Morpholine-4-carboxylic acid

However, morpholine-4-carboxylic acid 2-hydroxy-1-methyl-ethyl ester is formed by the reaction of PC and the substrate morpholine in an undesired side reaction. By use of 1.4-dioxane or the pyrrolidones as mediator s3 about 30 to 45% of the morphoUne is consumed by this side reaction. The by-product is contained in the PC phase and can not be extracted to the non-polar product phase. The selectivity to the desired amines is lowered, because of the consiunption of the morphoUne. Thus, PC has to be substituted by another polar solvent (e.g. water, methanol or ethylene glycol) in future experiments. The lactates react with the morphoUne, too resulting in the corresponding amide. Overall, the hydroaminomethylation in the TMS systems PC/dodecane/lactate results in a conversion of 1-octene of about 80%, but in selectivities to the amines of only 50 to 60%. 

M.l. Emmanuel, L.L. Frye, E.R. Hickey, W. Liu, T.M. Morwick, D.M. Spero, S. Sun, D.S. Thomson, Y.D. Ward, E.R.R. Young, Novel spiroheterocyclic compounds [morpholine-4-carboxylic acid amides of heterocyclic cyclohexylalanine and neopentylglycine derivatives and their analogs], useful as reversible inhibitors of cysteine proteases such as cathepsin S, PCT Int. Appl. 2001 (2001) 361pp W02001019816. 

Another method for deallylation of ally esters is the transfer of the allyl group to reactive nucleophiles. Amines such as morpholine are used[415-417], Potassium salts of higher carboxylic acids are used as an accepter of the allyl group[418]. The method is applied to the protection and deprotection of the acid function in rather unstable /f-lactam 664[419,420]. 

Stem nuclei. Morpholine, 5. Hydroxy compounds Scopolamine, 99. Carbonyl compoimds, 135 Saccharin, 169. Carboxylic acids, 313. Sulphonio acids, 355. Amines, 361 Meldola s blue, 383. 

Fig. 16 DCVJ compared to the core fluorophore for the DNA-Dye-BSA/SSP assay (45). The 5 DNA strand is conjugated to the carboxylic acid group, leaving the morpholine group to access the hydrophobic pockets...

Amidation of W-BOC-tetrahydro-l,2-oxazine-6-carboxylic acid 47 with free oxanipecotic acid afforded amide 48 <2003TL3447>. The 3-methyl-substituted 1,2-oxazine Woxide 280 can be selectively transformed into 2-silyloxy-1,2-oxazines 281, upon treatment with silylating reagents (ClSiMe3). Now, the synthetic utility of 2-silyloxy-l,2-oxazine 281 is extended and it can be rearranged into 3-silyloxymethyl-l,2-oxazine 282 and can further react with morpholine to produce 3-morpholinomethyl-l,2-oxazine 283 which exists in a tautomeric equilibrium with the corresponding open-chain oxime <2003JOC9477>. 

Alternatively the oxidation of 4 -(methylsulfonyl) acetophenone with S8 and morpholine produces the 2-(4-(methylsulfonyl)phenyl)acetic acid ethyl ester (xiv), which is condensed with 2-methylpyridine-3-carboxylic acid methyl ester by means of terf-butyl magnesium chloride in hot tetrahydrofurane to give the ketosulfone (ix). 

Racemic morpholine-3-carboxylic acid (4-oxapipecolic acid, 18) is prepared by a multistep synthesis, starting from 3-methoxymorpholine 205 It can, however, be obtained as optically pure (3S)-morpholine-3-carboxylic acid (l-4-oxapipecolic acid) by base-mediated cyclization of 0(2-chloroethyl)-L-serine.[253] Similarly, (4S)-tetrahydro-2//-1, 3-oxazine-4-carboxylic acid (L-5-oxapipecolic acid, 19) is obtained from L-homoserine by reaction with aqueous formaldehyde under alkaline conditions 173 ... 

A further improvement is embodied in the Kindler variation of the Willgerodt reaction which is illustrated by several examples in Expt 6.148. This consists of heating the ketone with approximately equal amounts of sulphur and a dry amine (e.g. morpholine) instead of aqueous ammonium polysulphide. The principal product is a thioamide, and subsequent hydrolysis with acid or alkali affords the carboxylic acid, usually in good yield. 

Decarboxylation of a-keto carboxylic acids.1 The conversion of a-keto carboxylic acids into the morpholine enamine (TsOH) is accompanied by loss of C02 to form the enamine of an aldehyde in almost quantitative yield. The free aldehyde is liberated as usual by acidic hydrolysis. 

