FI76571C - FOERFARANDE FOER FRAMSTAELLNING AV MELLANFOERENINGAR LAEMPLIGA VID FRAMSTAELLNING AV PIROXICAM OCH I FOERFARANDET ANVAENDBARA UTGAONGSMATERIAL. - Google Patents

Description

1 76571

This invention relates to a novel process useful in the preparation of certain intermediates suitable for the preparation of the anti-inflammatory agent, piroxicam, by partitioning from patent application 823366.

Piroxicam, an effective anti-inflammatory agent, was first described by Lombardino in U.S. Patent 3,591,584. One of the methods for synthesizing piroxicam described therein is the reaction of a 3-carboxylic acid ester with 2-aminopyridine. More specifically, the ester is described as a (C 1 -C 4) alkyl ester or a phenyl (C 1 -C 4) alkyl ester. The specific ester described is a methyl ester, namely

20 OH O

Js. ^ CH-, 3 v \ 3 0 0 25 / see also Lombardino et al., J. Med. Chem. 14 pp. 1171-1175 (1971) .7.

A more recent U.S. Patent No. 4,289,879 mentions that, in order to achieve certain advantages, the corresponding 2-methoxyethyl ester may be used instead of the methyl ester in the reaction between the methyl ester 30 and 2-aminopyridine.

Other alternative syntheses of piroxicam described in the literature include the reaction of 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-1,1-dioxide with 2-35 pyridyl isocyanate (Lombardino, U.S. Patent 2 76571 3,591,584), transamidation of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxyanilides with 2-aminopyridine (Lombardino, U.S. Patent 3,891,637), compound 5 (C 1 -C 3) alkyl ex

SO.NCH.CONH

2.2 Ch3 10 cyclization (Lombardino, U.S. Patent 3,853,862), addition of 4- (C 1 -C 3) alkoxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide 2 aminopyridine followed by hydrolysis of the enol ether bond (Lombardino, U.S. Patent 3,892,740), coupling of 4-hydroxy-2-methyl-1H-2Η-1,2-benzothiazine-3-carboxylic acid, via acid chloride, 2 with aminopyridine (Hammen, U.S. Patent 4,100,347) and methylation of 4-hydroxy-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide (CA Patent 1,069,894).

According to the invention, compounds of formula are prepared

OH

R 1 (V) R 1 (ia) 25 V, wherein R 1 is alkoxy of one to four carbon atoms, 30 or 2-methoxylethoxy, so that the compound of formula y _ 'firV-cH, 1 (II) 35 02 3 76571 wherein X is chlorine, bromine or iodine, is reacted with one equivalent of a metal hydride in a polar, reaction-neutral solvent at about 25 to about 50 ° C until the reaction is substantially complete.

The process preferably uses a reaction-neutral solvent which is dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide or 1-methyl-2-pyrrolidone.

Potassium hydride, sodium hydride or calcium hydride is preferably used as the metal hydride.

The starting material is preferably a compound in which X is chlorine, the reaction-neutral solvent being dimethylformamide or dimethylsulfoxide, the metal hydride being sodium hydride and R 1 being methoxy or 2-methoxyethoxy.

The compounds prepared by the process are useful intermediates suitable for the preparation of piroxicam (2-pyridylimino in the compound of formula Ia) as described in the above-mentioned art references.

The advantages of this method are the yield of the desired products in the highest yields and also the avoidance of methyl-25-4-hydroxy-2H-1,2-benzothiazine ring system.

Also included within the scope of this invention are novel starting reagents for use in the method described above having the formula

30 «0 *> - C- R

L 1 C / N 2 CH 3 S 2 2 76571 wherein X is chlorine, bromine or iodine; and R 1 is alkoxy of one to four carbon atoms or methoxyethoxy.

Preferred compounds of this series are those wherein X is chlorine and R 1 is methoxy or 2-methoxy-5-toluene.

When readily apparent to one skilled in the art, the compounds of the invention may exist in either the ketone or enol tautomeric form:

10 ° OH

NRV ° ~~

nCH S ^^ CH

° 2 3 02 3 15

It will be apparent to those skilled in the art that these forms are of equal value. Both tautomeric forms are intended to be included within the scope of this invention, although for convenience, only one of them will be described.

