CA1190232A - Processes for preparing piroxican and intermediates leading thereto - Google Patents

Abstract

PROCESSES FOR PREPARING PIROXICAM AND
INTERMEDIATES LEADING THERETO

Abstract Intermediates for the preparation of the antiinflamma-tory agent piroxicam and their process of preparation which com-prises reacting N-methylsaccharin with alkyl haloacetates in the presence of an appropriate base to give the intermediates alkyl 2-(2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisosulfonazol-3-yl)-2-haloacetate which can then be converted into piroxicam.

Description

~ 3~ 4680-195D

This invention relates to certain intermediates which can be converted to piroxicam.
This application is divided from applicants copending application Serial No. 412,724 filed on October 4, 1982.
Piroxicam, a potent antiinflammatory agent, was first reported by Lombardino in United States Patent 3,591,584. One of the processes for 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 (C1-C12)al]cyl ester or phenyl(C1-C3)alkyl ester. The specific ester described is the methyl ester, vlz., OH O
,~ ~o/CH3 S,NCH3 O O
[See also Lombardino et al., J. Med. Chem. 14, pp. 1171-1175 (1971)]
It is also known that the corresponding 2-methoxyethyl ester can be used in place of the methyl ester in its reaction with 2-aminopyridine with certain advantages.

~' Other alternative syntheses of piroxicam which have been disclosed in the literature include reaction of 3,4-dihydro-2-methyl-4-oxo-2H-I,2-benzothiazine 1,1-dioxide with 2-pyridyl iso-cyanate (Lombardino, U.S. Patent 3,~91,584), transamidation of 4-hydroxy-2-methyl-2~-1,2-benzothiazine-3-carboxanilides with 2-aminopyr.idine (Lombardino, V.S. Patent 3,8~1,637), cyclization of ~ CO2(Cl-C3)alkyl I 1~
~/\ S02MCH 2CONH
c~3 (Lombardino, U.S. Patent 3,8~3,862), coupling of a 4-(C1-C3)al-koxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide with 2-aminopyridine followed by hydrolysis of the enolic ether linkage (Lombardino U.S. 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, U.S Patent 4,100,347) and methylation of 4-hydroxy-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide (Canada Patent 1,069,894).
According to the present invention, there is now pro-vided a process for preparing a compound selected from those of the formula X

~/ R
N-CH
0~
wherein X is selected from the group consisting of chloro, bromo and iodo; and R1 is selected from the group consisting of alkoxy having from one to four carbon atoms and 2-methoxyethoxy char-acterized by reacting a compound of the formula

3~
- 2a -~N-CH
S /

with a compound selected from those of the formula in the presence of two equivalents of a metal hydride in tetra-hydrofuran at a reaction temperature of about 40 to 50DC. The products produced by this process are novel intermediates useful in the preparation of piroxicam.
It is disclosed in applicant's aforementioned Canadian Appln~ Ser. No. 412,724, that a compound selected from -the for-mula OH
l~rcoy s~N\

I

3~

where Y is alkoxy of one to four carbon atoms, 2-methoxyethoxy or 2-pyridylimino can be prepared by reaction a compound of the formula o ~ , .

o ; with a compounds selected from the formula X-CH2C-Y
wherein X is chloro, bromo or iodo in a polar, re-action-inert solvent in the presence of at least two equivalents of a base selected from the group consist-ing of a metal hydride, an alkali metal alkoxide having one to four carbon atoms, potassium hexamethyl disilazane and potassium diisopropylamine at a temperature of from about 25C. to about 70C. until the reaction is substantially complete.
A preferred feature of this process is the use of a reaction-inert solvent selected from dimethylform-amide, dimethylacetamide, dimethylsulfoxide, hexa-methylphosphoramide and l-methyl-2-pyrrolidone.
A further preferred feature of this process is the use of a metal hydride selected from potassium hydride, sodium hydride and calcium hydride.
An especially preferred feature of the present process is the use of the compound X~CH2CO-Y wherein X
is chloro or bromo, the reaction-inert solvent is di-methylformaMide or dimethylsulfoxide, the metal hydride is sodium hydride and Y is methoxy, 2-methoxy-ethoxy or 2-pyridylimino. A second especially preferred feature of this process is the use of dimethylsulfoxide as solvent and potassium hexamethyl disilazane as the base, and wherein Y is methoxy and X is chloro.

Another preferred feature oE this process is the use of the aforementioned preferred solvents wherein the base is an alkali metal alkoxide having one to four carbon atoms. Especially preferred is the use of potassium t-butoxide as the base and dimethylsulfoxide as the solvent wherein X is chloro and Y is methoxyO
Those compounds of this process where Y is said al]coxy and methoxyethoxy are useful intermediates leading to piroxicam as described in the aEorementioned art references, while the compound where Y is ~-pyridylimino is piroxicam, a useful antiinflammatory agent.
This process offers distinct advantages over other pro-cesses leading to piroxicam and intermediates thereto since the methylation step of the 4-hydroxy-2H-1,2-benzothiazine ring system is avoided, the methyl group being introduced in the readily available N-methylsaccharin starting material. In addition, this process provides the desired products in a high yield one-step process.
The novel intermediates of the present invention are useful in a process for preparing compounds selected from the formula OH
CO-R

~CH3 wherein R1 is alkoxy of one to four carbon atoms or 2-methoxy-ethoxy which comprises reacting a compound selected from the formula 3~

X
~1 II
wherein X is chloro, bromo or iodo with one equivalent of a metal hydride in a polar, reaction-inert solvent at from about 25-C. to about 50-C. until the reaction is substantially complete.
A preferred feature of this process is the use of a reaction-inert solvent selected from dimethylformamide, dimethyl~
acetamide, dimethylsulfoxide, hexamethylphosphoramide and 1-methyl-2~pyrrolidone.
Another preferred feature of this process is the sel-ection oE a metal hydride Erom potassium hydride, sodium hydrideand calcium hydride.
An especially preferred feature oE this process is the use of a starting reagent wherein X is chloro, the reaction-inert solvent is dimethylformamide or dimethylsulfoxide, the metal hydride is sodium hydride and R1 is methoxy or 2-methoxye-thoxy.
The compounds of this process are useful intermediates leading to piroxicam as described in the aforementioned art refer-ences.
This process has the advantages of providing the desired products in high yield and also precludes the necessity for methylation of the 4-hydroxy-2H-1,2-benzothiazine ring system.

