A new reagent for the selective, high-yield N-dealkylation of tertiary amines: improved syntheses of naltrexone and nalbuphine

Olofson, R. A.; MARTZ, J. T.; Senet, J.‐P. G.; Piteau, Marc; Malfroot, Thierry

doi:10.1021/jo00185a072

Cited by 363 publications

(231 citation statements)

References 1 publication

(2 reference statements)

Supporting

Mentioning

225

Contrasting

Unclassified

Order By: Relevance

“…As reported previously, 26 reaction of CADA with R-chloroethyl chloroformate (ACE-Cl) 29,30 under the same conditions, followed by cleavage of the intermediate carbamate in hot methanol, results in complete removal of the tail group. Hydrochloride salt 94-129 is isolated in high yield from reactions starting with several grams of CADA per batch.…”

Section: Resultsmentioning

confidence: 58%

Synthesis and Structure−Activity Relationship Studies of CD4 Down-Modulating Cyclotriazadisulfonamide (CADA) Analogues

et al. 2006

View full text Add to dashboard Cite

HIV attachment via the CD4 receptor is an important target for developing novel approaches to HIV chemotherapy. Cyclotriazadisulfonamide (CADA) inhibits HIV at submicromolar levels by specifically downmodulating cell-surface and intracellular CD4. An effective five-step synthesis of CADA in 30% overall yield is reported. This synthesis has also been modified to produce more than 50 analogues. Many tailgroup analogues have been made by removing the benzyl tail of CADA and replacing it with various alkyl, acyl, alkoxycarbonyl and aminocarbonyl substituents. A series of sidearm analogues, including two unsymmetrical compounds, have also been prepared by modifying the CADA synthesis, replacing the toluenesulfonyl sidearms with other sulfonyl groups. Testing 30 of these compounds in MT-4 cells shows a wide range of CD4 down-modulation potency, which correlates with ability to inhibit HIV-1. Threedimensional quantitative structure-activity relationship (3D-QSAR) models were constructed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. The X-ray crystal structures of four compounds, including CADA, show the same major conformation of the central 12-membered ring. The solid-state structure of CADA was energy minimized and used to generate the remaining 29 structures, which were similarly minimized and aligned to produce the 3D-QSAR models. Both models indicate that steric bulk of the tail group, and, to a lesser extent, the sidearms mainly determine CD4 down-modulation potency in this series of compounds.

show abstract

Section: Resultsmentioning

confidence: 58%

Synthesis and Structure−Activity Relationship Studies of CD4 Down-Modulating Cyclotriazadisulfonamide (CADA) Analogues

et al. 2006

View full text Add to dashboard Cite

show abstract

“…10c (pale yellow oil); 45,46) was applied. A solution of 6-acetylamino-1-benzyl-4-ethylhexahydro-1,4-diazepine 20) (11, 20.1 g, 73 mmol) and 1-chloroethyl chloroformate (12.6 g, 88 mmol) in 1,2-dichloroethane (200 ml) was heated to reflux for 1 h and cooled to room temperature.…”

Section: -Amino-1-isopropyl-4-methylhexahydro-14-diazepine (8c)mentioning

confidence: 99%

Synthesis and Structure-Activity Relationships of 4-Amino-5-chloro-N-(1,4-dialkylhexahydro-1,4-diazepin-6-yl)-2-methoxybenzamide Derivatives, Novel and Potent Serotonin 5-HT3 and Dopamine D2 Receptors Dual Antagonist.

