1 - piperazine,4-alkylation

Sanofi-Aventis has disclosed a series of piperidine- and piperazine-alkyl carbamates as cannabinoid and/or FAAH modulators. No compounds are specifically claimed in the patent. Compound (60) is reported to have an IC50 value of 85 and is active in a mouse pain model [75]. 

A precursor to the nitrogen analogue of PEO, poly(N-acylethyleneimine), was obtained with a hydrocarbon and a fluorocarbon end group from MOz by initiatiation with perFCi7C2H40H triflic ester or C16H33OH triflic ester terminated with alkyl piperazine (alkyl = C H2 +i,n = 6,8,10,12,14,16,18) [85]. 

Classic A/-heterocychc ligands, eg, bipyridyl (bipy), terpyridyl, imidazole, pyrazine, phenanthroline, piperazine (including alkyl- and aryl-substituted derivatives), and polypyrazol-l-yl-borates (bis, tris, and tetra), have all been found to coordinate Th(IV) chlorides, perchlorates, and nitrates. The tripodal hydrotris(pyrazolyl)borates, HBPz, have been used to stabilize organometaHic complexes (31). Bis-porphyrin Th(IV) "sandwich" complexes have been... 

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). 

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

Alkylation of the p-chloro analog (102) of the monosubsti-tuted piperazine with m-methylbenzyl chloride (103) yields the... 

Treatment of a mixture of ortho anisidine and bis(2-hydroxy-ethyl) amine with hydrogen chloride affords the aryl-substituted piperazine, 171. (The first step in this reaction probably consists in conversion of at least one hydroxyl group to the chloride this then serves to alkylate the aromatic amine.) Alkyla-... 

Alkylation of the monocarbamate of piperazine with the halide, 173, affords 174 after removal of the protecting group by saponification. Alkylation of the amine with the chloroamide, 175 (obtained from amine, 176, and chloroacetyl chloride) gives the local anesthetic lidoflazine (177). ... 

Alkylation of phenothiazine with l-chloro-2-methyl-3-bromopropane affords the methylated analog (80) of the intermediate above. Use of this halide to alkylate the piperazine... 

The most complex side chain of the piperazine phenothiazines is to be found on chlorimpiphenine (86). The side chain is prepared by first alkylating monocarbethoxypiperazine with the chlorobenzimidazole 83 [itself attainable by alkylation of methylbenzimidazole with a dihalide). Removal of the carbethoxy group affords the substituted piperazine, 85. Alkylation of this base with the chloropropyl phenothiazine, 58, affords finally the desired compound (86). ... 

Replacement of the terminal nitrogen of the piperazine by carbon is said to enhance the antiemetic activity of the phenothiazines at the expense of the other pharmacologic effects. The simplest compound in this series, pipamazine (88), is prepared by alkylation of nipecotamide (87) with the chloropropyl phenothiazine (58). Preparation of the analogous sulfoxide begins with acetylation of the thiomethyl compound, 89 [prepared by a route... 

Alkylation of the intermediate, 41, with l-bromo-3-chloro-ethane affords 49, the use of this to alkylate iv-(2-hydroxyethyl) piperazine affords oxypendyl (50), a neuroleptic with good antiemetic and antivertigo properties. 

A cinnamoylpiperazine is described as an anti anginal agent. The key intermediate 1 can, in principle, be obtained by alkylation of the monobenzyl derivative of piperazine 71 with ethyl bromoacetate (72). Removal of the protecting group then affords the substituted piperazine (73). Acylation of this with 3,4,5-trimethoxycinamoyl chloride gives cinepazet (74). ... 

Alkylation of the monobenzhydryl derivative of piperazine ( ) with the same alkylating agent gives oxatomide (59), after removal of the protecting group.This agent shows antihistaminic activity as well as some mediator release inhibiting activity, a... 

Synthesis of the CNS depressant/tranquil izer tioperidone (59) begins by alkylation of piperazine derivative with 4-chlorobutyronitrile to give Lithium aluminum hydride... 

Condensation of piperazine with 2-methoxytropone gives the addition-elimination product 12 [2]. Alkylation of the remaining secondary amino group with bromoketone 13, itself the product from acylation of dimethyl catechol, gives aminoketone 14. Reduction of the carbonyl group with sodium borohydride leads to secondaiy alcohols 15 and 16. Resolution of these two enantiomers was achieved by recrystallization of their tartrate salts to give ciladopa (16) [3],... 

