56775-88-3

Usage

Uses

Used in Pharmaceutical Industry:
Zimeldine Dihydrochloride is used as an antidepressant for treating depression and modulating serotonin levels in the brain. It is particularly effective in modulating nociception and inducing hyperglycemia in vivo, making it a promising candidate for various applications in the pharmaceutical industry.

Originator

Normud ,Astra ,W. Germany ,1981

Manufacturing Process

To 9 g of n-butyl lithium in 200 ml of dry ether 20 g of 3-bromopyridine is added as quickly as possible at -40°C without raising the temperature. When the addition is finished the mixture is stirred for another 30 minutes. Thereafter 32.5 g of ω-dimethylamino-4'-bromopropiophenone is added in such a way that the temperature does not exceed -40°C. The cooling is discontinued and the mixture is stirred during the night whereupon the reaction mixture is poured onto ice and diluted HCl, which is washed with ether and is extracted with 20 ml of methylene dichloride. The methylene dichloride is dried and evaporated. The crystals are dissolved in water, which then is made alkaline with a solution of Na 2 CO 3 , is extracted with ether, dried, and evaporated and recrystallized from isopropyl ether, petroleum ether 1:1. Yield 4 g of 1-(4'-bromophenyl)-3-(N,N-dimethylamino)-1-(3''-pyridyl)- propanol. Melting point 67°C.3.6 g of 1-(4'-bromophenyl)-3-(N,N-dimethylamino)-1-(3''-pyridyl)-propanol are dissolved in 15 ml of 85% H 2 SO 4 and heated at 170°C for 10 minutes. The reaction mixture is poured into 60 ml of water, which is then made alkaline with 10 N NaOH, and is extracted with 2 x 25 ml of ether. The ether is dried with Na 2 SO 4 , treated with active carbon and evaporated. The residue is dissolved in 25 ml of acetone and an equivalent amount of oxalic acid dissolved in 25 ml of acetone is added. The precipitate obtained is filtered off, is dissolved in 50 ml of water, which is made alkaline with 10 N NaOH and is extracted with 2 x 25 ml of ether. The ether solution is dried with Na 2 SO 4 and is filtered, whereupon dry HCl is introduced. The precipitate obtained is filtered off. Yield 1.2 g of 3-(4'-bromophenyl)-3-(3''-pyridyl)- dimethylallylamine dihydrochloride (H 102/09). Melting point 193°C.

Therapeutic Function

Antidepressant

World Health Organization (WHO)

Zimeldine, an inhibitor of serotonin uptake, was introduced in 1982 for the treatment of depressive illness. By 1983 its use had been associated with incidences of hypersensitivity of varying severity and serious neurological side effects including the Guillain-Barr, syndrome. Following discussions with the National Board of Health and Welfare of Sweden, the major manufacturer decided to withdraw the drug on a worldwide basis.

Biological Activity

5-HT re-uptake inhibitor; selective over noradrenalin and dopamine uptake (IC 50 values are 0.33, 8.2 and 12 μ M respectively). Modulates nociception and induces hyperglycemia in vivo , and is an orally active antidepressant.

InChI:InChI=1/C16H17BrN2.2ClH/c1-19(2)11-9-16(14-4-3-10-18-12-14)13-5-7-15(17)8-6-13;;/h3-10,12H,11H2,1-2H3;2*1H/b16-9-;;

Upstream product

• 50-00-0 formaldehyd 
• 60324-59-6 Nomelidine 
• 14548-45-9 (4-bromophenyl)-pyridin-3-yl-methanone 
• 205582-30-5 [(dimethylamino)ethyl]triphenylphosphonium bromide 
• 506-59-2 N,N-dimethylammonium chloride 
• 83049-64-3 (E)-3-(4-Bromophenyl)-3-(3-pyridyl)propenal 
• 77470-68-9 (Z)-3-(4-bromophenyl)-3-(3-pyridyl)-2-propenal 
• 41910-98-9 1-(4-bromophenyl)-3-(dimethylamino)-1-(3-pyridyl)propan-1-ol 
• 77744-36-6 (Z)-3-Acetoxy-1-(4-bromophenyl)-1-(3-pyridyl)propene 
• 124-40-3 dimethyl amine 
• 77744-18-4 Acetic acid 1-(4-bromo-phenyl)-1-pyridin-3-yl-allyl ester 
• 70263-44-4 (Z)-3-(4-bromophenyl)-3-(3-pyridyl) allyl chloride 
• 2138-34-3 1-(4-bromo-phenyl)-3-dimethylamino-propan-1-one 
• 10400-19-8 3-pyridinecarbonyl chloride 