The present invention, together with that of applicants aforementioned Canadian Appln. Ser. No. 412,724 will now be fur-ther described and exemplified.
As one skilled in the art can readily recognize the compounds represented below can exist in either the ketonic or enolic tautomeric form:

rco~ o~
S \CH S ~CH3 Those skilled in the art will understand that these forms are equivalent. The present disclosure is intended to encompass both tautomeric forms while writing only one of them as a matter of convenience.
The Eirst process leading to the synthesis of the anti-inflammatory agent piroxicam and intermediates useful in the pre~
paration of this agent through an aminolysis reaction can be depicted as follows:

3~

OE~ ;
~/~~CO--y /N-CH3 + ~-CH2c_y~ ~ ~ CH3 where X and Y are as previously defined.
The process comprises the reaction of one mole of N-methylsacc'narin with one mole of a haloacetate or haloacetamide derivative. Although eguimoles of the reactant are required it is preferred, for optimum yields, that an excess of the haloacetate or ha'lo-acetamide be employed. It is further preferred that as much as 100% excess of these reagents be used.
Larger amcunts can be employed, but have little if any affect on the yield of the product.
Also utilized in this process for condensing N-methylsaccharin and haloacetate or haloacetamide derivatives is a metal hydride. For each mole of N
methylsaccharin two equivalents of a metal hydride are employed. Any metal hydride can be employed, although alkali metal hydrides are preferred since many are commercially available or can be readily prepared.
In addition to metal hydrides, other bases, when used in the manner prescribed for the metal hydrides, also facilitate the condensation reaction of this process. These include alkali metal alkoxides, potassium hexamethyl disilazane and potassium di-isopropylamine.

5~ r The present process is also conducted in a re-action-inert solvent. Such a solvent, or mixtures thereof, should solubilize the reactants to such an extent that the reaction is facilita-ted, but not re-acted with the reactants or product to any appreciable extent. Such solvents should also be highly polar, having a dielectric constant (e) of >35. These include such preferred solvents as dimethylformamide, dimethylacetamide, hexamethylphosphoramide, dimethyl-sulfoxide and 1-methyl-2-pyrrolidone.
Regarding the manner in which the reagents are combined, it i5 preferred that the metal hydride be added to a solution of the reactants in the reaction-inert solvent. In practice, the hydride is added to the reaction mixture, preheated to the desired reacting temperature, over a period of one to two hours, or at such a rate that the heat formed during the addition of the hydride does not cause overheating of the reaction ~ixture.
Concerning reaction temperature, the present process can be conducted at an ambient temperature of about 25C. to about 70C. Reaction -temperatures lower or higher than the preferred temperature range will provide product, but will have a deleterious affect on the product, and offer no distinct advantages.
Following the addition of the metal hydride, the reaction temperature is maintained for two to six hours to ensure completion of the reaction.

3~

On completion of the reaction mixture is quenched in cold 5% hydrochloric acid and the product either filtered and dried or extracted into a water immiscible solvent such as methylene chloride. The product, after filtration and drying or aEter removal o the extracting solvent, can be purified by con-ventional means, or can be employed in subsequent steps leading to piroxicam without purification.
The use of the intermediates oE the present invention leading to useful intermediates in the synthesis of the anti-inflammatory agent piroxicam can be depicted as follows:

HO ~ Metal O~II
N-cH3 1 hydrides ~ ;~COR

wherein X and R1 are as previously defined.
The process comprises reacting one mole of an appro-pria-te 1,2-benzisosulfona~ole with an equivalent of a metal hydride in a polar reaction-inert solvent. Any metal hydride can be used, although alkali metal hydrides and alkaline earth metal hydrides are preferred as many are commercially available or can be readily prepared. Especially preferred are sodium hydride, potassium hydride and calcium hydride.

-- 10 ~

The process is also carried out in a reaction-inert solvent. Such a solvent, or mixture~s thereof, should solubilize the reactants to such a degree that the reaction is facilitated but should not react with the reagents or the product to any appreciable extent. Such solvents should also be highly polar solvents having a dielectric constant (e) of ~35. These include such preferred solvents as dimethylsulEoxide, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidone and hexamethylphosphor-amide.
Regarding the combining of the reagents, the appropriat.e metal hydride can be added to the requisite 1,2-benzisosulfonazole in a reaction-inert solvent, or the 1,2-benzisosulfonazole in the reaction-inert solvent can be added to a suspension of the metal hydride in the reaction-inert solvent.
E'ollowing the combining of the reagents, the reaction is heated to the reaction temperature of from about 25-C. to about 50~C. Reaction temperatures lower or higher will provide product, but will have a deleterious affect on yields and purity of the product, and offer no distinct advantages~ At the preferred reaction temperatures the reaction is complete in about one-half to three hours.
On completion of the reaction the mixture is quenched in cold 5~ hydrochloric acid and the product filtered or extracted with a water immissible solvent, such as methylene chloride. The product remaining after removal of the extracting solvent or that obtained by filtration can be purified by conventional means, or can be employed in the preparation of piroxicam without further puriEication.