Yet another nonsedating zwitterionic H-1 antihistamine consists of the product from metabolism of the terminal hydroxyl of the potent antihistamine hydroxyzine terminating in hydroxymethyl instead of a carboxylic acid. This compound, cetirzine (123), can be obtained in straightforward fashion by alkylation of the monosubstituted piperazine 120 with halide 121, via the amide 122 [27]. 

A number of diarylmethyl alkylpiperazines, such as, for example lidoflazine, have found use as coronary vasodilators for the treatment of angina. The most recent of these interestingly incorporates a 2,6-dichloroaniline moiety reminiscent of antiarrhythmic agents. Treatment of the piperazine carboxamide 124 with acetone leads to formation of the nitrogen analogue of an acetal, the aminal 125. Alkylation of the remaining secondary nitrogen with chloroamide 126 leads to the intermediate 127. Exposure to aqueous acid leads to hydrolysis of the aminal function... 

A somewhat more complex theophylline derivative includes both the purinone nucleus and a piperazine side chain more commonly associated with HI antihistaminic compounds. The starting epoxide, 66, is available from treatment of the anion of purinone 65 with epichlorohydrin. Alkylation of the epoxide with monosubstituted piperazine derivative 67, leads to tazifylline (68) [11]. 

According to a hypothesis launched by Larionov et al in the 1960s, some new nitrogen mustard derivatives were developed. They contain metabolites and heterocyclic structures as carriers of the cytotoxic chloroethylamine groups. By this way the synthesis of aliylating metabolites started melphalan (sarcolysine) as L- or DL-phenylalanine derivative prospidine with a tricyclic piperazine moiety and chlorambucil as butyric acid derivative. It was proven that each alkylating metabolite has its own spectrum of selective antitumor activity. 

Piperazine, N-alkylation with benzyl chloride, 42, 19 Piperazine, 1-benzyl-, 42,19 Piperidine, addition to ethylene, 43, 45 as catalyst for Claisen-Schmidt condensation, 41, 40 Piperidine, 1-ethyl-, 43, 45 Piperidine, 1-(2-naphthyl)-, 40,74 Pivalic acid, oxidative coupling to a,a,-a, a -tetramethyladipic add, 40, 92... 

Benzhydrylamine Derivatives Attachment of piperazine nitrogen directly to a benzhydryl carbon leads to a pair of compounds which show vasodilator activity, and which should be useful in disease states marked by impaired blood circulation. Reaction of piperonyl chloride (18) with a mixture of piperazine and piperazine dihydrochloride leads to the monoalkylation product (19). (It may be supposed that the mixture of free base and salt equilibrates to the monobasic salt, thus making the second amine less nucleophilic.) Alkylation of 19 by means of benzhydryl chloride then... 

Azaperone (128) is yet another of the tranquilizers related to haloperidol. Nucleophilic aromatic displacement of 2-chloropyridine by piperazine leads to amine 126 which is then alkylated in turn by 4-chloro-p-fluorobuterophenone (127) to give... 

Alkylation of l-(2-pyrimidyl)piperazine (129) with 3-chloro-l-cyanopropane gives nitrile 130, which is reduced with LAH and then acylated with spiro-glutaric anhydride 131 to synthesize the tranquilizer buspirone (132).40... 

Alkylation of piperazine with the amide formed by reaction of chloroacetyl chloride with pyrrolidine gives amide 133. Acylation with 3,4,5-trimethoxy-... 

This or the reverse order will give the observed product (135). Alkylation of piperazine 136 with 1-bromo-3-chloropropane gives the piperazine derivative 137 use of that intermediate to alkylate heterocycle... 

C-Alkylations of l,4-dihydro-27/-pyrazino[2,l-A]quinazoline-3,6-diones at positions C-l and CM were studied in detail. Compounds of type 57 could be alkylated diastereoselectively at C-l, owing to the geometry of the piperazine ring, which is locked in a flat boat conformation with the R4 or R1 substituent in a pseudoaxial position to avoid steric interaction with the nearly coplanar C(6)-carbonyl group. Alkylation of 57 (R2 = Me, Bn, R4 = Me) in the presence of lithium hexamethyldisilazide (LHMDS) with benzyl and allyl halides resulted, under kinetic control, in the 1,4-trans-diastereomer 59 as the major product, with retention of the stereocenter at CM (Scheme 5). 

Alkylation of the 3-lactim ether, (4A)-3-ethoxy-4-isopropyl-l,4-dihydropyrazino[2,l-3]quinazolin-6-one with BnBr gave pure l,4-/ra r-diastereomer. The higher diastereoselectivity - as compared to the lactams - was explained by the fully boat conformation of the piperazine ring in the lactim ethers <2005TA3160>. 

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