The method according to the invention can be described as follows:

X

HO JL / 0 OH

25 Metal- \ R1 hydride f <^ ^ r / ^ vr'CO01

> -ch3 -> kiLA

° 2 ° Γ “3 30 wherein X and R 2 are as previously defined.

The process is characterized in that one mole of the appropriate 1,2-benzisosulfoniazole is reacted with an equivalent amount of a metal hydride in a polar, reaction-neutral solvent. Any of the 35 metal hydrides can be used, although 5,76571 alkali metal hydrides and alkaline earth metal hydrides are preferred, as many of them are commercially available or can be easily prepared. Particularly preferred are sodium hydride, potassium hydride and calcium hydride.

The process is carried out in a reaction-neutral solvent. Such a solvent, or mixtures thereof, must be capable of dissolving the reagents to the extent that the reaction is facilitated without, however, reacting substantially with the reagents or product. Such solvents must also be highly polar solvents with a dielectric constant (e) of = 35. These include preferred solvents such as dimethyl sulfoxide, dimethylformamide, dimethylacetamide, 1-methyl-2-15 pyrrolidone and hexamethylphosphoramide.

For the combination of reagents, the appropriate metal hydride may be added to the required 1,2-benzisosulfoniazole in a reaction-neutral solvent, or 1,2-benzisosulfoniazole in a reaction-neutral solvent may be added to a suspension in which the metal hydride is in a reaction-neutral solvent. .

After combining the reagents, the reaction mixture is heated to a reaction temperature of about 25 ° C to about 50 ° C. The product is obtained at lower or higher reaction temperatures, but they have a detrimental effect on the yields and purity of the product and do not offer any obvious advantages. At the preferred reaction temperatures, the reaction is complete in about an hour and a half to 30 hours.

After completion of the reaction, the reaction mixture is added to cold 5% hydrochloric acid and the product is filtered off or extracted with a water-immiscible solvent such as methylene chloride. The product remaining after removal of the extraction-35 solvent, or the product obtained by filtration 6,76571, can be purified by conventional means, or can be used without further purification in the preparation of piroxicam.

In a preferred embodiment of the process, the starting material in which X is chlorine is used, the reaction-neutral solvent being dimethylformamide or dimethyl sulfoxide and the metal hydride being sodium hydride.

Products in which R.j is methoxy and 2-methoxyethoxy are particularly preferably prepared.

The starting reagents used in the process are readily prepared by reacting one mole of N-methylsaccharin with one mole of the appropriate haloacetate in the presence of two equivalents of a metal hydride, such as sodium hydride, in a reaction-neutral solvent such as tetrahydrofuran, as follows: 20 ΟνΝ '“3 * XCH ^ R1-► ° 2

II

In practice, a solution of N-methylsaccharin in tetrahydrofuran is treated with two equivalents of sodium hydride and the resulting reaction mixture is heated to about 40 ° C. The required alkyl or 2-methoxyethyl haloacetate is added over about an hour, and the reaction mixture is heated for several hours at 40-50 ° C after the addition is complete. After completion of the reaction, the mixture is added to a cold 5% hydrochloric acid solution, and alkyl or 2-methoxyethyl 2- (2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisosulfoniazol-3-yl) -2-haloacetate is either The mixture is filtered off and dried or extracted with a water-immiscible solvent such as methylene chloride. If necessary, the product can be cleaned by conventional means.

7 76571

Also within the scope of the invention are certain 2- (2-methyl-3-hydroxy-2β-dihydro-1,2-benzisosulfonazole-3-haloacetate esters useful as intermediates in the process of the invention.

Preferred are compounds of formula II wherein X is chlorine. Particularly preferred are methyl 2- (2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisulfoniazol-3-yl) -2-chloroacetate and 2-methoxyethyl 2- (2-methylacetol). 3-Hydroxy-2,3-dihydro-1,2-benzisosulfone-10-azol-3-yl) -2-chloroacetate.

