CA1181749A - Process for the preparation of 2-methoxyethyl 4- hydroxy-2-methyl-2h-1,2-benzothiazine-3-carboxylate 1,1-dioxide - Google Patents
Process for the preparation of 2-methoxyethyl 4- hydroxy-2-methyl-2h-1,2-benzothiazine-3-carboxylate 1,1-dioxideInfo
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- CA1181749A CA1181749A CA000445578A CA445578A CA1181749A CA 1181749 A CA1181749 A CA 1181749A CA 000445578 A CA000445578 A CA 000445578A CA 445578 A CA445578 A CA 445578A CA 1181749 A CA1181749 A CA 1181749A
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- methoxyethyl
- dioxide
- methyl
- benzothiazine
- hydroxy
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Abstract
Abstract Process for the preparation of 2-methoxyethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide, an advantageous ester precursor for piroxicam (4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide), which is an antiinflammatory agent established in medical practice.
Description
I 18l~g This invention is concerned with a process for the prepara-tion of
2-methoxyethyl 4-hydroxy-2-methyl-2~1-1,2-benzothiazine-3-carboxylate 1,1-dioxide, q~l ~
~ ~o/~C~13 ~ NCH3 ~1) ~0 an ester having special value in the synthesis of piroxicam ~4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide) (II) ~ CH3 ~
an antiinflammatory agent of established value in the medicinal art. It will be noted that in past practice, the acyl radical of compounds of this type has been sometimes written as O O
and such compounds alternatively named as 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine l,l-dioxide derivatives. Those skilled in the art will 1~
l g understand that these are equivalent tautomeric forms of the same compound.
The present invention is intended to encompass both tautomeric forms while writing only one o~ them as a matter of conven:ience.
Piroxicam was originally disclosed by Lombarclino (United States Patent 3~591,584). One of the processes or the synthesis of piroxicam disclosed therein is to react a 3-carboxylic acid ester with 2-aminopyridine.
More specifically, the ester is disclosed as a (Cl-C12) alkyl ester or phenyl (Cl-C3) alkyl ester. The specific ester described is the methyl ester, viz., ~H O
O ~CH3 (III) ~NCH3 0~ ~0 (See also Lombardino et al., J. Med~ Chem. 1~, pp. 1171-1175 ~1971)). A
disadvantage in this otherwise useful process for piroxicam lies in the variable formation of quantitïes of a highly co]ored byproduct. This highly colored byproduct, which is removed only by multiple recrystallizations with major product loss, lends an unacceptable, strong yellow color to the prioxicam bulk product, even when present at very low levels (e.g., 0.5-1%). This 2~ byproduct has been isolated and determined to have the following structure:
I~CH3 ~IV) I~ ~
O O
It has been shown that (IV) is actuall~ formed as a byproduct in the reaction, rather ~han being derived from a contaminant in the precursor. How this compound is actually formed in the reaction mixture is not fully understood, although methods which are direc-ted to rapid removal of the methanol byproduct as it is formed in the reaction appear to reduce the incidence of piroxicam batches havin~ unacceptable color. However, these methods are of uncertaitl dependability and a goal has been to find an ester which is read:ily available by synthesis and which does not give rise to an ether such as ~IV) as a troublesome byproduct during conversion to piroxicam.
Alternative syntheses of piroxicam which have been disclosed in the literature include reaction of 3,4-dihydro-2-methyl-~-oxo-2E-l-1,2-benzothiazine 10 l,l-dioxide with 2-pyridyl isocyanate ~Lombardino, United States Patent
~ ~o/~C~13 ~ NCH3 ~1) ~0 an ester having special value in the synthesis of piroxicam ~4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide) (II) ~ CH3 ~
an antiinflammatory agent of established value in the medicinal art. It will be noted that in past practice, the acyl radical of compounds of this type has been sometimes written as O O
and such compounds alternatively named as 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine l,l-dioxide derivatives. Those skilled in the art will 1~
l g understand that these are equivalent tautomeric forms of the same compound.
The present invention is intended to encompass both tautomeric forms while writing only one o~ them as a matter of conven:ience.
Piroxicam was originally disclosed by Lombarclino (United States Patent 3~591,584). One of the processes or the synthesis of piroxicam disclosed therein is to react a 3-carboxylic acid ester with 2-aminopyridine.