Downstream Products

• 79567-81-0 (Z)-3-[4-(trimethylsilyl)phenyl]-N,N-dimethyl-3-(3-pyridyl)allylamine 
• 79567-83-2 (Z)-3-[4-(methylthio)phenyl]-N,N-dimethyl-3-(3-pyridyl)allylamine 
• 79567-85-4 (Z)-3-(4-cyanophenyl)-N,N-dimethyl-3-(3-pyridyl)allylamine 
• 79567-79-6 (Z)-3-(4-methylhenyl)-N,N-dimethyl-3-(3-pyridyl)allylamine 
• 77470-68-9 (Z)-3-(4-bromophenyl)-3-(3-pyridyl)-2-propenal 
• 58574-55-3 (Z)-1-(3-Pyridyl)-1-phenyl-3-dimethylamino-propen 
• 79362-30-4 I-ZIM 
• 82103-82-0 (Z)-1-(4-bromophenyl)-3-pthalimido-1-(3-pyridyl)propene 
• 60324-67-6 (Z)-3-(4-bromophenyl)-3-(3-pyridyl)allylamine 
• 60324-59-6 Nomelidine 

Relevant academic research and scientific papers

(E)-,(Z)-parallel preparative methods for stereodefined β,β-diaryl- and α,β-diaryl-α,β-unsaturated esters: Application to the stereocomplementary concise synthesis of zimelidine

Parallel and practical methods for the preparation of both (E)- and (Z)-β-aryl1-β-aryl2-α,β-unsaturated esters 1 and (E)- and (Z)-α-aryl1-β-aryl2-α,β-unsaturated esters 2 are described. These methods involve accessible, robust, stereocomplementary N-methylimidazole (NMI)-mediated enol tosylations (14 examples, 70-99 % yield), as well as stereoretentive Suzuki-Miyaura cross-couplings (36 examples, 64-99 % yield). The highlighted feature of the present protocol is the use of parallel and stereocomplementary approaches to obtain highly (E)- and (Z)-pure products 1 and 2 by utilizing sequential enol tosylations and cross-coupling reactions. An expeditious and parallel synthesis of (E)- and (Z)-zimelidine (3), which is a highly representative selective serotonin reuptake inhibitor (SSRI), was performed by utilizing the present methods.

Stereoconservative Reductive Methyl- and Dimethylamination of Isomeric 3,3-Diarylpropenals. Synthetic and Mechanistic Studies on Control of the Stereochemistry

The tertiary allylic amine zimeldine (1Z) and the secondary amine 2Z have been prepared by reductive aminations of (Z)-3-(4-bromophenyl)-3-(3-pyridyl)propenal (3Z) with sodium cyanoborohydride in the presence of dimethylammonium and methylammonium chlorid

Synthesis of pyridylallylamines related to zimelidine and their inhibition of neuronal monoamine uptake

Analogues of the antidepressant agent zimelidine [6, (Z)-3-(4-bromophenyl)-N,N-dimethyl-3-(3-pyridyl)allylamine], a selective inhibitor of neuronal 5-hydroxytryptamine reuptake, were synthesized by several routes with the aim of obtaining compounds having a cis configuration (with respect to pyridyl and allylamine). Two methods utilized suitably substituted benzoylpyridines as starting materials. In two other routes, the bromine in 6 was either directly displaced (CN) or converted via the corresponding lithio derivative to H, Cl, I, Me, SiMe3. The configurations were determined by UV, 1H NMR and lanthanide-induced shifts in 1H NMR. The compounds were evaluated as uptake inhibitors by measuring the accumulation of [3H]noradrenaline and 5-hydroxyl[14C]tryptamine in mouse brain slices (in vitro and in vivo). Para substitution favored 5-hydroxytryptamine activity and ortho substitution favored NA activity in the cis series. The in vitro effect on 5-hydroxytryptamine was rather insensitive to variations in the para substituent, whereas pronounced effects in vivo were observed only with Cl, Br (6), and I.

Synthesis of 3-Aryl-3-pyridylallylamines Related to Zimelidine via Palladium-Catalyzed Amination

Reaction of aryl pyridyl ketones 1 with vinylmagnesium bromide followed by acetylation of the products 2 with acetic anhydride/Et3N and with 4-(dimethylamino)pyridine (DMAP) as a catalyst gave acetates 3 in high yields.Treatment of acetates 3 with dimethylamine in the presence of a palladium catalyst produced a mixture of E and Z isomers of 3-aryl-3-pyridylallylamines 4.