1- Methyl-4- piperazine acylation

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). 

In many reactions the simple saturated nitrogen heterocycles—piperidine, pyrrolidine, piperazine, and morpholine—behave simply as secondary amines that happen to be cyclic. They do the sorts of things that other amines do, acting as nucleophiles in addition and substitution reactions. Morpholine, for example, is acylated by 3,4,5-trimethoxybenzoyl chloride to form the tranquillizer and muscle relaxant trimetozine, and N-methyl piperazine can be alkylated in an S l reaction with diphenylmethyl chloride to give the travel-sickness drug cyclizine. 

MED-2220, which are attached to antibodies with lysines thiolated by 2-IT (2-iminothiolane, Trout s reagent Figure 7.12). The phenol in the open form of the CBI alkylating unit is protected as a carbamate of tV-methyl piperazine, which likely increases stability and adds solubility. The cyclopropane precursor contains a bromine instead of chlorine for undisclosed reasons. The linker is attached via an acyl hydrazone similar to the AcBut linker in several cali-cheamicin conjugates. The linker contains a short PEG unit that would also likely improve solubility. 

Piperazine-N,N -diacetic acid dithioamide refluxed 3 hrs. with p-methoxyphen-acyl bromide in abs. ethanol containing 2-3 drops of pyridine, and the product shaken 10 min. with 1 1 aq. NHg -> N,N -di- (4-p-methoxyphenyl-2-thiazolyl-methyl)piperazine. Y 91%. F. e. s. H. A. Braun, H. Kiihne, and B. Prijs, Helv. 43, 659 (1960). 

Amines or amides Alkyl amines (iindecyloctyl and diamyl methyl amine) polyamides (acyl derivatives of piperazine) Boiler foam sewage foam fermentation dye baths... 

N-alkylation and N-acylation of piperazine-2,5-diones are quite common and have been routinely employed in several synthetic sequences (see Section IV,C). Such operations have also been performed as measures for the temporary protection of the nitrogen during further synthetic maneuvers in other parts of the molecule. Three different alkyl groups have been employed as such protecting groups. Kishi has used the methoxymethyl group for N-protection (potassium r-butoxide, chloro-methyl methyl ether 0°C, 75% yield). Deprotection was achieved by cone. HCl-ethanol at reflux temperature (81T2045). 

Note The Rh-catalyzed C-acylation of reduced pyrazines with carbon monoxide and ethylene appears to offer considerable potential for further development. l-Methyl-4-(pyridin-2-yl)piperazine (292) gave l-methyl-3-propionyl-4-(pyridin-2-yl)-l,4,5,6-tetrahydropyrazine (293) [Rh4(CO)12, PhMe, H2C=CH2 J, to 10 atm, CO l to 15 atm, 25°C, autoclave then 160°C, 20 h 85%] several N-alkyl/aryl homologues were made similarly.1404... 

Acylation of 40 with cyclohexanecarbonyl chloride and tetrahydropyran-4-carbonyl chloride affords HOE-28637a (8a) and HOE-26961a (8b), respectively [50]. Similarly l-methyl-4-(pyrrolidin-l-ylcarbonyl)piperazine (9, CDRI 72-70) has been prepared by action of phosgene on 40 to get N-methylpiperazinecarbonyl chloride (43) followed by treatment with pyrrolidine [51] (scheme 2). 

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