More specifically, the ester is disclosed as a (Cl-C12) alkyl ester or phenyl (Cl-C3) alkyl ester. The specific ester described is the methyl ester, viz., ~H O
O ~CH3 (III) ~NCH3 0~ ~0 (See also Lombardino et al., J. Med~ Chem. 1~, pp. 1171-1175 ~1971)). A
disadvantage in this otherwise useful process for piroxicam lies in the variable formation of quantitïes of a highly co]ored byproduct. This highly colored byproduct, which is removed only by multiple recrystallizations with major product loss, lends an unacceptable, strong yellow color to the prioxicam bulk product, even when present at very low levels (e.g., 0.5-1%). This 2~ byproduct has been isolated and determined to have the following structure:
I~CH3 ~IV) I~ ~
O O
It has been shown that (IV) is actuall~ formed as a byproduct in the reaction, rather ~han being derived from a contaminant in the precursor. How this compound is actually formed in the reaction mixture is not fully understood, although methods which are direc-ted to rapid removal of the methanol byproduct as it is formed in the reaction appear to reduce the incidence of piroxicam batches havin~ unacceptable color. However, these methods are of uncertaitl dependability and a goal has been to find an ester which is read:ily available by synthesis and which does not give rise to an ether such as ~IV) as a troublesome byproduct during conversion to piroxicam.
Alternative syntheses of piroxicam which have been disclosed in the literature include reaction of 3,4-dihydro-2-methyl-~-oxo-2E-l-1,2-benzothiazine 10 l,l-dioxide with 2-pyridyl isocyanate ~Lombardino, United States Patent
3,591,584), transamidation of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxanilides wi.th 2-aminopyridine (Lombardino~ United States Patent 3,891,637), cyclization of ~ ~C02(Cl-C3)alkyl ~--So2NCH2CONH~3 (Lombardino, United States Patent 3,853,862), coupling of a 4-~Cl-C3)alkoxy-20 2-methyl-2H-1,2-benzothiazine-3-carboxylic acid l,l-dioxide with 2-aminopyridine followed by hydrolysis of the enolic ether linkage ~Lombardino United States Patent 3,892,740), coupling of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid, via the acid chloride, with 2-aminopyridine ~Hammen, United States Patent 4,100,347) and methylation Gf 4-hydroxy-N-2-pyridyl-2H-l, 2-benzothiazine-3-carboxamide (Canada Patent 1,069,894).
Another ester related to the methoxyethyl ester of the present in~lention which has been specifically described in the literature is ethyl I t8~
~I-hydro~y-2-metllyl-2H-l,2-benzothiazine-3-carboxylate l,l-dioxide (Rasmussen, United States Patent 3,501,466; see also Zinnes et al., Un;ted States Patent 3,816,628~.
The 2-methoxyethyl ester ~ as been synthesized. In the known process of converti.ng a corresponding 3-carboxylic acid ester to pi-~oxicam, this ester has been substituted for the prior art methyl ester (III). Use of the novel ester ~I) has the surprising advan-tage that the piroxicam so produced contains no detectable level o-f the expected, highly-colored ether byproduct ~4-(2-methoxyethoxy)-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide)~ of the formula C 2CH20CH3,~
N ~V) O O
analogous ~o the ethor ~IV).
The 2-methoxyethyl ester ~I) of the present invention is readily prepared from saccharin-2-acetate ester (2-methoxyethyl-3-oxo-2H-1,2-benziso-thiazoline-2-acetate l,l-dioxide, formula (VI)) by the following sequence oE
reactions CH2COOCH2CH20CH3 (VI) ~ O
CH3CH2CH2~ ¦ rearrangement q ~
OOCH2CI~20CH3 ~VII) ~ methylation q ~ ~ COOCH2CH20CH3 ~I) 0~ ~0 The rearrangement is carried out by treating the intermediate saccharin-2-acetic acid ester with an alkoxide, preferably a 2-methoxyethoxide such as sodium 2-methoxyethoxide in order to avoid the complication o:E transester-ification, in a polar organi.c solvent such as dimethyl sulfoxide or dimetllylformamicle. Methylation is accomplished by a methylating agent~
such as dimethyl sulfate or a methyl halide, conveniently methyl iodide, in a reaction-inert solvent such as a lower ketone, a lower alkanol, formamide, dimethylformamide or dimethylsulfoxide.
