1 -Methyl-4- piperazine reduction

Reduction of acids or esters to aldehydes. Diaminoaluminum hydrides, particularly those derived from secondary cyclic amines such as N-methyl-piperazine or morpholine, are useful for reduction of carboxylic acids or esters to aldehydes, without contamination by the corresponding alcohols. The reduction is carried out in refluxing THF (6-20 hr.). In general, 2 moles of reagent are used for each mole of substrate. The reduction is applicable to both aromatic and aliphatic esters. Yields are in the range of 50-85%,... 

The DIPEA-mediated nucleophiUic displacement of the halogen atom by A-methyl piperazine in DMF was effected under microwave irradiation at 100°C for 5 min, followed by a microwave-assisted, SnC mediated reduction of the nitro group in DMF at KW C to generate the corresponding aniline in 5 min (Scheme 8.20). Introduction of the guanidine... 

Reduction of fluoroalkylpyrazines could be a promising method for the synthesis of chain-fluorinated piperazines. This method was used for the synthesis of difluoromethyl- and (l,l-difluoroethyl)piperazines 1283 nevertheless, it was obtained in low yield [322, 781], Therefore the synthesis of parent (trifluoro-methyl) piperazine 1284 is based on 4 steps synthesis started from methyl trifluoro-pyruvate and N,N -dibenzyl ethylenediamine (Scheme 287) [782]. 

Aliphatic Alcohols and Alkylene Glycols. Simple aliphatic alcohols, such as methanol [67-56-1], can be used to alkylate alkyleneamines. For example, piperazine reacts with methanol over a reductive amination catalyst to yield a mixture of 1-methyl- [109-01 -3J and 1,4-dimethylpiperazine [106-58-1] (12). 

Meclizine Meclizine, l-[(4-chlorphenyl)methyl]-4-[(3-methylphenyl)phenyl]piperazine (16.1.16), is synthesized by reductive amination of a mixture of 3-methylbenzaldehyde with l-(4-chlorbenzhydryl)piperazine using hydrogen over Raney nickel [27-29]. 

Cen at the Shanghai Institute of Pharmaceutical Industry has recently published a synthesis of olanzapine (Scheme 7). The thiophene 22 was treated with 2-chloronitrobenzene m the presence of lithium hydroxide to give 23. Reduction of the nitro group and subsequent ring closure gave 24. Addition of piperazine to the amidine 24 followed by methylation provided olanzapine (2) in an overall yield of 29%. 

There is little recent information in this area. The tine structure of 3-acetoxy-l, 4-dinitro-2-piperazinol (14) has been elucidated by X-ray analysis.1212 Treatment of 5,6-dichloro-3-nitro-2-pyrazinamine (15) with refluxing ethanolic sodium cyanide for 4 days induced displacement of the nitro by a cyano group as well as ethanoly-sis of one chloro substituent to afford 3-amino-6-chloro-5-ethoxy-2-pyrazinecar-bonitrile (16) in 55% yield.1313 L-Methyl-4-(/>nitrobenzoyl)pipcrazine (17) gave I -(/ -aminobenzoyl)-4-methy I piperazine (18) (75%) on refluxing in ethanolic hydrazine hydrate with a little Raney nickel catalyst for 6 h 135, cf 1032 other reduction procedures have been reported.496,1741... 

A convenient conversion of homopiperazine into the 1-methyl derivative involves reductive methylation with formaldehyde and a Raney nickel catalyst.199-199a A small amount of the 1,4-dimethyl derivative is also obtained in this reaction. Use of benzaldehyde with homopiperazine gave 177 which was hydrolyzed to starting materials with hydrochloric acid.199 Pyrolysis of the dihydrobromide of 148 (R = H, R = CH2CH2Br) gave 178, 179, homopiperazine, and piperazine.140... 

Anhydrous piperazine refluxed with methyl formate produced I-formylpiperazine (1725), which was reduced with lithium aluminum hydride to 1-methylpiperazine (1703). l-Nitroso-4-phenylpiperazine in tetrahydrofuran with diisopropylamine, methyllithium, and carbon dioxide formed 2-carboxy-l-nitroso-4-phenylpiperazine, which was cleaved by dry hydrogen chloride in benzene to 3-carboxy-l-phenyl-piperazine (1726). Distillation of the calcium salt of rra/is-2,3-dicarboxy-l, 4-di-phenylpiperazine gave 1,4-diphenylpiperazine (1669). Reduction of 1-ethoxy-carbonyl-4-trifluoroacetylpiperazine with borane in tetrahydrofuran formed... 

Electrochemical reduction of methyl (5)-Ar-benzhydroxyiminoformylprolinate (1) leads to a mixture of two diastereomers of l,4-diketo-3-phenylpyrrolidino[l,2- ]piperazine (2)2. 

The construction of the piperazine ring was carried out through a reductive animation of 154 with glycine methyl ester, followed by deprotection of the nitrogen and lactamization of diamino ester 155. Hydrogenolysis of the benzyl ether group afforded the amino phenol 151 required for the next crucial transformation. 

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