The following examples are provided for illustrative purposes only. Nuclear magnetic resonance (NMR) spectra were measured at 60 MHz from solutions in deuterochloroform (CDCl 3), perdeuterodimethyl sulfoxide (DMSO-d) or deuterium oxide (D 2 O) or otherwise taken into account, and peak locations are reported as ppm values. sodium 2,2-dimethyl-2-silapentane-5-sulfonate downwards. The following abbreviations have been used for peak shapes: s, singlet; d, dub-20 letti; t, triplets; g, quartet; m, multiplets.

Example 1 2-Methoxyethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide (Ia; ^ = -OCH2CH2OCH3) 25 a. 2-Methoxyethyl-2- (2 -methyl 3-hydroxy-2,3-dihydro-1,2-benzisosulfoniazol-3-yl) -2-chloroacetate (II; X = Cl, OCH2CH2OCH3)

11.6 g (0.24 mol) of a 50% oil dispersion of sodium hydride were placed in a flame-dried flask under a protection of a nitrogen atmosphere. The mineral oil was then removed by washing with pentane and decantation, and 50 ml of dry tetrahydrofuran was added. To the resulting suspension was added 20 g (0.1 mol) of N-methylsaccharin in 30 ml of the same solvent, and the mixture was warmed to 40 ° C. 2-Methoxyethyl chloroacetate (15.4 g, 0.1 mol) was added dropwise to the reaction mixture over 1 hour. At the end of addition 8 76571, the reaction mixture was kept at 40-50 ° C for two hours. The reaction mixture was then slowly added to a cooled, well-stirred 5% hydrochloric acid solution and the resulting precipitate was extracted (4 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 product, m.p.

Mp 125.5-126.5 ° C. From this, a sample batch was further purified by recrystallization from methylene chloride-hexane; mp. 133 to 135.5 ° C.

The NMR spectrum (DMSO-d 6) showed absorbances 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, 3H) ppm.

Analysis calculated for C 13 H 16 O 6 SNCl: C, 44.6; H, 4.6; N, 4.0%

Found: C, 44.3; H, 4.7; N, 4.0%.

B. 2-Methoxyethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide to 280 mg (5.8 mmol) of a 50% sodium hydride dispersion , washed with pentane, 10 ml of dimethyl sulfoxide were added at room temperature. To the resulting suspension was added 1.75 g (5 mmol) of 2-methoxy-25-ethyl-2- (2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisosulfoniazol-3-yl) -2- chloroacetate. The reaction mixture, which rose to 32 ° C, was stirred for 1.5 hours and then added to 150 ml of cold 5% hydrochloric acid solution. The precipitate was filtered off and dried; 1.29 g (82.4%).

The NMR spectrum (DMSO-d 6) showed absorbances at 8.0 (m, 4H), 4.5 (m, 2H), 3.7 (m, 2H), 3.34 (s, 3H) and 2.90 (s, 3H) ppm.

9 76571

The product is indistinguishable from the product described in Example 1 of FI Patent Application 823,366 and U.S. Patent No. 4,289,879.

Example 2 5 A. Following the procedure of Example 1A and starting from N-methylsaccharin and 2-methoxyethyl bromo and iodoacetates, 2-methoxyethyl 2- (2-methyl-3-hydroxy-2,3-dihydro-1 (2-Benzisosulfoniazol-3-yl) -2-bromoacetate and 2-methoxyethyl 2- (2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisulfoniazol-3-yl) -2-iodoacetate.

B. Using said 2-methoxyethyl 2- (2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisosulfoniazol-3-yl) -2-haloacetate, hydride, solvent and temperature, 15 and using the procedure of Example 1B, 2-methoxyethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide is prepared: 0 H <K * XS'0 <CH2> 20CH3 . Γ 20 f \\ h-CH Metal hydride f fi || ^ p: 02 <CK2'20CK3 3 solvent O b CM3

° 2 02 J

25 x Metal hydride Temperature, ° C Solvent

Cl KH 25 DMF1

Cl CaH2 45 DMF

Cl NaH 35 DMAC2

Cl NaH 50 1-M-2-P3 30 Cl KH 50 HMPA4

Cl KH 40 DMF

Br NaH 35 DMAC

Br NaH 35 DMSO 2

Br KH 25 DMF

35 Br CaH2 50 DMAC

Br CaH2 50 DMSO

Br KH 30 HMPA

10 76571 1 2 DMF = dimethylformamide; DMAC = dimethylacetamide; 3 4 1-M-2-P = 1-methyl-2-pyrrolidone; ^ HMPA = hexamethyl, phosphoramide; ^ DMSO = dimethyl sulfoxide.

