Morpholine nitrate

Wright found it more suitable to use the nitrate salts of the more basic amines, like in the case of morpholine, which ignites at ambient temperature in the presence of nitric acid-acetic anhydride mixtures. Morpholine nitrate is not nitrated with acetic anhydride-nitric acid in the absence of chloride ion at room temperature, but the addition of 4 mole % of zinc chloride generates a 65 % yield of A-nitromorpholine, and this yield rises to 93 % if the hydrochloride salt of morpholine is directly nitrated. While morpholine nitrate is unaffected by treatment with acetic anhydride-nitric acid at room temperature, the same reaction in the presence of ammonium nitrate at 65 °C is reported to yield A-nitromorpholine in 48 % yield. ... 

B. N-Nitromorpholine. Morpholine (34.8 g., 0.40 mole) and 26 g. (0.20 mole) of acetone cyanohydrin nitrate are mixed in a 50-ml. round-bottomed flask equipped with a thermometer well. A condenser is attached, and the mixture is heated slowly. At about 60° an exotherm ensues that raises the temperature of the mixture to 110°. The mixture is allowed to cool to 80° and maintained there for 1 hour. It is poured into 200 ml. of 10% hydrochloric acid (Caution Do in a hood Note 8) and extracted with three 100-ml. portions of methylene chloride (Note 9). The extracts are combined, washed successively with two 100-ml. portions of water, 100 ml. of 10% hydrochloric acid, and 100 ml. of water, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation on a water aspirator at room temperature to yield a pale-yellow oil (Note 10). 

The aqueous solution contains a-morpholinoisobutyronitrile in the form of its hydrochloride. It is formed by condensation of morpholine with the acetone and hydrogen cyanide formed in the nitration reaction. It is because of this side reaction that the excess amine is employed. 

In nitrating amines other than morpholine, particularly on a larger scale, it may be desirable to carry out the reaction in acetonitrile to control the temperature better.3... 

Chapman studied the nitrolysis of symmetrical methylenediamines. The nitrolysis of N, N, N, M-tetramethylmethylenediamine with nitric acid-acetic anhydride-ammonium nitrate mixtures gives both dimethylnitramine and RDX the latter probably arises from the nitroT ysis of hexamine formed from the reaction of ammonium nitrate and formaldehyde released from the hydrolysis of the methylenediamine. The same reaction with some morpholine-based methylenediamines (105) allows the synthesis of l,3,5-trinitro-l,3,5-triazacycloalkanes (106). 

Rats given lOg/kg in the diet, plus 0.2% sodium nitrite in the drinking water, had a significantly increased incidence of liver tumors compared with controls. The carcinogenic response is attributed to the in vitro production of N-nitrosomorpholine. In another study morpholine alone produced a low number of tumors of the liver, lung, and brain, and it was suggested that an unknown nitrate source reacted with the morpholine to form the carcinogenic iV-nitrosomorpholine. ... 

It is known that certain bacteria, including E. coli, could use nitrite (but not nitrate) to nitrosate amines, such as morpholine or 2,3-diaminona-... 

The fact that nitramino groups may arise under the influence of ammonium nitrate and nitric acid in the presence of acetic anhydride is shown by the reaction in which aminomethylnitramines (obtained from nitramine, formaldehyde and, say, morpholine) are treated with acetic anhydride in the presence of ammonium nitrate and nitric acid at 55°C (Lamberton et al. [65]) ... 

Bromination (Br2) of 4,5,6,7-tetrahydrobenzo[6]thiophen-4-one affords either a 2-bromo or a 5-bromo derivative, depending on whether the reaction is carried out at 0° in ether,445,446 or at—5 to 0°in 50% aqueous acetic acid.354 The 5-bromo derivative condenses with morpholine or potassium phthalimide to give 140a or 140b, respectively.445, 446 Hydrazinolysis of 140b fails to give any of the 5-amino derivative.445,446 On nitration, the 2-bromo derivative affords the 3-nitro compound or 141 (R = N02), depending on the reaction conditions.354 With sodium azide in PPA the 2-bromo and 2-bromo-3-... 