3~

A preferred feature of this process is the use of those reagents wherein X is chloro, the reaction-inert solvent in di-methylformamide or dimethylsulfoxide and the metal hydride is sodium hydroxide.
Especially preferred is the preparation of products by this process wherein Rl i5 methoxy and 2-methoxyethoxy.
The starting reagents for this process, i.e. the novel intermediates of the present invention, are prepared by reacting one mole of N-methylsaccharin with one mole of an appropriate haloacetate in the presence of two equivalents of a metal hydride, such as sodium hydride, in a reaction-inert solvent such as tetra-hydrofuran as follows:

~N-CH3 ~ XCH2C-Rl II
In practice a solution of N-methylsaccharin in tetra-hydrofuran is treated with two equivalents of sodium hydride and the resulting reaction mixture warmed to about 40-C~ The re-quisite alkyl or 2-methoxyethyl haloacetate is added over a period of about one hour, and the reaction mixture heated for several hours at 40-50-Co following the completion of the additionO On completion of the reaction the mixture is added to a cold 5~
hydrochloric acid solution, and the alkyl or 2-methoxyethyl 2-(2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisosulfonazol-3-yl)-2-halo-acetate either filtered and dried or extracted 3~
- 12 ~

with a water immiscible solvent such as methylene chloride. If necessary, the product can be purified by conventional means.
Preferred are those compounds of formula II wherein X is chloro. Especially preferred are methyl 2-(2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisosulfonazol-3-yl)-2-chloroacetate and 2-methoxyethyl 2-(2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisosul-Eonazol-3-yl)-2-ch:loroacetate.
Aside from the known antiinflammatory agent piroxicam, the other products of the processes oE the present invention are useful intermediates leading to piroxicam by preparatory methods described herein and/or described in the herein cited literature and patent references.
The following examples are provided solely for the pur-pose of further illustration. Nuclear magnetic resonance spectra (NMR) were measured at 60 MHz for solutions in deuterochloroform (CDCl3), perdeutero dimethyl sulfoxide (DMSO-d6) or deuterium oxide (D2O) or are noted otherwise, and peak positions are ex-pressed in parts per million (ppm) downfield Erom tetramethyl-silane or sodium 2,2-dimethyl-2-silapentane-5-sulfonate. The following abbreviations for peak shapes are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet.

3~

2-Methoxyethyl 4-hydroxy-2-methyl-2H~1,2-benzothiazine-3-carboxylate l,l-dioxide ~I; Y = -OCH2CH20CH3) _ . ... _ _. _ __ _ ~ . .
A.
~ tate Maintaining a temperature of -5 to 5C., 2-chloroace-tyl chloride ~11.2 g., 0.10 mole) in 15 ml.
of methylene chloride was added dropwise ovPr l hour -to a cold solution of pyridine (8.0 g., 0.11 mole) and 2-methoxyethanol (706 g., 0.10 mole) in 35 ml. of methylene chloride. The reaction mixture was stirred for a further 1 hour at 0C., warmed to room temperature and extracted with two 50 ml. portions of water. The two aqueous extracts were combined and back-washed with 50 ml. of chloroform. The original organic layer and chloroform back-wash were combined and washed with S0 ml. of 5% copper sulfate. The 5%
copper sulfate wash was back-washed with 25 ml. of chloroform and recombined with the organic phase.
Finally, the organic phase was washed with 50 ml. of brine, treated with activated carbon and anhydrous magnesium sulfate, filtered, concentrated to an oil and distilled to yield 2-methoxyethyl 2-chloroacetate (14.1 g.; b.p. 80-82C.).
B.
2-methoxyethyl 4-hydroxy-2-methyl-2H-1,2-~enzothiazine-3-car~oxylate l,I-dioxide To a solution of 3.0 g. (0.015 mole) of N-methylsaccharin and 2.3 g. (0.015 mole) of 2-methoxy-ethyl chloroacetate in 15 ml. of dimethylsulfoxide at 40C. was added 810 mg. (0.033 mole) of sodium hydride over a 2 hour period. The resulting reaction EXAMPLE I (Cont.) mixture was stirred for 2 hours at 40-50-C. and was then quenched in 5% hydrochloric acid solution. The resulting suspension was extracted with methylene chloride (2 x 100 ml.) and the organic layers separated, combined and washed with water (50 ml.) and a brine solution (50 ml.). The organic layer was dried over mag-nesium sulfate and concentrated to an oil, 4.1 g. The product was purified by dissolution of the residue in 5 ml. of acetone and addition of the acetone slowly to 125 ml. of 0.25N hydrochloric acid. The suspension was allowed to stir Eor several hours, and was then filtered and dried 2.6 g. (55~).

