L-Amino-4-methylpiperazine

Formylrifamycin SV is treated with l-amino-4-methylpiperazine in tetrahydrofuran to give rifampin. 

A semi-synthetic antibiotic, rifampicin (rifampin) (19), was prepared from compound 5, obtained by the formylation of the C-3 position of rifamycin SV (3), followed by the reaction of 5 with l-amino-4-methylpiperazine in tetrahydrofuran (Fig. 2) [69]. 

Fig. 6. Chemical structures of the rifamycin nucleus and of rifampicin (/ = l-amino-4-methylpiperazine)...

Rifamycins B and O can be transformed into rifamycin S, and rifamycin SV is obtained by treating rifamycin S with ascorbic acid [5]. Formylation of the C3 position of rifamycin SV, followed by the combination of this alkaloid with l-amino-4-methylpiperazine, gave the semisynthetic ansamy-cin rifampicin. Rifampicin was prepared in 1966, and it is one of the most effective antituberculosis agents at present. The chemical structures of the rifamycins were finally clarified in 1973-1974 [6,7]. 

Hydrazones (140) derived from 4-amino-1-methylpiperazine can be reduced by sodium borohydride to l-arylmethylamino-4-methylpiperazine (141) (1708). 1-Methylpiperazine vacuum distilled with formalin gave bis-(l-methylpiperazinyl)-methane, which refluxed with methyl iodide in methanol formed 1,4-dimethyl-piperazine dimethiodide (1709). 1-Methylpiperazine with carbon disulfide in ethanol produced l-dithiocarboxy-4-methylpiperazine, which was reduced by lithium aluminum hydride to 1,4-dimethylpiperazine (1709). 

Reaction of potassium 9-fluoro-3-methyl-10-(4-methylpiperazin-l-yl)-2,3-dihydro-7H-pyrido[l,2,3-de][l,4]benzoxazine-6-carboxylate with 2-[3-(2,4-dichlorophenoxy)propyl]-3-[(2-chloroacetyl)amino]quinoxa-lin-4(3H)-one gave ester derivative of 2,3-dihydro-7H-pyrido[l,2,3-de] [l,4]benzoxazine-6-carboxylic acid. 3-Amino-2-(aryloxymethyl)quinox-alin-4(3H)-ones were N-acylated with 9-fluoro-3-methyl-10-(4-methyl-piperazin-l-yl)-2,3-dihydro-7H-pyrido[l,2,3-de][l,4]benzoxazine-6-car-boxylic acid chloride in the presence of K2C03 in boiling benzene for 6 h (07MI71). 

Chemical Name l- [5-(4-Chlorophenyl)furan-2-ylmethylene]amino -3-[4-(4-methylpiperazin-l-yl)butyl]imidazolidine-2,4-dione dihydrochloride... 

To the (2S)-2-benzyl-3-(l-methylpiperatin-4-ylsulfonyl)propionic acid (1.0 g, 3.064 mmol), the H-L-(4-thiazolyl)Ala amide of (2S,3R,4S)-2-amino-l-cyclohexyl-3,4-dihydroxy-6-methylheptane (1.11 g, 2.792 mmol), and 1-hydroxybenzotriazole (1.022 g, 7.563 mmol) in dimethylformamide (20 ml) was added N-methylmorpholine (0.35 ml, 3.2 mmol). The mixture was cooled to -23°C and treated with l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.760 g, 3.96 mmol). After 2 h at -23°C and 14 h at room temperature, the reaction was poured into saturated NaHC03 solution (100 ml) and extracted into ethyl acetate (2x50 ml) which was washed with water (2x50 ml) and brine (50 ml) and then was dried over Na2S04 and evaporated to afford 1.94 g. Recrystallization from ethanol (15 ml)/hexane (90 ml) afforded 1.55g (79%) of (2S)-2-benzyl-3-(l-methylpiperazin-4-ylsulfonyl)propionyl-(L)-(4-thiazolyl)Ala-amide of (2S,3R,4S)-2-amino-l-cyclohexyl-3,4-dihydroxy-6-methylheptane as a white solid, melting point 169°-170°C. 

Methylpiperazine (203, Q = Me) gave l-(l-amino-2-nitrovinyl)-4-methylpiper-azine (204) [Me0C(NH2)=CHN02, EtOH, reflux, 90 min 84% or (MeS)2C=CHN02, NH31, EtOH, reflux, 1 h 64%].704... 

The furanopyridine l-754,394, A-[2(/ )-hydroxy- l(S)-indanyl]-5-[2(5 )-((l,l-dimethylethyl)amino)carbonyl]-4-[(furo[2,3-6] pyridin-5-yl)methylpiperazin-l-yl]-4(5)-hydroxy-2(/ )-(phenylmethyl)pentenamide, is also a potent mechanism-based inactivator of human liver microsomal CYP3A4 but is less selective, as it... 

Reaction of 9,10-difluoro-7-oxo-2,3-dihydro-7//-pyrido[l, 2,3- e]-1,4-ben-zothiazine-6-carboxylic acid and its ethyl ester with B(OH)3 in AC2O in the presence of ZnCl2 afforded 6-[(diacetoxyboryl)oxycarbonyl] derivative 323 (R = OAc)], which was reacted with primary and cyclic amines to give 10-amino-9-fluoro-7-carboxylic acid derivatives 324 (97MI41, 98MI30). 6-[(Difluoroboryl)oxycarbonyl derivative 323 (R = F) was obtained from ethyl 9,10-difluoro-7-oxo-2,3-dihydro-7//-pyrido[l,2,3- fe]-l,4-benzothiazine-6-carboxylate with BF3-THF complex. Reaction of 323 (R = F) and 1-methylpiperazine in DMF at 50-60 °C and subsequent acidic hydrolysis afforded 7 (97MI1). 

Crude 4-amino-2-methyl-10H-thieno[2,3-b][l,5]benzodiazepine, hydrochloride (4.3 g) was refluxed in a mixture of N-methylpiperazine (15 mL), dimethylsulfoxide (20 mL) and toluene (20 mL) under a nitrogen atmosphere for 20 hours. The mixture was cooled to ca. 50°C, water (20 mL) added, and the product allowed to crystallise at 5°C over night. The product was filtered and crystallised from acetonitrile (30 mL) to give the title compound (1.65 g) m.p. 195°C. The structure of the compound was confirmed spectroscopically. 

Producing of (2S)-2-benzyl-3-(l-methylpiperazin-4-ylsulfonyl)propionyl-(L)-(4-thiazolyl)Ala-amide of (2S,3R,4S)-2-amino-l-cyclohexyl-3,4-dihydroxy-6-methylheptane ... 

Reduction of A7-nitropyrazole into A -aminopyrazole has been succesfully achieved by lithium aluminum hydride <92AQ724>. Reactions of l-nitro-3,5-dimethyl-4-halopyrazoles (195) with dbu and dbn affords derivatives (196) <94X865>. Reaction of 5-chloro-2-nitroindazole with amines affords 3-amino-5-chloroindazoles <85Phaio5>, while 2,5-dinitroindazole on treatment with A -methylpiperazine affords 3,5-dinitroindazole and 3-(7V-methylpiperazino)-5-nitroindazole <94PHA319>. 

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