Morpholine alkylation

However, there are occasions ia which the use of a respiratory stimulant may be warranted. By far the leading respiratory stimulant marketed ia the United States is doxapram [309-29-5] (13), prepared by a unique rearrangement of the pyrroHdine [3471-97-4] (14) to the pyrroHdinone [3192-64-1] (15), followed by alkylation using morpholine (15). 

Mel, CH3CN morpholine or diethylamine, methanol, 76-95% yield. These conditions also cleave tlie 4 -pyridyl derivative. The Pet ester is stable to the acidic conditions required to remove the BOC and r-butyl ester groups, to the basic conditions required to remove the Fmoc and Fm groups, and to hydrogenolysis. It is not recommended for use in peptides that contain methionine or histidine since these are susceptible to alkylation with methyl iodide. 

In recent years there has been some substitution of TDI by MDI derivatives. One-shot polyether processes became feasible with the advent of sufficiently powerful catalysts. For many years tertiary amines had been used with both polyesters and the newer polyethers. Examples included alkyl morpholines and triethylamine. Catalysts such as triethylenediamine ( Dabco ) and 4-dimethyla-minopyridine were rather more powerful but not satisfactory on their own. In the late 1950s organo-tin catalysts such as dibutyl tin dilaurate and stannous octoate were found to be powerful catalysts for the chain extension reactions. It was found that by use of varying combinations of a tin catayst with a tertiary amine... 

The presence of 1,3-diaxial interaction between the C-2 alkyl group and the C-4 axial hydrogen atom is reflected in the rate of enamine formation of 2-substituted cyclohexanone. It has been shown by Hunig and Salzwedel (20) that even under forcing conditions, the yield of pyrrolidine and morpholine enamines of 2-methylcyclohexanone does not exceed 58%, whereas the C-2 unsubstituted ketones underwent enamine formation under rather milder conditions in better than 80 % yield. 

In their original communication on the alkylation and acylation of enamines, Stork et al. (3) had reported that the pyrrolidine enamine of cyclohexanone underwent monoacylation with acid chlorides. For example, the acylation with benzoyl chloride led to monobenzoylcyclohexanone. However, Hunig and Lendle (33) found that treatment of the morpholine enamine of cyclopentanone with 2 moles of propionyl chloride followed by acid hydrolysis gave the enol ester (56), which was proposed to have arisen from the intermediate (55). 

Anotheranalogy between the enolate anions derived from a,)3-unsatura ted ketones and the corresponding enamines is encountered in their alkylation reactions (57), which proceed by the kinetically controlled attack at the a-carbon atom. For instance, Stork and Birnbaum (51) found that the alkylation of the morpholine enamine of /J -octalone-2 (117) with methyl iodide gave the C-1 methylated derivative (118). 

Madsen and Lavvesson (6/), however, have reported recently that the treatment of /7-alkyl methyl ketones with morpholine in the presence of p-toluenesulfonic acid for a short period of time resulted in the formation of a mixture of condensation product of the ketone (122) and the corresponding dienamine (123). 

Similar results were encountered by Bianchetti et al. (i52), who found that e ketal derivatives of //-alkyl methyl ketones with morpholine led to the enamines of the condensation products of these ketones. The authors have Suggested the following probable mechanism for the dienamine formation. 

Experimental evidence, obtained in protonation (3,6), acylation (1,4), and alkylation (1,4,7-9) reactions, always indicates a concurrence between electrophilic attack on the nitrogen atom and the -carbon atom in the enamine. Concerning the nucleophilic reactivity of the j3-carbon atom in enamines, Opitz and Griesinger (10) observed, in a study of salt formation, the following series of reactivities of the amine and carbonyl components pyrrolidine and hexamethylene imine s> piperidine > morpholine > cthyl-butylamine cyclopentanone s> cycloheptanone cyclooctanone > cyclohexanone monosubstituted acetaldehyde > disubstituted acetaldehyde. 

At higher temperatures the mixture of 10 and methyl vinyl ketone yields the 1,4-carbocyclic compound as described previously. Methyl isopropenyl ketone (5), ethyl acetylacrylate (d), 2-cyclohexenone (21), and 1-acetyl-1-cyclohexene (22) also undergo this type of cyclization reaction with enamines at higher temperatures. This cycloalkylation reaction occurs with enamines made of strongly basic amines such as pyrrolidine, but the less reactive morpholine enamine combines with methyl vinyl ketone to give only a simple alkylated product (7). Chlorovinyl ketones yield pyrans when allowed to react with the enamines of either alicyclic ketones or aldehydes (23). 

Nitroolefins also offer the possibilities of 1,2 cycloaddition (37,57) or simple alkylation (57-59) products when they are allowed to react with enamines. The reaction of nitroethylene with the morpholine enamine of cyclohexanone led primarily to a cyclobutane adduct in nonpolar solvents and to a simple alkylated product in polar solvents (57). These products are evidently formed from kinetically controlled reactions since they cannot be converted to the other product under the conditions in which the other... 

