CS233749B2 - Processing of 1,1-dioxide alkyl-4-hydroxy-2-methyl-2h-1,2-benzothiazine-3-carboxyl - Google Patents

Abstract

Process for preparing alkyl-4-hydroxy-1,1-dioxides -2-methyl-2H-. 1,2-benzothiazine-3-carboxylates of formula (I) in which R 1 is alkoxy and 1 to 4 atoms carbon or 2-methoxyethoxy, characterized in that it is a compound of the formula 11 in which R 1 is as defined above and X represents chloro, bromo or iodo, allowed to react with one equivalent of hydride metal in a polar inert solvent at a temperature of from 25 ° C to 50 ° C. Produced the products are useful as starting materials for the manufacture of an anti-inflammatory agent known in the art under the name piroxicam.

Description

The invention relates to a novel process for the production of certain intermediates which can be converted to an anti-inflammatory agent known as piroxicam (4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothlazine-3-carboxamide-1,1) -dioxide).

Piroxicam, which is an effective anti-inflammatory agent, was first described by Lombardino in U.S. Pat. No. 3,591,584. One of the plroxicam syntheses mentioned in this work is the reaction of a 3-carboxylic acid ester with 2-aminopyridine. More specifically, this ester is described as an alkyl ester of 1 to 12 carbon atoms in the alkyl moiety or a phenylalkyl ester of 1 to 3 carbon atoms in the alkyl moiety. The ester specifically described is the methyl ester of the formula

OH O

[see also Lombardino et al., J. Med. Chem. 14, 1171-1175 (1971)].

It has further been found that the corresponding 2-methoxyethyl ester may be used in place of the methyl ester mentioned above with certain advantages for the reaction with 2-aminopyridine.

Other alternative syntheses of piroxicam which have been reported in the literature include the reaction of 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine 1,1-dioxide with 2-pyridyl isocyanate (Lombardino, U.S. Pat. 3,591,584), transamidation of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxanilides by reaction with 2-aminopyridine (Lombardino, U.S. Pat. No. 3,891,637), cyclization of compounds of formula (II); CO ₂ ^{and |} ^^ ch SOjNCHjCONH to ₃ wherein Alk is an alkyl group having 1-3 carbon atoms (Lombardino, U.S. Pat. No. 3,853,862), condensation of 1,1-dioxide 4-alkoxy-2-methyl-2H-1,2- benzothiazine-3-carboxylic acids wherein the alkoxy group contains 1 to 3 carbon atoms, with 2-aminopyridine followed by hydrolysis of the enol ether moiety (Lombardino, U.S. Pat. No. 3,892,740), condensation of 4-hydroxy-2-methyl-2H-1 2-behzothiazine-3-carboxylic acid via the corresponding acid chloride with 2-aminopyridine (Hammen, U.S. Patent No. 4,100,347) and methylation of 4-hydroxy-N-2-pyridyl-2H-1,2-benzothiazine-3 -carboxamide (Canadian Patent No. 1,069,894).

The present invention provides a process for the preparation of compounds of formula I

OH

(I) wherein r znamená represents a C 1 -C 4 alkoxy or 2-methoxyethoxy group, characterized in that the compound of formula (II)

O

O.

(XX) in which

X is chlorine, bromine or iodine and R ¹ is as defined above, is reacted with one equivalent of a metal hydride in a polar inert solvent at from about 25 ° C to 50 ° C until substantially complete reaction.

A preferred embodiment of this process is to use an inert solvent selected from the group consisting of dimethylformamide, dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoramide and 1-methyl-2-pyrrolidone.

Another preferred embodiment of this process is to use a metal hydride selected from the group consisting of potassium hydride, sodium hydride and calcium hydride.

The particularly preferred embodiment of the above process employs a starting material in which X is chlorine and R ₁ is methoxy or 2-methoxy, dimethylformamide or dimethylsulfoxide as solvent and an inert natriurahydridu as metal hydride.

The compounds produced by this method are useful intermediates for the production of piroxycam as described in the above references.

This process has the advantage that the desired products are produced in high yield and that it is not necessary to methylate the 4-hydroxy-2H-1,2-benzothiazine ring system.

