Abstnact-A facile synthesis of 6-amino-I-benzyl4methyland 6-amino-1.4dimethylhexahydro-1H-l+diazepines (16a and 16b) which have sewed as the amine part of the new and novel benzamides (3 and 4) with a potent serotonin 3 receptor antagonistic activity is reported.The formation of 1.4-diazepine ring system was achieved by the reaction of tris(hydroxymethyl)nitromethane (11) with NP-disubstituted ethylenediamines (12a a n d 12b).T h e dehydroxymethylation of the resultant 6-hydroxymethyl-6-nitro-1.4-diazepines (13a and 13b) and successive reduction gave the target compounds (16a and l a ) , in approximately 15-30% overall yield.During recent years, a number of potent and selective serotonin 3 (SIT3) receptor antagonists have been reported,' and granisetron (1) and ondansetron (2) are used clinically for the control of the emesis induced by cancer chemotherapeutic agents such as cisplatin and cyclophosphamide.2IHT3 antagonists are being studied in man for the treatment of gastrointestinal motility disorders, migraine, schizophrenia, and anxiety.3On the basis of random screening, we found that the structurally novel benzamides (3 and 4) containing a 1.4-diazepine ring in an amine moiety showed a potent 5-HT3 receptor antagonistic activity.4This paper describes a facile synthesis of 6-amino-I-benzyl4methyland 6-amino-1.4-
An efficient and practical method for large scale synthesis of (R)-6-benzyloxycarbonylamino-1-methyl-4-(3-methylbenzyl)hexahydro-1, 4-diazepine (R-3), which is a key intermediate in the synthesis of DAT-582, a potent and selective serotonin-3 receptor antagonist, is described. The precursor of R-3, the (S)-2, 3-diaminopropylaminoacetate S-5, was obtained from the chiral triaminopropane derivative R-19. Nucleophilic reaction of the chiral mesylate R-11 with 3-methylbenzylamine gave the racemic 2, 3-diaminopropylaminoacetate (±)-5 via the achiral azetidinium cation 12, while the reaction of the N-protected mesylate R-14 produced the desired triamine S-15 but in poor yield.However, reaction of the N-protected mesylate S-18 with a large excess of methylamine proceeded smoothly to afford R-19 in good yield. S-5 was converted into R-3 with >99% enantiomeric excess using an intramolecular reductive cyclization method.
New kinds of cast and wrought (C & W) Ni-Co base superalloys (TMW alloys) have been developed based on the innovative concept of combining two kinds of γ-γ′ two-phase alloys, Ni-base and Co-base alloys, for the applications of turbine disks and high-pressure compressor blades. The results based on testing 20 kg ingots indicate that TMW alloys show excellent high temperature strength and formability, may provide 50°C temperature advantage in 630 MPa/100 h creep performance over C & W alloy U720Li. In this paper, we report our new results on the full-scale pancakes manufactured through the C & W process for real components. The results indicate that TMW alloys had good process-ability in the ingot making and forging into disk pancakes. Pancake disks with fine grain size of about 10 μm were successfully obtained for TMW alloys. TMW alloys provide 58°C to 76°C temperature advantages in 0.2% creep strain life under the 630 MPa condition, over alloy U720Li.
Abstract Five variants (methods A—E) of a synthetic route to 6‐amino‐1‐benzyl‐4‐methylhexahydro‐1 H ‐1,4‐diazepine (3b) using N ‐benzyl‐ N' ‐methylethylenediamine (8a) are described. The reaction of 8a with 1‐benzenesulfonyl‐2‐bromomethylaziridine (7) , 2‐phenyl‐4‐( p ‐toluenesulfonyloxymethyl)oxazoline (13) , and β, β‐dibromoisobutyric acid (15) resulted in the direct cyclization to give the precursor of 3b , 6‐substituted 1,4‐diazepine derivatives 9, 14 , and 16 , respectively (methods A—C). These compounds were transformed into the desired 3b , The preparation of 1,4‐diazepine ring from methyl 2‐ tert ‐butoxycarbonyl‐aminopropenate (18) was alternatively achieved by the intramolecular amidation of the intermediate 19a (method D) or reductive cyclization of the aminoaldehyde 23a (method E). Method E was found to efficiently produce the 6‐amino‐1,4‐diazepine 3b.
Swern oxidation of 2-substituted amino-1, 3-propanediols 20a-d, 38, 41, and 42 smoothly proceeded to give the oxidative dehydration products, 2-substituted aminopropenals 17a-d, 43, 45 and 46, respectively. Reaction of the intriguing 2- substituted aminopropenals 17a-d with N-benzyl-N'-methyl- or N, N'-dimethylethylenediamine(12o or 12p) followed by NaBH4 reduction of the iminium salt intermediates afforded the corresponding 6-substituted aminohexahydro-1H-1, 4-diazepines 16 and 24-28. The similar ring formation of 1H-indazole derivatives 43 and 45 employing 12o directly furnished the 1H-dindazole-3-carboxamide 4, which showed a potent serotonin-3(5-HT3) receptor antagonistic activity.
A b s t r a c t -2-Indolyl-1.4-benzodiazepin-5-ones(3) have been efficiently synthesized from Boc-a-amino acids (4).3-hydroxyanthranilic acid (8).and indole; the key step is a Mannich type cyclization accompanied with introduction of indole.Tilivalline ( l a ) , a metabolite isolated from Klebsiella pneumoniae var.~x y t o c a .~ belongs to a group of pyrrolo[2,1-~l[l,4]benzodiazepines. a characteristic skeleton of anthramycin-type antibiotics.We have already accomplished a completely stereoselective, efficient, and convenient synthesis of tilivalline ( l a ) utilizing a new Mannich type cyclization as a key step.3Application of the analogous synthetic methodology culminated in the synthesis of Oand 2-substituted tilivallines ( l b -e ) and 11-substituted-5H-pyrro10[2,1-clI1,4lbenzodiazepin-5ones ( z ) .~ Since the anthramycin-type antibiotics are known to exhibit interesting antitumoractivity,4 tilivalline and its analogs will also be expected to have analogous biological activity.To aim at both the extension of the scope of the new Mannich type cyclization and the studies on the structures and biological activities relationship, we now extended the method to the synthesis of 2-indolyl-1.4-benzodiazepin-5-ones(3) lacking the C-ring of tilivalline.-