A mixture of 2 ml of morpholine, 3 ml of dimethylformamide and 10 ml of water was heated to 60°C and under stirring the equal molecular quantity of 6-isopropyl-4-oxo-4H-l-benzopyran-3-carbonitrile was added for 5 minutes. The mixture was heated at that temperature for one hour and the resultant precipitate was filtered, rained with water recrystallized from acetic acid and washed with chloroform. By the above procedure was obtained 2-amino-6-isopropyl-4-oxo-4H-l-benzopyran-3-carboxaldehyde melting at 206°-208°C. A mixture of 4 ml ethyl cyanoacetate, 50 ml of ethanol, 5 ml of piperidine and the equal molecular quantity of 2-amino-6-isopropyl-4-oxo-4H-l-benzopyran-3-carboxaldehyde was refluxed for 30 minutes and, after cooling, the crystalline precipitate was filtered and washed with chloroform. By above procedure was obtained ethyl-2-amino-7-isopropyl-l-azaxanthone-3-carboxylate, melting after recrystallization from ethanol at 243°-244°C. A mixture of 10 ml of acetic acid and 10 ml of 55% sulfuric acid the equal molecular quantity and 2-ethyl-amino-7-isopropyl-l-azaxanthone-3-carboxylate was stirred at 130°C for 4 hours and, after water was added, the precipitate was collected by filtration and recrystalllized from dimethylformamide to give the 2-amino-7-(l-methylethyl)-5-oxo-5H-[l]benzopyrano[2,3-b]pyridine-3-carboxylic acid, melting point 300°C. 

During the development of rivaroxaban 1, Pleiss et al. at Bayer Health Care prepared [14C]-radiolabeled rivaroxaban,22 which was required for clinical studies of drug absorption, distribution, metabolism, and excretion (ADME studies). The approach taken for the synthesis of l4C labeled rivaroxaban 38 relies on the previously reported synthesis. In the presence of EDC HCl and HOBT, 4- 4-[5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl -morpholin-3-one 22 was coupled with 5-chloro-2-thiophene [14C]-carboxylic acid 37 and was purified using chiral HPLC to afford the [l4C]-radiolabelled rivaroxaban 38 in 85% yield with high chemical and radiochemical purity and with an enantiomeric excess of > 99% ee (Scheme 5). Meanwhile, the metabolite M-4 of rivaroxaban (compound 39) was prepared from 5-chlorothiophenecarboxylic acid chloride 23 and [14C]glycine in 77% yield (Scheme 6). 

C H NO/, 103003-01-6) see Indeloxacine ( )-2-(hydroxymethyl)morpholine see under 2-hydroxyrnethylmorpholine 4-hydroxy-7-methyl-l,8-naphthyridine-3-carboxylic acid (CmttjNiO, 13250-97-0) see Nalidixic acid 4-hydroxy-7-methyl-l,8-naphthyridine-3-carboxylic acid ethyl ester... 

Amongst other examples of pharmacologically active seven-membered heterocyclic ring compounds the following are of interest 5-(2-morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid (,S)-3-methyl-1 - 3-oxo-1 -[2-(3-pyridin-2-yl-phenyl)-ethenoyl]azepan-4-... 

Preparation of 2-(2-morpholin-4-yl-ethyl)-4-trifluoromethyl-thiazole-5 -carboxylic acid ethyl ester (general procedure)... 

Amides have also been prepared from carboxylic acids as follows a mixture of 2-carboxypyrazine and triethylamine in methylene chloride treated with ethyl chloroformate and then morpholine gave 2-(A-morpholinocarbonyl)pyrazine (1351) 2-carboxy-5(and 6)-methylpyrazine in dioxane with tributylamine and ethyl chloroformate and then treated with ammonia gave 2-carbamoyl-5(and 6)-methylpyrazine (673), and 2-carbamoyl-5(and 6)-ethylpyrazine were prepared... 

The Kindler modification dodges heating in closed vessels under pressure by using, instead of aqueous ammonium polysulfide, a mixture of sulfur and morpholine. After being refluxed for 6-12 h, the ketone is converted into the thiomorpholide of the carboxylic acid. Subsequent alkaline hydrolysis yields the carboxylic acid as the final product [501, 503, 504, 1170]. 

The reaction of elemental sulfur in pyridine with 1,2-dithiolylium salts has been used for the synthesis of several l,2-dithiole-3-thiones.7 3-Chloro-1,2-dithiolylium salts give l,2-dithiole-3-thiones with sulfur-free bases such as ethanol, ammonia, methyl- and dimethylamine, piperidine, morpholine, and the azide ion.8 These salts form l,2-dithiol-3-ones with carboxylic acids.8... 

N(2-Indolylethyl)glutarimide, 871 Inosine, 740-741 N-oxide, 754 Inositol, 179 -2-carboxylic acid, 326 derivatives, 740 hexamethyl ether, 683 Inositols, 256 Iodic acid, 496 Iodine, 495-500,1107, 1281 Iodine azide, 500-501 Iodine isocyanate, 501 Iodine monobromide, 501-502 Iodine monochloride, 258, 502 Iodine-Morpholine complex, 502-SOS Iodine pentafluoride, 503 Iodine-Pyridine, 503-504 Iodine-Silver salts, 504 lodoacetamide, 504-505 lodoacetone, 1188... 

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