The saccharin-2-acetic acid ester required as starting material in the above sequence is prepared from saccharin and 2-methoxyethyl chlor-oacetate in analogy to the method for preparation o the corresponding methyl ester (Chemische Berichte 30, p. 1267 (1897))J or, less directly, by hydrolysis of said methyl ester to the corresponding saccharin acetic acid and coupling, such as via the acid chlorideJ wi~h 2-methoxyethanol.
The reaction of the methoxy ester (I) with 2-aminopyridine to produce piroxicam, ~1 8 ,~
,~ ~ ~ \ N ~II) ~\ ~ S~ NC 3 H
is generally conducted by mixing the t~o components together in a reaction-inert solvent system at or near room temperature, and then heating the resultant system at 115-175 degrees Celsius for a period of about one-half to several hours. Al~hough it is only necessary that these two reactants be present in substantially equimolar amounts in order ~o effect the reaction3 a slight excess of one or the other (and preferably the more readily available amine base reagent) is not harmful in this respect and may even serve to shift the ammonGlysis reaction to completion. Preferred reaction-inert organic solvents for use in the ammonolysis reaction include such lo~er N,N-dialkylalkanamides as dimethylformamide, dimethylace~amide and the like, as well as such aromatic ~ ~3 i7~9 hydrocarbon solvents as benzene, toluene, xylene and so forth. In any event, it is found most helpful and usually sui~able to distill of:E the volatile alcohol byproduct as it is formed in the reaction and -thereby shift the am~lonolysis equillbrium to completion in -this manner. In the presen-t instance, the most highly preferred so]vent is xylene, since byprod~lct 2-methoxyethanol is ef-flclently removed as a lower bolllng azeotrope. The volume of xylene can be maintained by the addition of more xylene during distillation. After removal of the alcohol and completion of the reaction, the resulting piroxicam is conveniently recovered by cooling and simple filtration of the crystallized product. If desired, the piroxicam is recry-stallized from dimethylacetamide/acetone/water.
The present invention is illustrated by the following examples.
However, it should be understood that the invention is not limited to the specific details of these examples.
~XAMPLE I
~-~2-Methoxyethoxy)~2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide l,l-Dioxide ~04-(2-methoxyethyl)piroxicam) (V) In a flame dried flask maintained under a dry nitrogen atmosphere, piroxicam (1~814 g., 5.47 mmoles) was dissolved in 13 ml. of dry dime-thyl-form~mide. Sodium hydride (0.131 g., 5~47 mmoles) was added slowly in portions and the resulting mixture heated at 40-45 degrees Celsius for abo~l-t 3 hours, until such time as ~he sodium hydride had completely reacted. 2-Methoxyethyl chloride ~1.0 ml., 0.94 mmoles) and sodium iodide (0.821 g., 7 ~l ~
5.~7 mmoles) were then aclded and the reaction then heated at 89 degrees Celsius for 51 hours. The cooled reaction mixture was dlluted with about 50 g. of ice and extracted with five 10 ml. portions of me-thylerle chloride.
The organic extracts were com~inedl back washed with seven l5 ml. portions of water~ washed once with brine, dried over anhydrous magnesium swlfate~
filtered and evaporated to an oil (1.44 g.). The oil was triturated with ether, yielding solids (0.84 g.), which were recrys~allized ~rom acetonitrile (yielding 0.57 g.). Recrystallized product (0.45 g.) was chromatographed on silica gel ~13.5 g.), eluting with 2:3:6 methanol:cyclohe~ane:ethyl acetate and monitoring by TLC ~same eluant) with phosphomolybdic spray.
Early cuts, containing clean product, were combined, evaporated in vacuo to solids, Ihe solids were chased with carbon tetrachloride an~ dried under high vacuum yielding 04-~2-methox~ethyl~piroxicam. ~0.31 g.; m.p. 155-157 degrees Celsius; Rf 0.5 ~2:3:6 methanol:cyclohexane:ethyl acetate); Rf 0.4 ~10:4:3 xylene:methallol:water); pnmr/CDC13/delta 3.15 (s, 3H), 3.35 (s, 3H), 3.68 ~m, 2H), 4.23 (m, 2H), 7.2 (m lH), 7.9 (m, 5H), 8.9 (m, 2H), 10.2 (broad s, lH)).
2-Methox~eth_1 2~ -Ch oroacetate Maintaining a temperature of -5 to 5 degrees Celsius, 2-chloro-acetyl chloride ~11.2 g., 0.10 mole) in 15 ml. of methylene chloride was added dropwise over 1 hour to a cold solution of pyridine ~8.0 g., 0.11 mole) and 2-methoxyethanol ~7.6 g., 0.10 mole) in 35 ml. of methylene chloride.