EXAhlP1E 2

4-Hydroxy-2-methyl-N-2-pyridyl-2H 1,2-benzo-thiazin -3-carboxamide l,I-Dioxide (Piroxicam) . . . _ _ 2-Methoxyethyl 4-hydroxy~2H-1 r 2-benzothiazine-3-carboxylate l,1-dioxide (28 g., 0.089 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 addition funnel and a reflux, variable take-off distillation head. The stirred reaction mi~ture was heated -to reflux and the xylene distilled at the rate of approximately 100 ml./hour, while maintaining the pot volume almost constant by the addition of fresh xylene. ~fter 6 hours, the head temperature, which had been relatively constant at 134C., rose to 142C. 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 45C. in vacuo to yield piroxicam (28.5 g., 96~6; m.p. 167-174C.).
For purposes of recrystallization, the above piroxicam (25 g.) was taken up in 190 ml. of di-methylacetamide a-t 70-75C., treated with 1.26 g. of activated carbon at 75-80C. and filtered through diatomaceous earth with 55 ml. of warm dimethyl-acetamide for transfer and wash. A mixture of 173 ml. of acetone and 178 ml. of water was cooled to 510C. The carbon-treated filtrate was added slowly over 10-15 minutes to the chilled aqueous acetone, and the resulting crystals granulated at 0-5C. for

5 minutes. Recrystallized piroxicam was recovered by filtration with 154 ml. of cold methanol for transfer and wash. Yield: 18.75 g., 75~6; lr(nujol mull) identical with authentic piroxicam.

3 ;~

2-~ethoxyethyl 4-hydroxy-2-methyl-2H-1,2 benzo thiazine-3 carboxylate l,l-dioxide (I; Y = OCH2CH2OCH3) In a manner similar to Example lB, 1.0 g. of 91~
sodium hydride was added over a period of one hour to a solution of 3.0 g. (0.015 mole) of N-methylsaccharin and 2.6 g~ (0.017 mole~ of 2-methoxyethyl chloro-acetate in 15 ml. of dimethylformamide at 35C. The exothermic reaction (55C.) was allowed to stir for 2 hours after the addition was complete, and was then quenched in 5% hydrochloric acid solution and the product extracted with methylene chloride. The residue, remaining ater the solvent was removed, was dissolved in 10 ml. o warm dimethylformamide and added to 100 ml. of 2% hydrochloric acid. The cooled suspension was stirred for 30 minutes and filteredO
Drying of the filtered material gave 1~12 g. (24%) of the product identical with that prepared in Example lB.

~a.~lul~3~

In a manner similar to Examples lB and 3, 864 mg. of 99% sodium hydride was added over a period of one hour to 3.0 g. (0.015 mole) of N-methylsaccharin and 6.0 g. (0.03 mole) of methoxyethyl bromoacetate in 20 ml. of dimethylformamide. The reaction mixture was heated to 40-45C. for 3 hours and was then allowed to stand at room temperature over a weekend~
The reaction mixture was quenched in 150 ml. of 5%
hydrochloric acid solution and the product filtered and dried 1.9 g. The product was used as an intermediate without further purification.

Starting with N-methylsaccharin and the indicat~d 2-methoxyethyl haloacetate, hydride, temperature, and solvent ana following the procedure of Example lB, 2-methoxyethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate l,l-dioxide i~ pre~ared:

~-CH3 ~ XCH2CO(CH2)2OCH3 hy1ridet P~
~C2 t CH2 ) 20CH3 ~ \CH

X Metal Hydride Temp.C. Solvent Cl KH 25 DMSOl Cl KH 50 DMAC2 Cl KH 65 HMPA3 Cl 2 DMSO
Cl NaH 60 1-M-2-P4 Br 2 DMF5 Br KH 25 D~IF
Br NaH 30 HMPA
Br 2 DMAC
Br CaH2 65 DMSO
I NaH 50 DMF
I NaH 60 DMSO
:1: KH 50 1--M--2-P

CaH2 7 0 DMF
I NaH 60 l M-2-P

EXAMPLE 5 (Cont~) 1D~SO = dimethylsulfoxide 2DMAC = dimethylacetamide ~MP~ = hexamethylphosphoramide 41~M-2-P = 1-methyl-2-pyrrolidone 5DMF = dimethylformamide D~

Methyl 4 hydroxy-2-methyl-2~-1,2~ben2Othiazine-3-carboxylate l,I-diox de (~ OCH3) To a solution of 2.9 g~ (0.015 mole) of N-methylsaccharin and 2.63 g. t0.03 mole) of methyl-chloroacetate in 10 ml. of dimethylforma~ide at 400CA was added over a period of two hours 864 mg.
(0.036 mole) of 99% sodium hydride. Stirring was continued ~or two hours, maintaining a reaction temperature of 40-50C. The reaction mixture was quenched in 150 ml. of 5% hydrochloric acid, and the precipitated product filtered and dried, 3.41 g.
(84%), The product was identical from that reported in V.S. Patent 3,591,584.

Methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate I,l-dioxide (I; Y = OCH ) In a manner similar to Example 6, 864 mg.
(0.036 mole) of 99~ sodium hydride was added over a two hour period to a solution of 2.9 g. (0.015 mole) of N-methylsaccharin and 9.8 g. (0.09 mole) of methylchloroacetate in 10 ml. oE dimethylsulfoxide at 40C. Stirring was continued at 40-45C. for an additional two hours, and the reaction mixture was poured into 150 ml. of 5s hydrochloric acid solution.
The precipitate was filtered and dried to give 3.07 ~76%~ of the desired product.