Hirokawa

Harada

Yoshikawa

et al. 2002

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

A number of the 2-alkoxy-4-amino-5-chlorobenzamide family possessing a potent serotoninergic or dopaminergic activity has been reported.1) The potency and selectivity of the benzamides are dependent upon the structure of their basic moiety. The classic and parent benzamide of this family is metoclopramide, which is used clinically as a stimulant of upper gastrointestinal motility and an antiemetic agent. 2,3) Effects of metoclopramide are believed to be due to a combination of a relatively weak serotonin (5-hydroxytryptamine) 5-HT 3 (5-HT 3 ) and dopamine D 2 receptors antagonism and a serotonin 5-HT 4 receptor agonism. The weak affinity and lack of selectivity of metoclopramide for these receptors can be explained by the large number of permissible conformers due to the flexibility of the 2-(diethylamino)ethyl chain. To date, several benzamide derivatives with potent and selective activity for the dopamine D 2 , and the serotonin 5-HT 4 , and 5-HT 3 receptors have been reported. Thus, zacopride, 4) BRL 24682, 5) renzapride, 6) SC 53116, 7) and mosapride 8,9) with a rigid folded framework as the amine moiety showed good affinity for the 5-HT 3 and/or serotonin 5-HT 4 receptors. On the other hand, clebopride, a compound 1, and BRL 25594 having a benzyl group on the nitrogen atom in the amine moiety had high affinity for the dopamine D 2 and D 3 receptors. 10)Several potent and selective 5-HT 3 receptor antagonists such as ondansetron and granisetron have been used clinically to prevent nausea and emesis induced by cancer chemotherapeutic agents such as cisplatin and radiation treatment. [11][12][13][14] The nausea and emesis are common side effects that can cause patients to refuse subsequent chemotherapeutic sessions.15) On the other hand, dopamine D 2 receptor antagonists such as phenothiazines and butyrophenones are known to be effective in the treatment of emesis and vomiting induced by centrally acting emetic stimuli such as antiparkinsonian drugs, loperamide, apomorphine, and morphine. 16) In addition, the traditional antiemetic agent domperidone, a peripheral dopamine D 2 receptor antagonist, has been shown to be effective for the treatment of chronic upper gastrointestinal distress and the prevention of nausea and vomiting resulting from variety of causes. 17,18) However, dopamine D 2 receptor antagonists including domperidone are only minimally effective against chemotherapy-or radiationinduced nausea and vomiting.19) Previously, we reported that the structurally novel 4-amino-N-(1-benzyl-4-methylhexahydro-1,4-diazepin-6-yl)-5-chloro-2-methoxybenzamide (2x) and the corresponding 4-amino-5-chloro-2-ethoxybenzamide (2y) are potent and selective 5-HT 3 receptor antagonists. 20) In the course of our studies on the structure-activity relationships (SARs) of 2x, y, we found that replacement of the benzyl group in the hexahydro-1,4-diazepine ring by an alkyl group results in a significant increase in the dopamine D 2 receptor binding affinity along with a potent 5-HT 3 receptor antagonistic activity. 21) Thu...

show abstract

“…Isolation of compound 4 from the final reaction mixture was a surprise since such a reaction is rather atypical if not completely unprecedented. 11 The most plausible mechanism is outlined in Scheme 2. The desired product 3 is probably an intermediate which forms a quaternary salt with another equivalent for 2-chlorobenzimidazole 12 which decomposes to compound 4 after loss of CH 3 Cl.…”

Section: Resultsmentioning

confidence: 99%

“…A similar mechanism is widely used for N-demethylation using alkyl chloroformates (Scheme 3). 11 Use of simple alkyl chloroformates necessitates an additional carbamate deprotection step but this may be avoided by use of α-chloroethyl chloroformate.…”

Section: Resultsmentioning

confidence: 99%

Unusual synthesis of 1-(4-fluorobenzyl)-N-(1-(1-(4-fluorobenzyl)-6-isopropoxy-1H-benzo[d]imidazol-2-yl)piperidin-4-yl)-6-isopropoxy-1H-benzo[d]imidazol-2-amine

Jha¹

2005

Arkivoc

View full text Add to dashboard Cite

The title compound was formed while attempting the synthesis of 1-(4-fluorobenzyl)-6-isopropoxy-N-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-amine, a candidate antihistamine. Its formation involves an unusual mechanism where 1-(4-fluorobenzyl)-2-chloro-6-isopropoxy-1H-benzo[d]imidazole reacts with 1-methylpiperidinamine presumably through Ndemethylation followed by self-catalyzed N-diarylation. Apparently the formation of the desired 1-(4-fluorobenzyl)-6-isopropoxy-N-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-amine is rate limiting and, once formed, it reacts faster with 1-methylpiperidinamine to yield the title compound. A plausible explanation for this unusual behavior is proposed.

show abstract

A new reagent for the selective, high-yield N-dealkylation of tertiary amines: improved syntheses of naltrexone and nalbuphine

Cited by 363 publications

References 1 publication

Synthesis and Structure−Activity Relationship Studies of CD4 Down-Modulating Cyclotriazadisulfonamide (CADA) Analogues

Synthesis and Structure−Activity Relationship Studies of CD4 Down-Modulating Cyclotriazadisulfonamide (CADA) Analogues

Synthesis and Structure-Activity Relationships of 4-Amino-5-chloro-N-(1,4-dialkylhexahydro-1,4-diazepin-6-yl)-2-methoxybenzamide Derivatives, Novel and Potent Serotonin 5-HT3 and Dopamine D2 Receptors Dual Antagonist.

Unusual synthesis of 1-(4-fluorobenzyl)-N-(1-(1-(4-fluorobenzyl)-6-isopropoxy-1H-benzo[d]imidazol-2-yl)piperidin-4-yl)-6-isopropoxy-1H-benzo[d]imidazol-2-amine

Contact Info

Product

Resources

About