Example 3 Methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide (Iarhl = och3) A. Methyl-2- (2-methyl-3- hydroxy-2,3-dihydro-1,2-benzisulfoniazol-3-yl) -2-chloroacetate 10 (II; r1 = OCH3) to 0.2 g (0.19 mol) of a 50% oil dispersion of sodium hydride which was washed with pentane to remove oil, 20 ml of dry tetrahydrofuran was added under a nitrogen atmosphere. To the resulting suspension was added 15.9 g (0.08 moles) of N-methylsaccharin in 50 ml of the same solvent, and the slurry was heated to 40 ° C.

Methyl chloroacetate (7 mL, 0.08 mol) in 20 mL of dry tetrahydrofuran was added over 1 hour, maintaining the reaction temperature between 40-45 ° C. After the addition was complete, the reaction mixture was stirred for 4 hours at 35-42 ° C. The reaction mixture was then added to 700 ml of 5% hydrochloric acid solution and the product was extracted into methylene chloride (7 x 100 ml). The combined extracts were washed with 5% hydrochloric acid solution and saturated brine, and dried over magnesium sulfate. Removal of the solvent in vacuo gave 21 g of product as a heavy oil which solidified on standing. An aliquot was triturated with isopropanol to give a white solid, m.p. 122-125 ° C.

The NMR spectrum (DMSO-d 6) showed absorbances at 8.1-7.6 (m, 5H), 5.05 (s, 1H), 3.45 (s, 3H) and 2.7 (s, 3H). ) ppm. Analysis for ciiHi205NSCl:

Calculated: C, 43.2, H, 3.9, N, 4.6%

Found: C, 43.1, H, 4.0, N, 4.6%.

35 B. Methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide 11 76571 to 63 mg (0.0013 moles) of sodium hydride which had been washed free of oil pentane in 8 ml of dry dimethyl sulfoxide was added 400 mg (0.0013 moles) of methyl 2- (2-methyl-3-hydroxy-2,3-dihydro-1,2-benz-5-isosulfoniazole-3). -yl) -2-chloroacetate in 8 ml of dimethyl sulfoxide. The reaction mixture was heated at 35 ° C for 1 hour and 15 minutes and then added to 80 ml of cold 5% hydrochloric acid solution. The precipitate was filtered off and dried, yielding 280 mg (80%) of the desired product, m.p. 162-163 ° C.

The product was indistinguishable from the product described in U.S. Patent 3,591,584 and Examples 6 and 7 of FI Patent Application 823,366.

Example 4 A. Following the procedure of Example 3A, starting from N-methylsaccharin and the appropriate alkyl haloacetate, the following 1,2-benzisosulfoniazoles are prepared:

Uv ° 2 12 76571 x _Ri

Cl “OCH2CH3

Cl -O (CH2) 2CH3

Cl -OCH (CH3) 2 Cl -O (CH2) 3CH3

Cl -OC (CH3) 2

Cl -OCH2CH (CH3) 2

Br “0CH3

Br -OCH2CH3 10 Br -O (CH2) 2CH3

Br -O (CH2) 3CH3

Br -OCH 2 CH (CH 3) 2 I -och 3 I -OCH.CH.

15 1 J

I -OCH (CH 3) 2 I -O (CH 2) 3 CH 3 I “OCH 2 CH (CH 3) 2 I -OC (CH 3) 3 20 b. Following the procedure of Example 3B and using said 1,2-benzisosulfoniazole, hydride, reaction temperature and solvent, prepare the appropriate alkyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide: 13,76571

O

H XV ^ ”R10H

/ j ^ N / sycoR, N-CH metal hydride II * ·

5/1 - * k 1 J

S solvent X / "Vu · O ** CH3 2 O 2 χ R-i Metal hydride temperature f ° C Solvent 10 - - - - -

