合成路线1

The synthesis of meloxicam is performed as follows: The reaction of benzisothiazolo-3(2H)-one-1,1-dioxide (I) with methyl chloroacetate gives the methyl 2(3H)-acetate derivative, which is isomerized with sodium methoxide in toluene/tert-butanol yielding methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide. The subsequent methylation with methyl iodide in methanol yields 2-methyl compound (II). Finally, this compound is treated with 2-amino-5-methylthiazole in xylene.

合成路线2

This compound can be prepared by two similar ways: 1) The monoacylation of ethylene glycol (I) with chloroacetyl chloride (II) and triethylamine gives 2-hydroxyethyl chloroacetate (III), which is condensed with saccharine (IV) by means of NaOH in ethylene glycol yielding 2-hydroxyethyl 3-oxo-1,2-benzisothiazoline-2-acetate 1,1-dioxide (V). Isomerization of (V) by means of potassium tert-butoxide in DMSO affords2-hydroxyethyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (VI), which is methylated with NaOH and methyl iodide in aqueous ethanol giving the corresponding N-methyl derivative (VII). Hydrolysis of (VII) with NaOH in ethanol - water yields the corresponding free acid (VIII), which is acylated with cinnamoyl chloride (IX) by means of triethylamine in dichloromethane to afford the biscinnamoyl derivative (X). Finally, this compound is treated with 2-aminopyridine (XI) in dichloromethane. 2) The preceding sequence can also be carried out with cyclohexanol (XII) instead of ethylene glycol (I), then producing compounds (XIII), (XIV), (XV) and (XVI), which by hydrolysis affords the free acid (VIII).

合成路线3

Saccharin (II) was obtained by acidification of a solution of sodium 2-sulfamoylbenzoate (I). Alkylation of the sulfimide N of (II) with N-(2-pyridyl)bromoacetamide (III) under phase-transfer conditions afforded (IV). Rearrangement of sulfimide (IV) in the presence of sodium methoxide gave rise to the benzothiazine derivative (V). From this, the title compound was prepared by two related ways. Esterification of (V) with trimethylacetyl chloride yielded pivalate ester (VI), which was subsequently alkylated at the sulfamide N with iodomethane in the presence of NaOH. Alternatively, methylation of (V), followed by esterification of the resultant (VII) with pivaloyl chloride led to the title compound.

合成路线4

An enantioselective synthesis of the desired (S)-isomer was further developed starting from saccharin (VI). After conversion to the magnesium amide enolate (VII) by means of phenylmagnesium bromide, addition of Grignard reagent (VIII) produced the aryl sulfonimide (IX). Enantioselective reduction to the (S)-sulfonamide (X) was then accomplished using a chiral rhodium catalyst. Then, N-methylation of (X) with yodomethane in the presence of Cs2CO3 provided the title compound.

合成路线5

合成路线6