanmin
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supporting information
p. 2781 - 2786
(2015/01/08)
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- Stereoselective synthesis of (z)-1-benzhydryl-4-cinnamylpiperazines via the wittig reaction
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A synthetic method of producing (E)- and (Z)-isomers of 1-benzhydryl-4-cinnamylpiperazines in a specific ratio from corresponding benzhydrylpiperazine is described. Of the three compounds synthesized (5a-c), the ratio of E/Z-isomers remained around 15:85. The key intermediates, 1-benzhydryl-4-(2,2-dimethoxyethyl)piperazine derivatives (3a-c), were prepared by nucleophilic substitution reaction of benzhydrylpiperazines (2a-c) with chloroacetaldehyde dimethylacetal in good yield (up to 88%). Hydrolysis of 3a-c gave the corresponding aldehydes 4a-c, which when subjected to the Wittig reaction followed by column purification to afford 1a-c (E-isomers) and 6a-c (Z-isomers) in pure form. The isolated compounds were characterized by NMR and mass spectral analysis. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.] Copyright
- Shivprakash,Reddy, G. Chandrasekara
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p. 600 - 609
(2014/01/17)
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- Palladium catalyzed intermolecular hydroamination of 1-substituted allenes: An atom-economical method for the synthesis of N-allylamines
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The palladium complex [(3IPtBu)Pd(allyl)]OTf previously displayed excellent catalytic activity for the hydroamination of 1,1-dimethylallene with anilines, selectively producing the branched substituted allylamine product (kinetic product) in high conversion. In the current report, the scope of this hydroamination reaction has been expanded to include both alkyl amines and anilines in combination with an array of seven alkyl and aryl allenes. For the majority of amines investigated, the hydroamination of 1,1-dimethylallene, cyclohexylallene, benzylallene, and select aryl allenes with alkyl amines gave the branched substituted allylamine product in nearly quantitative conversion at ambient temperature in less than 1 hour. In contrast, anilines displayed a more limited reaction scope and yielded the linear hydroamination product (thermodynamic product) with all allenes other than 1,1-dimethylallene. Both branched and linear products could be formed selectively in the hydroamination of p-fluorophenylallene with alkyl amines through careful control of [(3IPtBu)Pd(allyl)]OTf catalyst loading and reaction duration. Overall, the branched allylamines produced are useful synthetic intermediates due to their available unsaturated vinyl group, while the linear allylamine products are chemically similar to a class of known pharmaceuticals. The Royal Society of Chemistry 2013.
- Beck, John F.,Samblanet, Danielle C.,Schmidt, Joseph A. R.
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p. 20708 - 20718
(2013/11/06)
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- Palladium-catalyzed vinylation of aminals with simple alkenes: A new strategy to construct allylamines
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A novel, highly selective palladium-catalyzed vinylation reaction for the direct synthesis of allylic amines from styrenes and aminals has been established. The utility of this method was also demonstrated by the rapid synthesis of cinnarizine from aldehydes, amines, and simple alkenes in one-pot manner. Mechanistic studies suggested that the reaction proceeds through a valuable cyclometalated Pd(II) complex generated by the oxidative addition of aminal to a Pd(0) species.
- Xie, Yinjun,Hu, Jianhua,Wang, Yanyu,Xia, Chungu,Huang, Hanmin
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supporting information
p. 20613 - 20616
(2013/02/23)
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- Solid Pharmaceutical Preparations Containing Copolymers Based On Polyethers Combined With Poorly Water-Soluble Polymers
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The invention relates to dosage forms which contain preparations of poorly water-soluble substances in a polymer matrix of polyether copolymers, said polyether copolymers being obtained by the radically initiated polymerization of a mixture from 30 to 80% by weight of N-vinyl lactam, 10 to 50% by weight of vinyl acetate and 10 to 50% by weight of a polyether, and at least one poorly water-soluble polymer, the poorly water-soluble substance being present in the polymer matrix as an amorphous substance.
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- Dry gel composition
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There is provided a dry gel composition comprising 40% by weight or below of a medicine which can be orally administered, 3% by weight or above of a gelling agent and 5% by weight or below of a binder, which composition is capable of forming a gruel-like aqueous gel composition upon mixing with 2 to 15 parts by weight of water per part by weight of the composition at a temperature of 40° C. or below. The gelling agent usable herein is, for example, pregelatinized starch having a concentration of 50% by weight or above. The medicine which can be orally administered is, for example, cinnarizine. Upon mixing with a predetermined quantity of water, the dry gel composition forms a homogeneous aqueous gel composition having a viscosity of about 100 to 500 cp, which is preferably thixotropic. Even aged people having a weak swallowing function can easily swallow the aqueous gel composition, without causing improper sucking into their tracheas. Thus, the dry gel composition of the present invention is very useful in their medical care. The aqueous gel composition can be prepared in a short time by an extremely simple operation at the time of use.
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- Phenoxyalkylcarboxylic acid salt of 1-cinnamyl-4-diphenylmethyl piperazine, method of preparation and antihypercholesteremic
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Salts of 1-cinnamyl-4-diphenylmethyl piperazine and their method of preparation of compositions thereof is described. These compounds have antihypercholesteremic activity.
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