The reaction mixture was stirred for a further 1 hour at 0 degrees Celsius, warmed to room temperature and extracted with two 50 ml. portions of wa~er.
The two aqueous extracts were combined and back-washed with 50 ml. of (3 chlorofrm- Th~ origlnal organic layer and chloroform back-wash were combined and ~ashed with 50 ml. o~ 5% copper sulfate. The 5% copper sulfate wash was backwashed wi~h 25 ml. of chloroform and recomb;ned with the organic phase. ~inally, khe organic phase was washed with 50 ml. of brine, treated with activated carbon and anhydrous magnesium sulfate, ~iltered, concentrated to an oil and distilled to yield 2-methoxyethyl 2-chloroacetate ~14.1 g.; b.p. 80-82 degrees Celsius.) 2-Methoxyethyl 3-Oxo-2H-1,2-benzisothiazoline-2-acetate l,l-Dioxide ~2-Methoxyethyl Saccharin-2-acetate) ~I3 Sodium saccharin ~18 g., 0.088 mole) and 2-methoxyethyl 2-chloro-acetate ~13.4 g. J 0.088 mole) were combined in 40 ml. of dimethylformamide and heated at 120 degrees Celsius for 4 hours. The reaction mixture was cooled to 25 degrees Celsius~ poured into 100 ml. of waterJ granulated at 5-10 degrees Celsius l`or 0.5 hour, filtered with water wash and air dried to yield 2-methoxyethyl saccharin-2-acetate ~23.2 g., 90%; m.p. 91-92 degrees Celsius; m/e 299; ir~KBr) 2985 cm 1) 2-Methoxyethyl 4-llydroxy-2H-1,2-benzothiazine-3-carboxylate l,l-dioxide Under a dry nitrogen atmosphereJ 2-methoxyethanol (72.9 ml., 0.924 mole) was charged to a stirred, flamedried flask. Sodium spheres (10.6 g.~
0.463 mole; pentane washed and slightly flattened with tweezers) were added _g_ I L~17~3 portionwise over 2 hours, keeping the temperature of the reaction mix-ture in the range of 25-~5 degrees Celsius. After an additional 1 hour o-f stirring, a fur-ther 10 ml. o~ 2-methoxyethanol was added and the reaction mixture warmed to 57 degrees Celsius. On slight cooling the reaction mix-ture solicl-ified. The reaction mixture was thinned with 75 mL. o~ dry dime-thylsul~oxicle and a single remaining particle of soclium metal removed mechanically. The 2-methoxyethyl saccharin-2-acetate (50 g., 0.167 mole) in 70 ml. of warm, dry dimethylsul~oxide was added dropwise over 20 minutes. The reaction mixture was stirred for 1 hour at ambient temperature, quenched into a mixture of concentrated hydrochloric acid ~276 ml.) and water (1.84 1.), maintaining the temperature of the quench at 20-25 degrees Celsius by an ice-water bath and rate of addition. The slllrry was granulated at 6-8 degrees Celsius for 1 hour, filtered with cold water wash and dried in air to yield 2-methoxy-ethyl ~-hydroxy-2H-1l2-benzothiazine-3-carboxylate l,l-dioxide ~32.8 g., 66%; m.p. 120-122 degrees Celsius; ir(KBr) 3~8, 3226 cm ).
2-Methoxyethyl ~-Hydroxy-2-methyl-21~-1,2-benzothiazine-3-carboxylate l,l-Dioxide ~I) 2-Methoxyethyl ~-hydroxy-2E~-lJ2-benzothiazine-3-carboxylate 1,1-dioxide ~31.0 g., 0.1035 mole) was combined with 230 ml. of acetone and cooled to 10 degrees Celsius. Methyl iodide ~21.9 g., 0.155 mole) was added, followed by the dropwise addition, over 10 minutes, of sodi~ hydroxide ~103.5 ml. of lN). The cooling bath was removed and the reaction mixture allowed to slowly warm to room temperature ~about ~5 minutes~, then heated -].0-7 ~ '3 at 35 degrees Celsius for 2 hours and finally at 39-40 degrees Celsius for 16 hours. The reaction mixture was cooled to room temperature, diluted with 200 ml. of acetone, treated with activated carbon, flltered and concentrated in vacuo at 0-5 degrees Celsius to about 50 ml. The resulting slurry was filtered, and solids washed witZ~ ice-water and then dried in vacuo to yield 2 m0thoxyethyl 4-hydroxy-2-methyl-2H-1l2-benzothiazine-3-carboxylate 1,1-dioxide (29.26 g., 90%; m.p. 106-107.5 degrees Celsius; m/e 313; ir~KBr) 3345, 2~41, 1684, 1351, 1053 cm 1~.