Fluorine Miscellaneous materials, 4304 Magnesium perchlorate Cellulose, etc., 4078 /V-Meth yI morpholine oxide, 1991 Nitric acid Cellulose, 4430 Perchloric acid Cellulose and derivatives, 3992 Perchloric acid Hydrofluoric acid, Structural materials, 3992 Potassium chlorate Cellulose, 4011 Potassium nitrate Cellulose, 4645 Sodium chlorate Paper, etc., or Wood, 4033 Sodium nitrate Fibrous material, 4716 Sodium nitrite Wood, 4715 Sodium peroxide Fibrous materials, 4797 Zinc permanganate Cellulose, 4705 BLEACHING POWDER Wood perchlorates Organic matter See SUGARS... 

Cellulose Nitrate. High-surface-area cellulose nitrate ignites spontaneously on contact with morpholine.3... 

The reaction of diallyl ether with mercury(II) nitrate in dichloromethane in the presence of an alkyl carbamate proceeds with total stereoselectivity and moderate yield. Under these conditions (thermodynamic control) the reaction gave, after reductive cleavage, the more stable diequatorial alkyl 3,5-dimelhyl-4-morpholine carboxylate 1124. 

We wanted to apply this idea to HMD 503982, a factor Xa-inhibitor [14] under development at Merck KGaA as an antithrombotic agent. Phase I has been finished recently and phase II is scheduled. A key component of this compound is 4-(4-aminophenyl)morpholin-3-one (3). This aniline can be generated by hydrogenation from the corresponding 4-(4-nitrophenyl)morpholin-3-one (2) [15], which in turn is accessible by nitration of the precursor 4-phenylmorpholin-3-one (1) [16] (Scheme 15.1). 

Because of the expected better workup and disposal procedures, nitration in acetic acid was tried first. Stock solutions of4-(phenyl)morpholin-3-one in glacial acetic acid (2 m) and nitric acid (65%) in concentrated sulfuric acid (4.8 m) were used. For the reaction optimization, two disposable polypropylene syringes (3 mL capacity) were hlled with the different stock solutions and mounted on a syringe pump. The syringes were connected with the silicon micromixer that was connected with a residence time unit, a Teflon tube of known inner diameter and length. The flow of the syringe pump was adjusted according to the residence time required, the only variable. For simplicity, nitrations were carried out at room temperature. 

For the next experiment a 1 m solution of 4-(phenyl)morpholin-3-one in acetic acid was treated with neat fuming nitric acid. Then the nitrating species was used in roughly 24-fold molar excess. Now (Table 15.3) the reaction proceeds much faster. 

From all the different test-reactions we learnt that the nitration should be sufficiently fast and para-selective. From all the preliminary experiments we decided to use a double molar excess of nitrating species. In the laboratory setup we used 1 m 4-(phenyl)morpholin-3-one in concentrated sulfuric acid and 2 m 65% nitric acid in concentrated sulfuric acid. It turned out that this solution was stable at least 3 months at room temperature, as evidenced by HPFC. 

So far, in all experiments the nitrating agent was prepared by dissolving the appropriate amounts of 65% nitric acid in concentrated sulfuric acid. This is an additional process in the whole procedure. Therefore, it was decided to add the 65% nitric acid directly to the stream of the 1 m solution of4-(phenyl)morpholin-... 

Tablel5.6 Experimental plan forthe nitration of4-(phenyl)morpholin-3-one with neat 65% nitric acid. 

Fig. 15.19 Single-step arrangement for the nitration of 4-(phenyl)morpholin-3-one.

The high viscosity of concentrated sulfuric acid causes a fairly high backpressure, which was mandatory for residence times as short as possible. The homemade pilot plant continuous reaction system consisted of a static mixer and a residence time loop with a total volume of565 mb (Fig. 15.19). The maximum temperature of the whole system was limited to 60 °C, because it was foimd that the complete heat of reaction was liberated within one second during the flow through the static mixer. To control the reaction temperature in this scale correctly dimensioned heat sinks are mandatory. With these precautions the same results were obtained as before. Using this equipment over 200 kg of4-(phenyl)morpholin-3-one were nitrated within 50 h. 

METHYL MORPHOLINE or V-METHYL MORPHOLINE or 4-METHYL MORPHOLINE (109-02-4) Forms explosive mixture with air (73°F/23°C). Violent reaction with strong oxidizers. Incompatible with organic anhydrides, acrylates, alcohols, aldehydes, alkylene oxides, substituted allyls, cellulose nitrate, cresols, caprolactam solution, epichlorohydrin, ethylene dichloride, isocyanates, ketones, glycols, maleic anhydride, nitrates, phenols, vinyl acetate. Increases the explosive sensitivity of nitromethane. 

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