1- Amino-4-methylpiperazine

Formylrifamycin SV is treated with 1-amino-4-methylpiperazine in tetrahydrofuran to give rifampin. 

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). 

Ester group of l-(ethoxycarbonylmethyl)-7-aryl-5-oxo-1,2,3,5-tetrahydro-pyrido[l,2,3-i/e]quinoxaline-6-carboxamides was hydrolyzed and the 1-carboxymethyl moiety was converted to an aminocarbonylmethyl group with 1-methylpiperazine (01MIP12). Bromo atom of l-(2-bromoacetyl) derivatives was substituted by different amines. An amino group in the side chain attached to the position 1 of 7-aryl-5-oxo-l,2,3,5-tetrahydropyr-ido[l,2,3-i/e]quinoxaline-6-carboxamides was acylated, and terc-butoxycarbonyl protecting group of amino group was eliminated. 

Yet another approach to these compounds consists of substituting the piperazine ring onto the preformed heterocyclic moiety. Ullman condensation of the substituted thiosalyciclic acid (40-1) with ort/zo-chloronitrobenzene results in the displacement of chlorine by thiophenoxide and the formation of the thioether (40-2). The nitro group in this last intermediate is then reduced to an aniline (40-3) the resulting amino acid is then cyclized thermally to the lactam (40-4). Treatment of that with phosphorus oxychloride gives the imino chloride (40-5). Reaction with N-methylpiperazine leads to the replacement of chlorine by nitrogen and the formation of clothiapine (40-6) [39]. 

Chakrabarti and coworkers at Eli Lilly in the United Kingdom have reported the initial discovery and synthesis of olanzapine (Schemes 5 and,6). The thiophene 22 was synthesized by adding a DMF solution of malononitrile to a mixture of sulfur, propionaldehyde and triethylamine in DMF. The anion of amino thiophene 22 underwent a nucleophilic aromatic substitution with 2-fluoronitrobenzene to provide 23. The nitro group was reduced with stannous chloride and the resulting anihne cyclized with the cyano group to form amidine 24. Finally, a mixture of N-methylpiperazine and 24 were refluxed in DMSO/toluene to afford olanzapine (2). 

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... 

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 ... 

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. 

Nakamura et al. have reported a one-step multiple addition of amine to [60] fullerene [95]. Here, a mixture of [60]fullerene and N-methylpiperazine was irradiated by means of an incandescent lamp in air to give a tetra(amino)fullerene epoxide in excellent yield (Scheme 4.64). 

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... 

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). 

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>. 

This follows the ionisation potential of the amino groups. Both conventional and microsecond flash photolysis confirmed the involvement of intramolecular hydrogen atom abstraction and this is illustrated by the mechanistic processes in scheme 3 for an N-methyl derivative and scheme 4 for a diethylamino derivative. Here it is seen that the N-methylpiperazine derivative, does not undergo intermolecular hydrogen atom abstraction. Intramolecular hydrogen... 

That leaves just one nucleophile to introduce, the piperazine ring. After hydrolysis of the ester, iV-methylpiperazine 212 displaces the fluorine para to the ketone and ofloxacin is formed. Amino alcohols are closely related to amino acids so this one example will be enough. The next group of antibiotics also look as though they might come from amino alcohols, but wait... 

Orthoesters annulate aminomethyl and amino groups to form a fused pyrimidine ring [2159]. Two amino groups in peri positions form a similar ring when treated with benzoic acid and. -diphenylphosphinyl-iV -methylpiperazine [3286] (see also Chapter 76, Section 1.1.A). 1,8-Naphthalenediamine is converted into perimidine by heating with 2-acylindanedione and 4-toluenesulphonic acid [2354]. Formic acid similarly cyclizes 4,5-quinolinediamine or the isomeric isoquinolinediamine in about 89VO yield [3338]. 

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