Employing the procedure of Example 6 and starting With N-methylsaccharin and the indicated alkyl halo-acetate, hydride~ reaCtion temperature and solvent the appropriate alkyl 4-hydroxy-2-methyl-2H-1,2-ben20thiazine-3-ca.rboxylate l,l-dioxide is prepared:
OH

-CH3 ~ XCH2C-Y solvent ~ ~ COY

Metal X - ~ . .......... hydride Temp.C. S_l _ nt _~
0 Cl 2 3 KH 45 DMFl Cl ( 2)2 3 NaH 50 DMF 2 Cl -OCH(CH3)2 CaH2 60 DMS03 Cl -OCH3 2 HMPA4 Cl ( 2)3 3 NaH 30 DMAC
Cl -OC(CH3)3 KH 45 DMF
Cl -OCH2CH(CH3) 2 NaH 45 1-M-2-P
Br -OCH2 NaH 25 DMF
Br 2 3 NaH 45 DMF
Br ( 2)2 3 KH 45 DMSO
~ Br ( 2)2 3 2 DMAC
Br ( 2~3 ~ KH 60 1-M-2-P
Br -OCH2CHtCH3)2 NaH 45 DMSO
I -OCH3 NaH 45 DMF

I -OCH(CH3)2 KH 35 DMSO
I -OtCH2)3CH3 NaH 40 HMPA
I -OCH2CH(CH3)2 CaH 70 DMSO
I -OC(CH3)3 NaX 4 5 DMAC

EXAMPLE_8_rCont.) DMF = dimethylformamide DMSO = dimethylsulfoxide 3~MPA = hexamethylphosphoramide 4DMAC = dimethylacetamide l-M-2-P = l~methyl-2~pyrrolidone ~?~ ?~

4-Hydroxy-2-methyl-N-2-pyridyl-2H 1,2-benzothia-zine-3-carboxamide l,l-dioxide (Y = N~C5H4N) - (Piroxicam)''''''''''' A. N-(2--pyridyl)chloroàcetam d_ To a solution of 9.42 g. (0.1 mole) of 2-amino~
pyridine in 50 ml. of methylene chloride was added dropwise 4.0 ml. (0.05 mole) of chloroacetyl chloride in 20 ml. of the same solvent, keeping the reaction temperature at -20 to -10C. for one hour. After stirring at room temperature for 10 hours, 50 ml. of water was added and the organic layer separated. The organic solution was washed with water and a brine solution and was dried over magnesium sulfate.
Removal of the solvent in vacuo gave 6.64 g. (78~), . . . _ m~p. 114-117C., of the desired product.
A small sample was purified for analysis Dy recrystallization from acetonitrile, m.p. 122C.
The NMR (CDC13) spectrum showed absorption at 9.0 (s, lH), 8.4-6.9 (m, 4H) and 4.15 (s, 2H) ppm.
B. ~-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-ben othia-zine-3-carboxamide l,l-dioxide ~Y = NHC5H4N) (Piroxicam) To a solution of 590 mg. (3 mmole) of N-methyl-saccharin and 1.02 g. (6 mmole) of N-(2-pyridyl)-chloroacetamide in 3 ml. of dimethylformamide at 40C. was added 250 mg. (10.3 mmole) of 93~ sodium hydride portionwise over a period of one hour. The reaction mixture was allowed to stir at 40C. for 2.5 hours and was then added to 100 ml. of 5~ hydrochloric acid solution and 300 ml. of ice. The precipitate was filtered and dried to give 24 mg.

~3j~ 3 EXA~PLE 9 (Cont.) The filtrate was extracted with methylene chloride (6 x 50 ml.) and the extracts are combined, washed with water and a brine solution and dried over magnesium sulfate. Removal of khe solvent gave 400 mg. of crude product. The product was identified by thin-layer chromatography and high-pressure liquid chromatography.

3~
-~5-Employing the procedure of Example 9, and starting with N-methylsaccharin and the indicated N-(2-pyridyl)haloacetamide, hydride, temperature and solvent, 4-hydroxy-2-methyl-N-2-pyridyl~2H-1,2-benzothiazine-3-carboxamide l,l-dioxide (Piroxicam) i5 prepared:

~(~-CH3 + XCH2CONHC5H4N hYldVer~t OH
~CONHC5Hd~N

S"N~ CH

X Metal hydride Temp.C. SoIvent Cl KH 50 DMSO
Cl KH 70 DMAC2 Cl CaH2 60 DMAC3 Cl NaH 45 ~MPA
Cl NaH 25 1-M-2-P4 Br NaH 40 DMF5 Br NaH 50 DMAC
Br KH 40 DMF
Br CaH2 70 DMSO
Br CaH2 60 HMPA
I NaH 45 DMF

I CaH2 60 1-M-2-P

3~

EXAMPLE 10 (Cont.) DMSO - dimethylsulfoxide 2DMAC = dimethylacetamide 3HMPA = hexamethylphosphoramide 41-M-2-P - l-methyl-2-pyrrolidione DMF = dimethylformamide EXAM LE Il 2~Methoxyethyl 4-hydroxy-2-methyl-2H-1,2-benzo-thiazine-3-carboxylate l,l--dioxide (I; Y - -OCH2CH2OCH3) 5 A. 2-methoxyethyl 2-(2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisosulfonazol~3-yl)~2-chloroacetate (II; X=Cl, Rl = OCH2CH2OCH3~ -In a flame dried flask under a nitrogen atmosphere was placed 11.6 g. ~0.24 mole) of 50~ sodium hydride in an oil dispersion. The mineral oil was then removed by pentane washing and decantation, and 50 ml. of dry tetrahydrouran was added. To the resulting suspension was added 20 g. (0.1 mole) of N-methylsaccharin in 30 ml. of the same solvent and the mixture heated to 40C. 2-Methoxyethyl chloroacetate (15.4 g., 0.1 mole) was added to the reac-tion mixture dropwise over a period of one hour. The reaction was maintained at 40-50C. for two hours following the completion of the addition. The reaction was then quenched slowly into a cooled, well stirred 5~ hydrochloric acid solution and the resulting precipitate extracted ( d X
100 ml.) with methylene chloride. The extracts were combined, dried over magnesium sulfate and concentrated in vacuo to give the crude desired product as a yellow oil, 37.6 g.
The crude product was crystallized from methylene chloride-hexane to give 22.75 g. (65%) of the product, m.p. 125.5-126.5C. A sample was further purified by recrystallizing from methylene chloride-hexane, m.p.
3~ 133-135.5C.