The side chain hydroxy group of 3-(2-hydroxyethyl)-2-methyl-9-methoxy-4//-pyrido[l,2-u]pyrimidin-4-one, and that of its 6,7,8,9-tetrahydro derivative was acylated with MeS02Cl in the presence of NEts in CH2CI2 at room temperature (95MIP4, 96MIP2). The hydroxy group of 2-[4-(4-hydro-xybenzoyl)benzyloxy]-3-methyl-4//-pyrido[l, 2-u]-pyrimidin-4-one, its 6-methyl derivative and 2-[4-(4-hydroxybenzoyl)benzylthio]-3-methyl-4//-pyrido[l, 2-u]pyrimidin-4-one was alkylated with 4-(2-chloroethyl)morpholine hydrochloride and 4-picolyl chloride hydrochloride (96EUP733633). 

As shovm above, the attachment of the aromatic ring to the carbon chain bearing the basic nitrogen may be accomplished through an ester or an amide configured in either direction. A simple ether linkage fulfills this function in yet another compound that exhibits local anesthetic activity. Thus, alkylation of the mono potassium salt of hydroquinone with butyl bromide affords the ether (77) alkylation of this with w-C3-chloropropyl)morpholine affords pramoxine (78)... 

Although chemically related to the above cycloalkylamines, pentethylcyclanone (71) is stated to have antitussive activity. The compound is prepared rather simply by alkylation of the anion (70a) of the self-condensation product of cyclopentanone (70) with N-(2-chloroethyl)-morpholine. ... 

Replacement of the ketone by an amide leads to Increased potency. Hydrolysis of nitrile, 133 (obtained by alkylation of diphenylacetonitrile with the morpholine analog of the chloro-amine used in the original preparation of methadone), affords acid, 134. Conversion to the acid chloride followed by reaction with pyrrolidine affords racemoramide (135) Separation of the (+) isomer by optical resolution gives dextromoramide, an analgesic an order of magnitude more potent than methadone. 

Alkylation of the 5(4)-nitro compound with methyl sulfate in nonpolar solvents affords dimetridazole (91), ° an antitrichomonal agent used in veterinary practice. Alkylation with chlorohydrin leads to metronidazole (92), a drug that has found widespread use in the treatment of vaginal trichomoniasis. Finally, alkylation by means of iv-(2-chloroethyl)morpholine affords nitrimida-zine (93),... 

Alkylation of that amine with p-(2-chloroethyl)aniline affords anileridine (82), an analgesic similar to the parent compound but somewhat more potent. In similar fashion alkylation by means of w-(2-chloroethyl)morpholine gives morpheridine (83), while the use of 2-(chloroethyl)-ethanol yields carbethl-... 

Boilers and steam systems Steel steam lines can be inhibited by the use of a volatile amine-based inhibitor such as ammonia, morpholine or cyclohexylamine introduced with the feedwater. It passes through the boiler and into the steam system, where it neutralizes the acidic conditions in pipework. The inhibitor is chemically consumed and lost by physical means. Film-forming inhibitors such as heterocyclic amines and alkyl sulphonates must be present at levels sufficient to cover the entire steel surface, otherwise localized corrosion will occur on the bare steel. Inhibitor selection must take into account the presence of other materials in the system. Some amine products cause corrosion of copper. If copper is present and at risk of corrosion it can be inhibited by the addition of benzotriazole or tolutriazole at a level appropriate to the system (see also Section 53.3.2). 

When enamines are treated with alkyl halides, an alkylation occurs that is analogous to the first step of 12-14. Hydrolysis of the imine salt gives a ketone. Since the enamine is normally formed from a ketone (16-12), the net result is alkylation of the ketone at the a position. The method, known as the Stork enamine reaction is an alternative to the ketone alkylation considered at 10-105. The Stork method has the advantage that it generally leads almost exclusively to monoalkylation of the ketone, while 10-105, when applied to ketones, is difficult to stop with the introduction of just one alkyl group. Alkylation usually takes place on the less substituted side of the original ketone. The most commonly used amines are the cyclic amines piperidine, morpholine, and pyrrolidine. 

As yet, a number of experiments have failed to convert ureas 205 such as N-phenylurea or imidazolin-2-one by silylation amination with excess amines R3NHR4 such as benzylamine or morpholine and excess HMDS 2 as well as equivalent amounts of NH4X (for X=C1, I) via the silylated intermediates 206 and 207 in one reaction step at 110-150°C into their corresponding guanidines 208 with formation of NH3 and HMDSO 7 [35] (Scheme 4.13). This failure is possibly due to the steric repulsion of the two neighbouring bulky trimethylsilyl groups in the assumed activated intermediate 207, which prevents the formation of 207 in the equilibrium with 206. Thus the two step Rathke-method, which demands the prior S-alkylation of 2-thioureas followed by amination with liberation of alkyl-mercaptans, will remain one of the standard syntheses of guanidines [21, 35a,b,c]. 

In a similar vein, alkylation of 4-(5)-nitro-imidazole with N-(2-chloroethyl)morpholine affords a mixture of N-alkylated imidazoles (61 and 62). The compound containing the adjacent ring substituents (61) is the antitrichomonal agent nimorazole.15... 

---