N-substituted morpholine as an organic chemical intermediate, with the dual properties of tertiary amine and ether, has a wide range of applications, can be used as a catalyst in the production of polyurethane foam, apoxycillin, amino benzylpenicillin and carboxy benzylpenicillin synthesis process catalyst, but also as a surfactant, extractant, corrosion inhibitors, its derivatives N-methyl oxymorpholine, Lyocell natural fibers and Newcell man-made fiber filament is a very ideal spinning solvent. (3S)-3-(Hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester is a key intermediate in the synthesis of BMS-599626, a selective and orally effective inhibitor of human epidermal growth factor receptor 1 and 2 kinase. (3S)-3-(Hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester Chinese alias: 3(S)-hydroxymethyl-4-boc morpholine, English name: (S)-3-Hydroxymethylmorpholine-4-carboxylic acid tert-butyl Ester, CAS No.: 714971-28-5,. Molecular Formula: C10H19NO4, Molecular Weight: 217.262, Density: 1.118g/cm3, Boiling Point: 320.7C at 760mmHg.

Preparation
N-substituted morpholine contains the double groups of tertiary amine and ether, which is not only an important catalyst in the semi-synthesis of penicillin and polyurethane foaming process, but also an important raw material for the synthesis of N-substituted morpholine oxide. The current synthesis process mainly includes morpholine method, N-methyldiethanolamine method, diethanolamine method, diethylene glycol method and dichloroethyl ether method. The substitution of (3S)-3-(hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester was prepared by reacting (R)-(4-benzyl-3-morpholinyl)-methanol with di-tert-butyl dicarbonate as the starting material [1], and the synthetic reaction equation is as follows.

Figure 1 Synthesis reaction equation of tert-butyl (3S)-3-(hydroxymethyl)morpholine-4-carboxylate

Experimental operation.
To a dichloromethane solution of (R)-(4-benzyl-3-morpholinyl)-methanol was added triethylamine, and a dichloromethane solution of di-tert-butyl dicarbonate was added dropwise, and the reaction was carried out for 15 h. The solvent was evaporated under reduced pressure, and the concentrate was purified by silica gel column chromatography [eluent: V (ethyl acetate) /V (petroleum ether) = 1/10] to obtain the compound (3S)-3-(hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester .

Summary
Through the study of the synthesis process of (3S)-3-(hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester, it can be seen that the production route of morpholine compounds is more mature, but the production process is green, environmentally friendly, clean, efficient and low-cost is still the future direction of the synthesis of N-substituted morpholine, only to break through the limitations of the laboratory to achieve industrial production, in order to finally play a role in the market application.

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