EXAMPLE ll (Cont.) The NMR spectrum (DMSO d6) showed absorption at 7.6-8.2 (m, 5H), 5.1 (s~ 1H), 4.0 (m, 2H), 3.3 (m, 2H), 3.1 ~s, 3H) and 2~7 (s, 3~) ppm.
~nal. Calcd. for C13H16O6SNCl: C, 44.6; H, 4.6; N, 4Ø
Found : C, 44.3; H. 4.7; N, 4Ø
B. 2-methoxyethyl 4-hydroxy-2-methyl-2H-1,2-benzo thiazine-3-carboxylate 1,1-dioxide To 280 mg. (5.8 mmole) of 50~ sodium hydride dispersion which had been washed with pentane was added lO ml. of dimethyl-sulfoxide at room temperature. To the resulting suspension was added 1.75 g. (5 mmole) of 2-methoxyethyl 2-(2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisosulfonazol-3-yl)-2-chloroacetate. The reaction mixture, which rose in temperature to 32C. was allowed to stir for 1.5 hours, and was then added to 150 ml. of a cold 5%
hydrochloric acid solution. The precipitate was filtered and dried, 1.29 9. (82.4%).
The NMR spectrum (DMSO-d6) showed absorption at 8.0 ~m, 4H), 4~5 (m~ 2H), 3.7 (m, 2H), 3.34 (s~ 3H) and 2.90 (s, 3H) ppm.

EXAMP~E 12 A.
Following the procedure oE Example llA, and starting with N-methylsaccharin and 2-methoxyethyl bromo- and iodoacetates, 2-methoxyethyl 2-(2 methyl-3~hydroxy-2,3-dihydro-1,2-benzisosulfonazol-3-yl)-2-bromoacetate and 2-methoxyethyl 2-(2-methyl-3-hydroxy--2,3-dihydro-1,2--benzisosulfonazol-3-yl)-2-iodoacetate are prepared, respectively.
B.
Starting with the indicated 2-methoxyethyl 2-(2-methyl-3-hydroxy-2,3-dihydro-1,2-ben~isosulfonazol-3-yl)-2-haloacetate~ hydride, solvent and temperature, and employing the procedure of Example llB, 2-methoxyethyl ~-hydroxy-2--methyl-2H-1,2-benzothiazine-3-carboxylate-l,l-dioxide is prepared:

HO ~ y C-O(CH2)20CH3 OH
-CH3 Metlal hydride ~ ~ ~ 02(C~2)20CH3 X Metal hydride ~ Solvent Cl KH 25 DMFl Cl 2 DMF 2 Cl NaH 3s DMAC
Cl NaH 50 l-M 2-P3 Cl RH 50 HMPA~

¢~

EXAM _E 12`(Cont.) X etal hydrideTem~_ Co Solvent Br NaH 35 DM~C
Br NaH 35 DMSo5 Br KH 25 DMF
Br CaH2 50 DMAC
Br 2 DMSO
Br XH 30 HMPA
DMF = dimethylformamide DMAC = dimethylacetamide 31-M-2-P - l-methyl-2-pyrrolidone 4HMPA = hexamethylphosphoramide 5DMSo = dimethylsulfoxide ~3~1~ 3~'~

Methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxyIate I,I-dioxide (Ij Y = OCH ) ~ 3 A. methyl 2-(2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisosulfonazol-3-yl)-2-chloroacetate (II; R = OCH ) To 9.2 gO t0.19 mole) of a 50~ sodium hydride-oil dispersion~ which had been washed free of oil with pentane, was added under a nitrogen atmosphere 20 ml. of dry tetrahydrofuran. To the resulting suspension was added 15.9 g. (0.08 mole) bf N-methyl-saccharin in 50 ml. of the same solvent and the slurry heated to 40C. Methyl chloroacetate (7 ml., 0.08 mole) in 20 ml. of dry tetrahydrofuran was added over a period of one hour, keeping the reaction -temperature at 40-45C. Following the completion of the addition the reaction mixture was allowed to stir at 35-42C. for 4 hours. The reaction mixture was then quenched in 700 ml. of a 5% hydrochloric acid solution and the product extracted with methylene chloride (7 x 100 ml.). The combined extracts were washed with a 5~ hydrochloric acid solution and a saturated brine solution, and dried over magnesium sulfate. Removal of the solvent in vacuo gave 21 g.
of the product as a heavy oil which solidified on standing.
A portion was triturated with isopropanol to give a white solid, m.p. 122-125C.
The N~R spectrum (DMSO-d6) showed absorption at 8.1-7.6 (m, 5H), 5.05 (s, 1~), 3.45 (s, 3H) and 2.7 (s, 3H) ppm.
Anal. Calcd. for CllH12O5~SCl: C, 43.2; H, 3.9; N, 4.6.
Found : C, 43.1; H, 4.0; N, 4.6.

3~
-3~-EXAMPLE 13 (Cont.) B. methyl 4-hydroxy~2-methyl-2H-1,2-benzothiazine 3-carbox~Iatè l,l-dioxide To 63 mg. (.0013 mole~ of sodium hydride washed free of oil with pentane in 8 ml. of dry dimethylsul-foxide was added 400 mg. ~.0013 mole) of methyl 2-(2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisosulfonazol-3-yl)-2-chloroacetate in 8 ml. of dimethylsulfoxide.
The reaction mixture was heated at 35C. for one hour and fif-teen minutes and was then quenched in 80 ml.
o a cold 5~ hydrochloric acid solution. The precipi-tate was filtered and dried to give 280 mg. l80~) of the desired product, m.p. 162-163C. The product was undistinguishable from that reported in U.S. Patent 3,591,584 and Examples 6 and 7.