EX~IPLE 6
Another ester related to the methoxyethyl ester of the present in~lention which has been specifically described in the literature is ethyl I t8~
~I-hydro~y-2-metllyl-2H-l,2-benzothiazine-3-carboxylate l,l-dioxide (Rasmussen, United States Patent 3,501,466; see also Zinnes et al., Un;ted States Patent 3,816,628~.
The 2-methoxyethyl ester ~ as been synthesized. In the known process of converti.ng a corresponding 3-carboxylic acid ester to pi-~oxicam, this ester has been substituted for the prior art methyl ester (III). Use of the novel ester ~I) has the surprising advan-tage that the piroxicam so produced contains no detectable level o-f the expected, highly-colored ether byproduct ~4-(2-methoxyethoxy)-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide)~ of the formula C 2CH20CH3,~
N ~V) O O
analogous ~o the ethor ~IV).
The 2-methoxyethyl ester ~I) of the present invention is readily prepared from saccharin-2-acetate ester (2-methoxyethyl-3-oxo-2H-1,2-benziso-thiazoline-2-acetate l,l-dioxide, formula (VI)) by the following sequence oE
reactions CH2COOCH2CH20CH3 (VI) ~ O
CH3CH2CH2~ ¦ rearrangement q ~
OOCH2CI~20CH3 ~VII) ~ methylation q ~ ~ COOCH2CH20CH3 ~I) 0~ ~0 The rearrangement is carried out by treating the intermediate saccharin-2-acetic acid ester with an alkoxide, preferably a 2-methoxyethoxide such as sodium 2-methoxyethoxide in order to avoid the complication o:E transester-ification, in a polar organi.c solvent such as dimethyl sulfoxide or dimetllylformamicle. Methylation is accomplished by a methylating agent~
such as dimethyl sulfate or a methyl halide, conveniently methyl iodide, in a reaction-inert solvent such as a lower ketone, a lower alkanol, formamide, dimethylformamide or dimethylsulfoxide.
The saccharin-2-acetic acid ester required as starting material in the above sequence is prepared from saccharin and 2-methoxyethyl chlor-oacetate in analogy to the method for preparation o the corresponding methyl ester (Chemische Berichte 30, p. 1267 (1897))J or, less directly, by hydrolysis of said methyl ester to the corresponding saccharin acetic acid and coupling, such as via the acid chlorideJ wi~h 2-methoxyethanol.
The reaction of the methoxy ester (I) with 2-aminopyridine to produce piroxicam, ~1 8 ,~
,~ ~ ~ \ N ~II) ~\ ~ S~ NC 3 H
is generally conducted by mixing the t~o components together in a reaction-inert solvent system at or near room temperature, and then heating the resultant system at 115-175 degrees Celsius for a period of about one-half to several hours. Al~hough it is only necessary that these two reactants be present in substantially equimolar amounts in order ~o effect the reaction3 a slight excess of one or the other (and preferably the more readily available amine base reagent) is not harmful in this respect and may even serve to shift the ammonGlysis reaction to completion. Preferred reaction-inert organic solvents for use in the ammonolysis reaction include such lo~er N,N-dialkylalkanamides as dimethylformamide, dimethylace~amide and the like, as well as such aromatic ~ ~3 i7~9 hydrocarbon solvents as benzene, toluene, xylene and so forth. In any event, it is found most helpful and usually sui~able to distill of:E the volatile alcohol byproduct as it is formed in the reaction and -thereby shift the am~lonolysis equillbrium to completion in -this manner. In the presen-t instance, the most highly preferred so]vent is xylene, since byprod~lct 2-methoxyethanol is ef-flclently removed as a lower bolllng azeotrope. The volume of xylene can be maintained by the addition of more xylene during distillation. After removal of the alcohol and completion of the reaction, the resulting piroxicam is conveniently recovered by cooling and simple filtration of the crystallized product. If desired, the piroxicam is recry-stallized from dimethylacetamide/acetone/water.
The present invention is illustrated by the following examples.
