Racemization of (S)-(+)-10,11-dimethoxyaporphine and (S)-(+)-aporphine: efficient preparations of (R)-(−)-apomorphine and (R)-(−)-aporphine via a recycle process of resolution

Ni, Feng; Shang, Haitao; Yan, Ming-Le; Su, Jun-Quan

doi:10.1016/j.tetasy.2006.08.005

Cited by 6 publications

(5 citation statements)

References 44 publications

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“…Total synthesis of (±)-apomorphine hydrochloride (21) was achieved from aporphine core 22 by modifications of procedures reported in the literature. 24b, 30,31 Intermediate 22 was hydrolyzed using excess of LiOH in a mixture of EtOH/water (2:1) under microwave heating at 180 °C for 40 minutes, leading to the secondary amine 34 in 57% yield. 24b Compound 34 was N-alkylated by reaction with a 37% aqueous solution of formaldehyde in MeOH at room temperature for 30 minutes followed by reduction with NaBH 4 at room temperature for 1 hour, affording tertiary amine 35 in 89% yield.…”

Section: Syn Thesismentioning

confidence: 99%

“…The material obtained was dissolved in water and NaHCO 3 was added to the solution until pH 8. The residue produced was subjected to reaction with concentrated HCl in EtOH containing activated carbon under reflux for 1 hour to produce (±)-apomorphine hydrochloride (21) in 42% yield 31 (Scheme 11). Thus, the apomorphine prototype 21 was synthesized after 9 steps in an overall yield of 8%.…”

Section: Syn Thesismentioning

confidence: 99%

“…The residual solvent was evaporated under reduced pressure, affording the desired product 21; yield: 30.0 mg (42%); off-white solid; mp 243-246 °C. 31…”

Section: (±)-Apomorphine Hydrochloride (21) 31mentioning

confidence: 99%

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Convergent Total Synthesis of (±)-Apomorphine via Benzyne Chemistry: Insights into the Mechanisms Involved in the Key Step

et al. 2017

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Convergent total synthesis of (±)-apomorphine hydrochloride was accomplished by an approach that employs in the key step a sequence of transformations involving a [4+2]-cycloaddition reaction followed by a hydrogen migration. Through this sequence of transformations, the desired aporphine core was obtained regioselectively in 75% isolated yield. Since only one regioisomer was produced in the key step of the synthesis, a polar [4+2]-cycloaddition mechanism was proposed. Furthermore, NMR experiments and theoretical calculations were carried out to elucidate the hydrogen migration mechanism. (±)-Apomorphine hydrochloride was achieved after 9 steps in an overall yield of 8% involving benzyne chemistry.

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Section: Syn Thesismentioning

confidence: 99%

Section: Syn Thesismentioning

confidence: 99%

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Convergent Total Synthesis of (±)-Apomorphine via Benzyne Chemistry: Insights into the Mechanisms Involved in the Key Step

et al. 2017

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“…The optimization of yield for the formation of the compound 3 will be carried out and the synthesis of (R)-(-)-aporphine (1) will be completed from the intermediate 10 by well-known reactions of reduction 5 and resolution 6 shown in Scheme 2.…”

Section: Scheme 1 Retrosynthetic Analysis For (R)-(-)-aporphine (1)mentioning

confidence: 99%

Study toward the synthesis of (R)-(-)-aporphine

Perecim¹,

Raminelli

2013

Proceedings of the 15th Brazilian Meeting on Organic Synthesis Proceedings

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“…This synthetic route gave a racemic mixture of apomorphine analogs. Yet the racemic mixture has been shown to be less than half as potent as the ( R )-(−) isomer, since the ( S )-(+) enantiomer is known to be a dopamine (DA) receptor antagonist that blocks the ( R )-(−) isomer actions. − Thus, we separated two enantiomers via either chiral resolution with (+)-DBTA or chiral HPLC to generate enantiopure novel apomorphine analogs ( R )- 3 and ( S )- 3 , ( R )- 4 and ( S )- 4 , as well as ( R )- 5 and ( S )- 5 , for comparison in the SFSR studies.…”

mentioning

confidence: 99%

Structure–Functional–Selectivity Relationship Studies of Novel Apomorphine Analogs to Develop D1R/D2R Biased Ligands

Park

Urs

Zimmerman

et al. 2020

ACS Med. Chem. Lett.

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Loss of dopamine neurons is central to the manifestation of Parkinson’s disease motor symptoms. The dopamine precursor L-DOPA, the most commonly used therapeutic agent for Parkinson’s disease, can restore normal movement yet cause side-effects such as dyskinesias upon prolonged administration. Dopamine D1 and D2 receptors activate G-protein- and arrestin-dependent signaling pathways that regulate various dopamine-dependent functions including locomotion. Studies have shown that shifting the balance of dopamine receptor signaling toward the arrestin pathway can be beneficial for inducing normal movement, while reducing dyskinesias. However, simultaneous activation of both D1 and D2Rs is required for robust locomotor activity. Thus, it is desirable to develop ligands targeting both D1 and D2Rs and their functional selectivity. Here, we report structure–functional–selectivity relationship (SFSR) studies of novel apomorphine analogs to identify structural motifs responsible for biased activity at both D1 and D2Rs.

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Racemization of (S)-(+)-10,11-dimethoxyaporphine and (S)-(+)-aporphine: efficient preparations of (R)-(−)-apomorphine and (R)-(−)-aporphine via a recycle process of resolution

Cited by 6 publications

References 44 publications

Convergent Total Synthesis of (±)-Apomorphine via Benzyne Chemistry: Insights into the Mechanisms Involved in the Key Step

Convergent Total Synthesis of (±)-Apomorphine via Benzyne Chemistry: Insights into the Mechanisms Involved in the Key Step

Study toward the synthesis of (R)-(-)-aporphine

Structure–Functional–Selectivity Relationship Studies of Novel Apomorphine Analogs to Develop D1R/D2R Biased Ligands

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