,P~3~

~.
A.
Following the procedure of Example 13A, and starting with N-methylsaccharin and the appropriate alkyl haloacetate the following 1,2-benzisosulfonazoles are prepared:

R

`X ' ' ' ' '' ~1 ' ' ' ' '' Cl 2C 3 Cl ( 2)2 3 Cl -OCH(CH3)2 Cl ( 2)3 3 Cl -OC(CH3)2 Cl -OCH2CH(CH3)2 Br -OCH3 Br 2 3 Br ( 2)2 3 Br ( 2)3 3 Br -OCH2CH(CH3)2 I -OCH(CH3)2 I ( 2)3 3 I -OCH2CH(CH3)2 I -OC(CH3)3 EXAMPLE I4 (Cont.) B.
Following the procedure o~ Example 13B, and em-ploying with the indicated 1,2-benzisosulfonazole, hydride, reaction tempera-ture and solvent the appro-priate alkyl 4-hydroxy-2-methyl-2H-1,2-benæothiazine-3-car~oxylate l,l-dioxide is prepared:
o CH Metal hydride ~ ~ COR
~ 3 solvent R Metal X l ~ Temp.C. Solvent Cl -OCH3 KX 25 DMFl Cl 2 3 NaH 30 DMAC2 Cl ( 2~2 3 NaH 35 DMF 3 Cl -OCH(CH3~2 2 DMso : 15 Cl ( 2~3 3 NaH 45 DMAC4 Cl -OC(CH3)3 KH 30 HMPA
Cl -OCH2CH(CH3)2 KH 25 1-M-2-P5 Br -OCH3 NaH 35 DMF
Br 2 3 KH 35 DMF
Br ( 2)3 3 KH 25 DMAC

Br -O(CH2~CH3 CaH2 A5 DMSO
Br -OCH2CH(CH3)2 NaH 50 l-M-2-P

I -OCH2CH3 NaH A0 H~PA
I -OCH(CH3) KH 35 DMSO
( 2)3 3 2 5 DMSO
I -OCH2CH(CH3) NaH 30 DMAC
: I -OC(CH3)3 KH 25 DMF

EXAMPLE 14 (COnt~ ) 1DMF = dimethylformamide 2DMAC = dimethylacetamide 3DMSo = dimethylsul~oxide 4HMPA = hexamethylphosphoramide l-M~2-P = l-methyl-2 pyrrolidone -~6-Methyl 4-hydroxy-2-methyl 2H-1,2-benzo-thiazine-3-carboxylate l,l~dioxide (I; Y = OCH ) _ - 3 To 27 ml. of dimethylsulfoxide containing 5.18 g. (26.3 mmoles) of N-methylsaccharin and 4.6 ml. (52.5 mmcles) of methyl chloroacetate at 25C. was added 14.1 g. (126 mmoles) of potassium t-butoxide in 4~ ml. of the same solvent at the rate of . 0.1 ml. every minute. After 42.2 ml. of the potassium t-butoxide solution had been added the addition was stopped. During the addition the reaction temperature was maintained at about 30-32C.
After the addition was complete the reaction mixture was allowed to stir at 30C. for 10 minutes.
The reaction mixture was quenched in 2G2 ml. of 5%
hydrochloric acid at 25C. r and the precipitated product was filtered, washed with water and dried,

6.53 g.

3~

Methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate l,l-dioxide lI; Y = OC~ ) ~ 3 To a solution of 9.86 g. t50 mmoles) of N-methylsaccharin and 10.8 ml. of methyl chloroacetate (123.8 mmoles) in 50 ml. of dimethylsuloxide was added at the rate of 0.15 ml./minute 9.2 g. (170 mmoles) of sodium methoxide in 30 ml. of methanol. After the addition was complete an additional 2~7 g. (50 mmoles) of sodium methoxide in 11 ml. of methanol was added at the same rate for a total addition time of about 6 hours.
The reaction mi~ture was added to 800 ml. of 0.25N hydrochloric acid, and the precipitated product Eiltered, washed with water and dried, 3.8 g.

~38-Methyl 4-hydroxy~2-methyl-2H-1,2-benzothiazine-3-carboxylate l,l-dioxide r I; Y = OCH ) __ - 3 In a manner similar -to Examples 15 and 16, to a solution of 2.86 y. (50 mmoles~ of N-methylsaccharin and 10.8 ml. (100 mmoles) of me-thyl chloroacetate in 17 ml. of dimethylsulfoxide was added 11.56 g. (170 mmoles) of sodium ethoxide in 63 ml. of dimethyl-sulfoxide over a period of 2.5 hours The reaction mixture wwas added to 800 ml. of 0.25N hydrochloric acid, and the precipitated product ~iltered, washed with water and dried, 3.0 g.