However, it should be understood that the invention is not limited to the specific details of these examples.
~XAMPLE I
~-~2-Methoxyethoxy)~2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide l,l-Dioxide ~04-(2-methoxyethyl)piroxicam) (V) In a flame dried flask maintained under a dry nitrogen atmosphere, piroxicam (1~814 g., 5.47 mmoles) was dissolved in 13 ml. of dry dime-thyl-form~mide. Sodium hydride (0.131 g., 5~47 mmoles) was added slowly in portions and the resulting mixture heated at 40-45 degrees Celsius for abo~l-t 3 hours, until such time as ~he sodium hydride had completely reacted. 2-Methoxyethyl chloride ~1.0 ml., 0.94 mmoles) and sodium iodide (0.821 g., 7 ~l ~
5.~7 mmoles) were then aclded and the reaction then heated at 89 degrees Celsius for 51 hours. The cooled reaction mixture was dlluted with about 50 g. of ice and extracted with five 10 ml. portions of me-thylerle chloride.
The organic extracts were com~inedl back washed with seven l5 ml. portions of water~ washed once with brine, dried over anhydrous magnesium swlfate~
filtered and evaporated to an oil (1.44 g.). The oil was triturated with ether, yielding solids (0.84 g.), which were recrys~allized ~rom acetonitrile (yielding 0.57 g.). Recrystallized product (0.45 g.) was chromatographed on silica gel ~13.5 g.), eluting with 2:3:6 methanol:cyclohe~ane:ethyl acetate and monitoring by TLC ~same eluant) with phosphomolybdic spray.
Early cuts, containing clean product, were combined, evaporated in vacuo to solids, Ihe solids were chased with carbon tetrachloride an~ dried under high vacuum yielding 04-~2-methox~ethyl~piroxicam. ~0.31 g.; m.p. 155-157 degrees Celsius; Rf 0.5 ~2:3:6 methanol:cyclohexane:ethyl acetate); Rf 0.4 ~10:4:3 xylene:methallol:water); pnmr/CDC13/delta 3.15 (s, 3H), 3.35 (s, 3H), 3.68 ~m, 2H), 4.23 (m, 2H), 7.2 (m lH), 7.9 (m, 5H), 8.9 (m, 2H), 10.2 (broad s, lH)).
2-Methox~eth_1 2~ -Ch oroacetate Maintaining a temperature of -5 to 5 degrees Celsius, 2-chloro-acetyl chloride ~11.2 g., 0.10 mole) in 15 ml. of methylene chloride was added dropwise over 1 hour to a cold solution of pyridine ~8.0 g., 0.11 mole) and 2-methoxyethanol ~7.6 g., 0.10 mole) in 35 ml. of methylene chloride.
The reaction mixture was stirred for a further 1 hour at 0 degrees Celsius, warmed to room temperature and extracted with two 50 ml. portions of wa~er.
The two aqueous extracts were combined and back-washed with 50 ml. of (3 chlorofrm- Th~ origlnal organic layer and chloroform back-wash were combined and ~ashed with 50 ml. o~ 5% copper sulfate. The 5% copper sulfate wash was backwashed wi~h 25 ml. of chloroform and recomb;ned with the organic phase. ~inally, khe organic phase was washed with 50 ml. of brine, treated with activated carbon and anhydrous magnesium sulfate, ~iltered, concentrated to an oil and distilled to yield 2-methoxyethyl 2-chloroacetate ~14.1 g.; b.p. 80-82 degrees Celsius.) 2-Methoxyethyl 3-Oxo-2H-1,2-benzisothiazoline-2-acetate l,l-Dioxide ~2-Methoxyethyl Saccharin-2-acetate) ~I3 Sodium saccharin ~18 g., 0.088 mole) and 2-methoxyethyl 2-chloro-acetate ~13.4 g. J 0.088 mole) were combined in 40 ml. of dimethylformamide and heated at 120 degrees Celsius for 4 hours. The reaction mixture was cooled to 25 degrees Celsius~ poured into 100 ml. of waterJ granulated at 5-10 degrees Celsius l`or 0.5 hour, filtered with water wash and air dried to yield 2-methoxyethyl saccharin-2-acetate ~23.2 g., 90%; m.p. 91-92 degrees Celsius; m/e 299; ir~KBr) 2985 cm 1) 2-Methoxyethyl 4-llydroxy-2H-1,2-benzothiazine-3-carboxylate l,l-dioxide Under a dry nitrogen atmosphereJ 2-methoxyethanol (72.9 ml., 0.924 mole) was charged to a stirred, flamedried flask. Sodium spheres (10.6 g.~
