Pyrazolo diazepines

In an extension of previous work on conjugated enamine carbonyl derivatives, reaction of the pyrazolone 91 with IV.lV-disubstituted hydrazines on heating in an alcohol solvent afforded the hexahydropyrazolo[4,3-Michael-type addition of the alcohol to a pre-formed pyrazolo-diazepine, was excluded <06T8126>. 

Pyrazoles can be prepared by ring opening reactions of fused systems already containing the pyrazole nucleus. Thus several [5.5], [5.6] and [5.7] fused heterocycles have been opened to substituted pyrazoles, usually in basic medium. In general, the method has little preparative interest since another pyrazole derivative has usually been used to build the ring-fused system. However, due to the unexpected structures obtained, two publications are worthy of notice. 6//-Cyclopropa[5a,6a]pyrazolo[l,5-a]pyrimidine (638) was readily obtained from the corresponding pyrazolopyrimidine by the action of diazomethane at room temperature (Scheme 59) (81H(15)265). When (638) was treated with potassium hydroxide, the pyrazole (640) was formed, probably via the diazepine (639). 

Pyrazolo[3,4-d][l,2]diazepines synthesis, 7, 597 Pyrazolop, 4- 6][ 1,4]diazepines synthesis, 5, 272 Pyrazolo[l, 4]diazepinones as anticonvulsant, 1, 170 Pyrazolo[2,3-e]diazepinones synthesis, 5, 272 1 H-Pyrazolo[l,5-6]imidazoles synthesis, 6, 992 Pyrazolo[2,3-a]imidazoles biological activity, 6, 1024 Pyrazolo[2,3-c]imidazoles reactions, 6, 1041 synthesis, 6, 1047 Pyrazolo[2,3-imidazoles synthesis, 6, 991 Pyrazolo[3,2- njisoquinolines synthesis, 5, 339 Pyrazolop, 4-c]isoquinolines synthesis, 5, 273 Pyrazolonaphthyri dines synthesis, 5, 339 Pyrazolone, diazophotolysis, 5, 252 Pyrazolone, 4,4-dihalo-rearrangements, 5, 250 Pyrazolone, ethoxy-hydrazinolysis, 5, 253 Pyrazolone, 4-halo-... 

The bis(imino-l5-phosphane) 1 reacts with a molar equivalent of an isocyanate in toluene at 20 C for 16 hours to give pyrazolo[3,4-<7]-l,3-diazepines 2. No further details were reported.167"b... 

Single crystal X-ray analysis definitively assigned different structures to products of oxidative cyclization of 58 as pyrazolo 1,2-/z][ l,2]diazepin-5(3//)-onc 59 <1984ZNB187> and pyrazolo[l,2-tf]pyrazol-l(5//)-onc 60 <1997ZNB994>, depending on the character of the R2 substituent. 

Pyrazolo[3,4-c]diazepin-2-ylidene)malonate (506, R = Et, R1 - Ph, X = N, Y = NMe) afforded pyrazoloazepine-2-acetate (1658) via 1657 under similar conditions (83USP4401597). 

Stanovnik and co-workers (100,101) systematically investigated the cycloaddition reactions of diazoalkanes with unsaturated nitrogen heterocycles, such as azolo-[l,5-fl]pyridines, pyridazin-3(2/7)-ones, and [fo]-fused azolo- and azinopyridazines. The Stanovnik group have studied the further transformations of the products and reviews of this chemistry are available. In a typical example, the reaction of 6-chlorotetrazolo[l,5-/7]pyridazine (37) with 2-diazopropane yields the NH,NH-dihy-dro-pyrazolo[4,3-(i]tetrazolo[l,5-/7]pyridazine 38 (102) (Scheme 8.11). The latter substrate reacts with acetone to produce an azomethine imine 39 that thermally rearranges to give the fused dihydro-1,2-diazepine 40. The azomethine imine obtained with glucose can be trapped with methyl acrylate to furnish the C-nucleoside 41 (103). 

Pyrazolo[l,5-fl]pyrimidine derivative 222, when treated with water, partially changes into 223. This reaction is assumed to proceed via attack of base at C-7 (81CPB1548 81JHC163). The C-6=C-7 double bond in 222 adds a variety of electrophiles (81CPB1548 81JHC163 83H(22)1913). Thus, treatment of 222 with acetic acid and water at 70°C affords 8-carbeth-oxy-3-substituted-7-methyl-6W-pyrazolo[ 1,5-a]-1,3-diazepin-6-one (224). Compound 222 reacts with phenylhydrazine to yield the pyrazolo[3,4-6,7]pyrazolo[l,5-n]pyrimidine derivative 225. The double bond in 222 also adds diazoalkanes to yield the pyrazolo[l,5-a]pyrimidine derivatives 226 (81CPB1548 81JHC163 83H(22)1913). 

In addition, another group of diazepines features replacement of the fused benzene ring with other heteroaromatic systems such as thieno or pyrazolo. Most compounds of this type are under investigation (e.g., brotizolam, a thienodiazepine). Because pharmacological effects are comparable with the BZDs, both groups of diazepines are considered BZDs from a clinical standpoint. 

Chemical Name l,3,8-Trimethyl-4-phenyl-4,8-dihydro-lH-pyrazolo[3,4-b] [l,4]diazepine-5,7-dione... 

Hydrazines react with 6-chloro-l-hexynylphosphonates 74 to provide the corresponding azaheterocyclic phosphonates 75 in good yields and purity <07TL3213>, while pyrazolo[4,3-c]diazepine carboxylates 77 were prepared by heating the to-enamine 76 with 1,2-dimethylhydrazine in methanol or ethanol at reflux <07H(71)657>. 

Dimethyl-7-oxo-l-phenyl-6,8-dihydro-7//-pyrazolo[3,4-Z>]-l,4-dia-zepine (426) gave a mixture of three products on reduction with LAH. After heating at reflux for 6 h in ether, the ratio of427 428 429 was 5 4 8 after 24 h only 429 was found. Reduction of 1-phenyl-3,5,7-trimethylpyra-zolo[3,4-Z>]-l,4-diazepine (430) under similar conditions led to the tetrahy-dro derivative 431 in 80% yield after 12 h. 7,8-Dihydro derivatives of 430 were isolated on catalytic hydrogenation and could be subsequently converted to 431 with LAH. ... 

Transformation of 5-aminopyrazoles into 5-(pyrrol-l-yl)pyrazoles has been achieved by means of 2,5-dimethoxytetrahydrofuran <94EJM233> which is the first step for the synthesis of pyrazolo-[4.3-/]pyrrolo[l,2-fl]diazepines, a new class of anxiolytics (see Section 3.01.13.2). Pyrazole 5-iminophosphoranes have been used by Wamhoff <94JOC3985> as starting materials for the synthesis of zwitterionic heteropolycyclic pyrazoles. 

Without doubt, the most useful pyrazole synthons for building fused heterocyclic systems are aminopyrazoles. For instance, l-methyl-4-cyano-5-aminopyrazole is the starting material for the synthesis of pyrazolo [4,3-/]pyrrolo[l,2-a][l,4]diazepines which possess anxiolytic activity <94EJM233) l-phenyl-3-methyl-4-nitroso-5-aminopyrazole has been used to prepare imidazo[4,5-... 

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