3~ ~ ~

Starting with N-methylsaccharin and the indicated ester, alkoxide~ temperature and solvent, and employing the procedure of Example 17, the following 4-hydroxy-2-rnethyl-2H-1,2-benzo-thi.aizne-3-carboxylate 1,1-dioxide es-ters are prepared:
OH

~-CH3 -~ XCH2C-Y alkoxide~ ~ ~ CO-Y
solvent S~ CH3 X Y Alkoxide ~E~~~ Solvent Cl C2H5 KO-t-C~Hg 35 DMSO12 Cl OC3H7 2 5 40 DMAC
Cl OCH3 KO-i-C3H7 30 HMPA
ClO-n-C~Hg Na-n-C4H9 45 DMSO
ClOCH3 XO-t-C~Hg 60 1-M-2-P
BrOCH3 NaOCH3 25 DMF
BrO-n-C3H7 NaOC2H5 35 DMF
BrO(CH2)2OCH3 K~t~C4~9 30 DMSO
BrC2H5 2H5 35 DMF
Br2 5 2H5 30 1-M-2-P
IOCH3 NaOCH3 30 DMSO
~O(CH2)2OcH3 KO t C4 9 HMPA
IOC2H5 Li9C2H5 35 DMF
IO-n-C4H9 KOCH3 60 1-M-2-P
1DMSO = dimethylsulfoxide DMAC = dimethylacetamide 3HMPA = hexamethylphosphoramide 41-M-2-P = l-methyl-2-pyrrolidone 5DMF - dimethylformamide EXAMPLE l9 Methyl 4-hydroxy-2-methyl~2H-1,2-benzothiazine-3-carboxylate l,l-dioxide (I; Y OCH3) ---To 870 mg. (4.4 mmoles) of N-methylsaccharin and 0.95 ml. (10.89 mmoles) of methyl chloroacetate in 3 ml. of dimethylsulfoxide under nitrogen was added at the rate of 0.084 ml./minute 3.99 g. (20 mmoles) of po-tassium hexamethyl disilazane in 9.98 mlO of dimethylsulfoxide.
The reaction mixture was then quenched in 130 ml. of lN hydrochloric acid, and the precipitated product was filtered, washed with water and dried, 1.05 g. The product was identical to that isolated in Example 6.

"

Employin~ the indicated starting reagents and reaction temperatures and following the procedure of Example 19, the following 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate l~l-dioxide esters are prepared:

N~CH3 + XCH2C-Y KN[Si(CH3)3 ~ ~ ~ CO-Y
2 sol~ent S ~ \CH

X Y Temp~ C. Solvent Cl OCH3 35 DMF12 Cl OC2H5 45 DMSO
Cl O-i-C3H7 30 HMPA3 Cl o-t-C4H9 35 DMSO
Cl O-i-C3H7 60 DMAC4 Br OCH3 30 1-M-2-P
Br O-n-C3~7 30 DMSO
Br O-n-C4H9 40 1-M-2-P
Br C2H5 50 DMF
Br ~ 2)2 3 30 DMAC

I O-n-C3H7 45 1-~-2-P
I O-n-C4H9 45 DMF
DMF = dimethylformamide 2DMSO = dimethylsulfoxide 3HMPA = hexamethylphosphoramide 4DMAC = dimethylacetamide 51-M-2-P = l-methyl-2-pyrrolidone -~2-Methyl 4-hydroxy-2-methyl-2H~1,2-benzothiazine-3-carboxylate 1,1-dioxlde ~ Y = OCH3)_ To a solution of 4.64 y. (23.5 mmoles) of N-methylsaccharin and 5.18 ml. (58.19 mmoles) of methyl chloroacetate in 20 ml. of dimethylsulEoxide was added at the rate of 0.3 ml./minute 13.9 g.
(100 mmoles~ of potassium diisopropylamine in 40 ml.
of dimethylsulfoxide and 18 ml. of nonane.
When the addition was complete the reaction mixture was assayed by liquid chromatography. Using a standard sample of methyl 4-hydroxy~2-methyl-2~-1,2-benzothiazine-3-carboxylate 1,1-dioxide the yield of produ~t was 67~.

-43~

-Following the procedure of Example 21 and employing the indicated starting reagents and reaction temperature, the following 4-hydroxy-2-methyl-2H-1,2-benzothiazine 3-carboxylate 1,1 dioxide esters are prepared:
OH

~-CH3 + XCH C-Y KN[CH(CH3)3]2 ~ CO Y
O 2 solvènt ~ S~ \CH

X Y Temp. C. SoIvent Cl OCH3 40 DMSO
Cl C2H5 60 DMAC
Cl 3 7 DMSO3 Cl 3 7 HMPA
Cl t-C4H9 35 DMSO
Br ( 2)2 3 1-M-2-P
Br OCH3 60 DMSO
Br 3 7 DM~C
Br -n~C4H9 45 DMF
Br OCH3 55 DMSO
I O(CH2)2OCH3 60 1-M~2-P

DMSO = dimethylsulfoxide 2DMAC = dimethylacetamide 3HMPA = hexamethylphosphoramide 41-M-2-P = l-methyl-2-pyrrolidone 5DMF = dimethylformamide

Claims (6)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound selected from those of the formula wherein X is selected from the group consisting of chloro, bromo and iodo; and R1 is selected from the group consisting of alkoxy having from one to four carbon atoms and 2-methoxyethoxy char-acterized by reacting a compound of the formula with a compound selected from those of the formula in the presence of two equivalents of a metal hydride in tetra-hydrofuran at a reaction temperature of about 40 to 50°C.

2. The process of claim 1, wherein the metal hydride is sodium hydride.

3. The process of claim 1, wherein X is chloro.

4. The process of claim 2, wherein R1 is methoxy.

5. The process of claim 2, wherein R1 is methoxyethoxy.

6. A compound selected from the group consisting of those of the formula wherein X is selected from the group consisting of chloro, bromo and iodo; and R1 is selected from the group consisting of alkoxy having from one to four carbon atoms and 2-methoxyethoxy, whenever prepared by the process of claim 1, or by an obvious chemical equivalent thereof.