0.463 mole; pentane washed and slightly flattened with tweezers) were added _g_ I L~17~3 portionwise over 2 hours, keeping the temperature of the reaction mix-ture in the range of 25-~5 degrees Celsius. After an additional 1 hour o-f stirring, a fur-ther 10 ml. o~ 2-methoxyethanol was added and the reaction mixture warmed to 57 degrees Celsius. On slight cooling the reaction mix-ture solicl-ified. The reaction mixture was thinned with 75 mL. o~ dry dime-thylsul~oxicle and a single remaining particle of soclium metal removed mechanically. The 2-methoxyethyl saccharin-2-acetate (50 g., 0.167 mole) in 70 ml. of warm, dry dimethylsul~oxide was added dropwise over 20 minutes. The reaction mixture was stirred for 1 hour at ambient temperature, quenched into a mixture of concentrated hydrochloric acid ~276 ml.) and water (1.84 1.), maintaining the temperature of the quench at 20-25 degrees Celsius by an ice-water bath and rate of addition. The slllrry was granulated at 6-8 degrees Celsius for 1 hour, filtered with cold water wash and dried in air to yield 2-methoxy-ethyl ~-hydroxy-2H-1l2-benzothiazine-3-carboxylate l,l-dioxide ~32.8 g., 66%; m.p. 120-122 degrees Celsius; ir(KBr) 3~8, 3226 cm ).
2-Methoxyethyl ~-Hydroxy-2-methyl-21~-1,2-benzothiazine-3-carboxylate l,l-Dioxide ~I) 2-Methoxyethyl ~-hydroxy-2E~-lJ2-benzothiazine-3-carboxylate 1,1-dioxide ~31.0 g., 0.1035 mole) was combined with 230 ml. of acetone and cooled to 10 degrees Celsius. Methyl iodide ~21.9 g., 0.155 mole) was added, followed by the dropwise addition, over 10 minutes, of sodi~ hydroxide ~103.5 ml. of lN). The cooling bath was removed and the reaction mixture allowed to slowly warm to room temperature ~about ~5 minutes~, then heated -].0-7 ~ '3 at 35 degrees Celsius for 2 hours and finally at 39-40 degrees Celsius for 16 hours. The reaction mixture was cooled to room temperature, diluted with 200 ml. of acetone, treated with activated carbon, flltered and concentrated in vacuo at 0-5 degrees Celsius to about 50 ml. The resulting slurry was filtered, and solids washed witZ~ ice-water and then dried in vacuo to yield 2 m0thoxyethyl 4-hydroxy-2-methyl-2H-1l2-benzothiazine-3-carboxylate 1,1-dioxide (29.26 g., 90%; m.p. 106-107.5 degrees Celsius; m/e 313; ir~KBr) 3345, 2~41, 1684, 1351, 1053 cm 1~.
EX~IPLE 6
4-~lydroxy-2-methyl-N-2-pyridyl-2~1-1,2 benzothiazine-3-carboxamide l,l-Dioxide (Piroxicam) ~II) 2-Methoxyethyl 4-hydrox~-2H-1,2-ben~othiazine-3-carboxylate 1,1-dioxide ~28 g., 0.08~ mole) and 2-aminopyridine ~9.26 g., 0.098 mole) were combined with 500 ml. of xylene in a 1 liter flask equipped with an additional funnel and a reflux, variable take-off distillation head. The stirred reaction mixture was heated to relux and the xylene distilled at the rate of approx-imately 100 ml./hour, while maintaining the pot volume almost constant bythe addition of fresh xylene. After 6 hours, the head temperature, which had been relatively constant at 134 degrees Celsius, rose to 142 degrees Celsius and reflux rate slowed. The reaction mixture was then cooled in an ice-bath and the precipitated solids recovered by filtration, with hexane for transfer and wash, and dried at 45 degrees Celsius in vacuo to yield piroxicam ~28.5 g., 96%; m,p. 167-174 degrees Celsius). This product was examined by high perform~nce liquid chromatography using 60:40 O.lM Na2~1P0~ adjusted to p}l 7.5 -Ll-7 ~1 g with citric acicl:methanol on Micro-Bonda pak C18 (Trademark of Waters Associates for a standard hplc column packing consisting of siloxy sub-stituted silica coated on micro-glass beads.) Under the conditions employed, piroxicam has a rete.ntion time of about 6 m.inutes, whereas the potential contaminant, 04-methoxyethylpiroxicam, has a retention time of 16.5 minutes.
