Process Development of the Synthetic Route to (<i>R</i>)-6-Amino-1-ethyl-4-methylhexahydro-1,4-diazepine

Hirokawa, Yoshimi; Horikawa, Tamaki; Noguchi, Hideto; Yamamoto, K.; Kato, Shiro

doi:10.1021/op010068e

Cited by 23 publications

(15 citation statements)

References 22 publications

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“…11 g (quantitative yield) of (R)-8a as a pale yellow oil, which was used in the next step without further purification. This compound was identical to the sample obtained in an alternative preparation, 47) on the basis of 1 H-NMR, MS, and the retention time of chiral HPLC comparison.…”

Section: Gave N-[1-(2-methoxyethyl)-4-methylhexa-mentioning

confidence: 75%

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

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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...

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Section: Gave N-[1-(2-methoxyethyl)-4-methylhexa-mentioning

confidence: 75%

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

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“…104 The key for allowing the reduction to take place was the high stability of amine boranes in aqueous medium.…”

Section: Via Amine Boranesmentioning

confidence: 99%

Boron Reagents in Process Chemistry: Excellent Tools for Selective Reductions

2006

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“…A synthetic procedure has been reported for (R)-6-amino-1-ethyl-4-methylperhydro-1,4-diazepine, which is the amine moiety of AS-8112, a novel and potent dopamine (D 2 and D 3 ) and 5-HT H 3 receptor antagonist, commonly used as an antiemetic agent. 12 It involved several steps, required a long reaction time, and afforded extremely low yields of the desired product. Another paper dealt with a solid-phase synthesis of the hitherto unreported 3,6-disubstituted 1Htetrahydro-1,4-diazepine-2,5-dione by a microwaveassisted Miller cyclization.…”

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confidence: 99%

A New, Easy Access to the 6-Aminoperhydro-1,4-diazepine Scaffold under Ultrasound and Microwave Irradiation

Füzerová¹,

Upadhyaya²,

Garella³

et al. 2008

Synthesis

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A novel, efficient, and rapid synthesis of the 6-aminoperhydro-1,4-diazepine scaffold is reported. It was promoted by microwave or sequential ultrasound/microwave irradiation under solvent-free conditions or in solution. Protected ethylenediamine derivatives and N-Boc-serinol dimesylate underwent rapid cyclization to give 6-aminoperhydro-1,4-diazepine derivatives in excellent yields and with high selectivity, whereas the same reaction failed or gave negligible yields under conventional heating. Cesium or potassium ions catalyzed the ring closure by coordinating the sulfonamide groups. All relevant work reported to date in the literature mostly concern about the syntheses of either 1H-tetrahydro-1,4-diazepine-2,5-dione or substituted 1,4-benzodiazepines, while the few published procedures for the preparation of 6-aminoperhydro-1,4-diazepines involved several steps, required long reaction times and afforded low yields. By the present method, access to 6-aminoperhydro-1,4-diazepines becomes much easier and faster.

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Process Development of the Synthetic Route to (R)-6-Amino-1-ethyl-4-methylhexahydro-1,4-diazepine

Cited by 23 publications

References 22 publications

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.

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.

Boron Reagents in Process Chemistry: Excellent Tools for Selective Reductions

A New, Easy Access to the 6-Aminoperhydro-1,4-diazepine Scaffold under Ultrasound and Microwave Irradiation

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