Cl - ° CH 3 KH 25 DMF A

Cl -OCH2CH3 NaH 30 DMAC2

Cl-O (CH 2) 2 CH 3 NaH 35 DMF

Cl -OCH (CH3> 2 CaH2 50 DMSO1

15 Cl-O (CH2) 3CH3 NaH 45 DMAC

Cl -OC (CH3) 3 KH 30 HMPA2

Cl -OCH2CH (CH3) KH25 1-M-2-P3

Br -OCH 3 NaH 35 DMF

Br -OCH 2 CH 3 KH 35 DMF

20 Br -O (CH 2) 3 CH 3 KH 25 DMAC

Br -O (CH 2) 2 CH 3 CaH 2 45 DMSO

Br -OCH 2 CH (CH 3) 2 NaH 50 1-M-2-P

ICH3 KH 40 DMF

I -OCH2CH3 NaH 40 HMPA

25 I -OCH (CH3) KH 35 DMSO

I -O (CH2) 3CH3 CaH2 50 DMSO

I-OCH 2 CH (CH 3) NaH 30 DMAC

I -OC (CH3) 3 KH 25 DMF

DMF = dimethylformamide; DMAC = dimethylacetamide; 4 2 DMSO = dimethyl sulfoxide; HMPA = hexamethylphosphoric amide; 1-M-2-P = 1-methyl-2-pyrrolidone.

14 76571

Example 5 (Preparation of a compound for the preparation of piroxicam by the process of the invention) 4-Hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzo-5-thiazine-3-carboxamide-1,1-dioxide (piroxicam) 2 -methoxyethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide (28 g, 0.089 mol) and 2-aminopyridine (9.26 g, 0.098 mol) was combined with 500 ml of xylene in a 1 liter flask equipped with an addition funnel and a reversible, adjustable removal-distillation head. The stirred reaction mixture was heated to reflux and the xylene was distilled off at a rate of about 100 ml / hour, keeping the volume of liquid in the flask almost constant by adding fresh xylene. After 6 hours, the temperature of the distillation head, which had been relatively stable at 134 ° C, rose to 142 ° C and the boiling rate slowed. The reaction mixture was then cooled in an ice bath and the precipitated solids were collected by filtration, using hexane for transfer and washing, and dried at 45 ° C under vacuum to give piroxicam (28.5 g, 96%; mp 167-174 ° C). .

For recrystallization, piroxicam (25 g) obtained above was dissolved in 190 [mu] l of dimethylacetamide at 70-75 [deg.] C., treated with 1.26 g of activated carbon at 75-80 [deg.] C. and filtered through diatomaceous earth using 55 ml of warm dimethylacetamide.

A mixture of 173 ml of acetone and 173 ml of water was cooled to 5-10 ° C. The charcoal-treated filtrate was slowly added over 10-15 minutes to cooled aqueous acetone, and the resulting crystals were ground at 0-5 ° C for 5 minutes. The recrystallized piroxicam was collected by filtration, using 154 ml of cold methanol for transfer and washing. Yield: 18.75 g, 75%; IR (nujol Mull) 35 identical to IR of authentic piroxicam.

Claims (7)

10 5 m- ° 2 10 wherein X is chlorine, bromine or iodine; and is alkoxy having one to four carbon atoms or 2-methoxyethoxy. A process for the preparation of a compound of the formula 5 OH λΛ / £ μι il I (Ia) NS A. NS that a compound of the formula 15 I 0 ^ vH ° N> <^ v4J ^ R1 fj0j-CH3 (II) 20 "(wherein X is chlorine, bromine or iodine) is reacted with one equivalent of a metal hydride in a polar, reaction in a neutral solvent at a temperature between about 25 ° C and about 50 ° C until the reaction is substantially complete. Process according to Claim 1, characterized in that the polar reaction-neutral solvent is dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide or 1-methyl-2-pyrrolidone. Process according to Claim 2, characterized in that the reaction-neutral solvent is dimethyl sulfoxide or dimethylformamide and the metal hydride is sodium hydride. 76571 BC 4. A compound characterized by the formula: Compound according to Claim 4, characterized in that X is chlorine. Compound according to Claim 5, characterized in that it is methoxy. Compound according to Claim 5, characterized in that it is methoxyethoxy. 17 76571