It will be understood that the compounds prepared as described above may exist in ketone or enol form, which are tautomeric to each other and whose relationship is as follows:

OH O

It will be apparent to those skilled in the art that the two forms mentioned above are equivalent, so that the invention encompasses both of these tautomeric forms, even though only one of them is drawn and shown for simplicity.

The process according to the invention can be described by the following reaction scheme:

X

metal hydride

OH

(II)

In the formulas shown in this scheme, X and R are as defined above,

The process consists in reacting 1 mol of the appropriate 1,2-benzisosulfonazole with an equivalent amount of metal hydride in a polar inert solvent. It can be used for this purpose. any metal hydride, although alkali metal hydrides and alkaline earth metal hydrides are preferred because many of them are commercially available or can be easily prepared. Sodium hydride, potassium hydride and calcium hydride are particularly preferred.

The above procedure is carried out in an inert solvent. The solvent, or mixtures of such solvents, must dissolve the reactants to an extent that facilitates the reaction but must not react to any significant extent with the reactants or product. These solvents should also be highly polar (their dielectric constant should be equal to or greater than 35). Preferred solvents of this type include dimethylformamide, dimethylacetamide, dimethylsulfoxide and 1-methyl-2-pyrrolidone.

For contacting the reactants, the appropriate metal hydride may be added to the starting 1,2-benzisosulfonazole in an inert solvent, or 1,2-benzisosulfonazole in an inert solvent may be added to a suspension of the metal hydride in an inert solvent.

After contacting the reactants, the reaction mixture is heated to a reaction temperature ranging from about 25 ° C to 50 ° C. While operating at a lower or higher reaction temperature than the above preferred range, the desired product is also formed, but these reaction temperatures have a detrimental effect on the product and do not provide any advantages. When operating within the preferred reaction temperature range, the reaction is complete in about 1/2 to 3 hours.

After completion of the reaction, the reaction mixture is poured into cold 5% hydrochloric acid and the product is filtered off or extracted with a water-miscible solvent such as methylene chloride. The product remaining after evaporation of the solvent used for extraction or the product obtained by filtration can be purified in a conventional manner or can be used to prepare piroxicam without further purification.

A preferred embodiment of this process is to use those reagents in which X is chlorine, to use dimethylformamide or dimethyl sulfoxide as an inert solvent, and to use sodium hydride as the metal hydride.

In this process, the particularly advantageously prepared those products in which R ₁ is methoxy or 2-methoxyethoxy.

The starting materials for this process of the invention are readily prepared by reacting 1 mol of N-methylsaccharin with 1 mol of the corresponding haloacetate in the presence of two equivalents of a metal hydride such as sodium hydride in an inert solvent such as tetrahydrofuran according to the following reaction scheme:

N + CH ₃ XCH ₂ C

(II)

In practice, two equivalents of sodium hydride are added to a solution of N-methylsaccharin in tetrahydrofuran and the resulting reaction mixture is heated to about 40 ° C. The appropriate alkyl or 2-methoxyethyl-haloacetate was added in about one hour and after the addition was completed, the reaction mixture was heated to 40-50 ° C for several hours. After completion of the reaction, the mixture is added to a cold 5% solution of hydrochloric acid and the resulting alkyl or 2-methoxyethyl-2- (2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisosulfonazol-3-yl) - The 2-haloacetate is filtered off and dried or extracted with a water-miscible solvent such as methylene chloride. If necessary, the product can be cleaned as usual.

The products produced by the process of the invention are useful starting materials for the production of piroxium by the preparative methods described herein or in the literature or patent references cited herein.

The invention is illustrated by the following non-limiting examples. NMR spectra were measured at 60 MHz in solutions in deuterochloroform (CDCl 3), perdeuterodimethylsulfoxide (DMSO-dg) or deuterium oxide (DgO) unless otherwise indicated, and signal positions are reported in ppm relative to tetramethylsilane or sodium-2,2-dimethyl-2. -silapentane-5-sulfonate as standard. Signal shapes are indicated by the following abbreviations:

s = singlet d = doublet t = triplet q = quartet m = multiplet

He did

2-methoxyethyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (I; R, = -OCH ₂ CH ₂ OCH ₃ )

A. 2-Methoxyethyl 2- (2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisosulfonazol-3-yl) -2-chloroacetate (II; X = Cl, R 1 = OCH ₂ CH ₂ OCH ₃ (

A flame-dried flask was charged with 11.6 g (0.24 mol) under a nitrogen atmosphere.