None of the potential contc~minant was detected in the product o the present Example .
For purposes o:E recrystallization, the above piroxicam ~25 g.) was taken up in 190 ml. of dime~.hylacetamide at 70-75 degrees Celsius, treated with 1.26 g. of activated carbon at 75-80 degrees Celsius and filt0red through diatomaceous earth with 55 ml. of warm dimethylacetamide for transfer and wash. A mixture of 173 ml. of ace~one and 173 ml. of watex was cooled to 5-10 degrees Celsius. The carbon-treated filtrate was added slowly over 10-15 minutes to the chilled aqueous acetone, and the resulting crystals granulated at 0-5 degrees Celsius for 5 minutes. Recrystallized piroxicam was recovered by filtration with 154 ml. of cold methanol for ui~
tran~sfer and wash. Yield: 18.75 g,, 75%; ir~ r~ mull) identical with authentic piroxicam.
Tradc mar ~--12~
None of the potential contc~minant was detected in the product o the present Example .
For purposes o:E recrystallization, the above piroxicam ~25 g.) was taken up in 190 ml. of dime~.hylacetamide at 70-75 degrees Celsius, treated with 1.26 g. of activated carbon at 75-80 degrees Celsius and filt0red through diatomaceous earth with 55 ml. of warm dimethylacetamide for transfer and wash. A mixture of 173 ml. of ace~one and 173 ml. of watex was cooled to 5-10 degrees Celsius. The carbon-treated filtrate was added slowly over 10-15 minutes to the chilled aqueous acetone, and the resulting crystals granulated at 0-5 degrees Celsius for 5 minutes. Recrystallized piroxicam was recovered by filtration with 154 ml. of cold methanol for ui~
tran~sfer and wash. Yield: 18.75 g,, 75%; ir~ r~ mull) identical with authentic piroxicam.
Tradc mar ~--12~
Claims (6)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of 2-methoxyethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide of the formula (I) which comprises methylating 2-methoxyethyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide of the formula (VII)
2. A process according to claim 1 wherein (VII) is prepared by subjecting 2-methoxyethyl 3-oxo-2H-1,2-benzisothiazolin-2-acetate 1,1-dioxide of the formula (VI) to rearrangement.
3. A process according to claim 1 wherein the methylation is effected by reacting (VII) with dimethyl sulfate or a methyl halide.
4. A process according to claim 2 wherein the rearrangement is effected by treating (VI) with alkali metal 2-methoxyethoxide.
5. A process according to claim 2 wherein the rearrangement is effected by treating (VI) with an alkali metal 2-methoxyethoxide, and wherein (VII) is methylated by reaction with dimethyl sulfate or a methyl halide.
6. 2-Methoxyethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide, when prepared by the process of claim 1, 2 or 5 or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000445578A CA1181749A (en) | 1980-09-29 | 1984-01-18 | Process for the preparation of 2-methoxyethyl 4- hydroxy-2-methyl-2h-1,2-benzothiazine-3-carboxylate 1,1-dioxide |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US191,716 | 1980-09-29 | ||
| US06/191,716 US4289879A (en) | 1980-09-29 | 1980-09-29 | Synthetic method and intermediate for piroxicam |
| CA000386690A CA1171413A (en) | 1980-09-29 | 1981-09-25 | Synthetic method and intermediate for piroxicam |
| CA000445578A CA1181749A (en) | 1980-09-29 | 1984-01-18 | Process for the preparation of 2-methoxyethyl 4- hydroxy-2-methyl-2h-1,2-benzothiazine-3-carboxylate 1,1-dioxide |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000386690A Division CA1171413A (en) | 1980-09-29 | 1981-09-25 | Synthetic method and intermediate for piroxicam |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1181749A true CA1181749A (en) | 1985-01-29 |
Family
ID=27167143
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000445578A Expired CA1181749A (en) | 1980-09-29 | 1984-01-18 | Process for the preparation of 2-methoxyethyl 4- hydroxy-2-methyl-2h-1,2-benzothiazine-3-carboxylate 1,1-dioxide |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1181749A (en) |
-
1984
- 1984-01-18 CA CA000445578A patent/CA1181749A/en not_active Expired
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