50Mb sodium hydride oil dispersion. The mineral oil was removed by washing with pentane and decanting, and 50 ml 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, the mixture was heated to 40 ° C and 15.4 g (0.1 mol) of 2- was added dropwise over one hour. methoxyethyl chloroacetate. After the addition was complete, the reaction mixture was heated at 40-50 ° C for 2 hours and then poured into a cooled 5% hydrochloric acid solution with vigorous stirring. The precipitate formed is extracted four times with 100 ml of methylene chloride each time, the extracts are combined, dried over magnesium sulphate and concentrated in vacuo. The desired crude product is obtained in the form of a yellow oil weighing 37.6 g.

The crude product was crystallized from methylene chloride / hexane to give 22.75 g (65%), m.p. 125.5-126.5 ° C. A sample of this material after recrystallization from methylene chloride / hexane melts at 133-135.5 ° C.

NMR (BMSO-d6) signals 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 ^ HH ^O ^ SNCl

44.6 * C, 44.3% C,

4.6% H,

4.7% H,

4.0% N; 4,0% N.

B. 2-Methoxyethyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide

To 280 mg (5.8 mmol) of sodium natriurohydride in the form of a dispersion which was washed with pentane, 10 ml of dimethylsulfoxide was added at room temperature, and 1.75 g (5 mmol) of 2-methoxyethyl-2- (2-methyl) was added. 3-hydroxy-2,3-dihydro-1,2-benzisosulfonazol-3-yl) -2-chloroacetate. The reaction mixture, which was allowed to rise to 32 ° C, was stirred for 1.5 hours and then added to 150 mL of cold 5% hydrochloric acid. The precipitate formed was filtered off and dried, yielding 1.29 g (82.4%) of product.

NMR (iMSO-d6): signals at 8.0 (m, 4H), 4.5 (m, 2H), 3.7 (m, 2H), 3.34 (s, 3H) and 2.90 (s) (3H) ppm

Example 2

AND.

Using the procedure of Example IA, 2-methoxyethyl-2- (2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisosulfonazole) was prepared using N-ethylsaccharin and 2-methoxyethylbromo- and iodoacetate as starting materials. 3-yl) -2-bromoacetate, respectively. 2-methoxyethyl 2- (2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisulfonazol-3-yl) -2-iodoacetate.

B.

Using the procedure of Example 1B, the appropriate 2-methoxyethyl-2- (2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisosulfonazol-3-yl) -2-haloacetate, metal hydride, solvent and reaction temperatures prepare 2-methoxyethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide.

CO (CH ₂ ) ₂ OCH ₃

N-CH _q-metal hydride Solvents Solvents

co ₂ (ch ₂ ) ₂ and ₃

X metal hydride temperature (° C) solvent ¹ Cl KH 25 IMF Cl CaHg 45 EMF Cl NaH 35 DMAC Cl NaU 50 1-M-2-P Cl KH 50 HMPA Cl KH 40 H4F Br NaH 35 DMAC Br NaH 35 EMSO Br KH 25 IMF Br CaH ₂ 50 EMAC Br CaH ₂ 50 DMSO Br KH 30 HMPA

Legend: 1) the solvents used are indicated by the following abbreviations:

EMF = diaethylformamide EMAC = dimethylacetamide

1-M-2-P = 1-methyl-2-pyrrolidone HMPA = hexamethylphosphoramide EMSO = dimethyl sulfoxide

Example 3

Methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide (I; R ₁ = OCH 2)

A. Methyl 2- (2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisosulfonazol-3-yl) -2-chloroacetate (II; R 1 = OCH ₃ )

To 9.2 g (0.19 mol) of a 50% dispersion of sodium hydride in oil, which was freed from oil by washing with pentane, was added 20 ml of dry tetrahydrofuran under nitrogen.

15.9 g (0.08 mol) of N-methylsaccharin in 50 [mu] l of the same solvent are added to the resulting suspension, the suspension is heated to 40 [deg.] C. and 7 ml are added over 3 hours maintaining the temperature at 40-45 [deg.] (0.08 mol) methyl chloroacetate in 20 ml dry tetrahydrofuran. After the addition was complete, the reaction mixture was stirred at 35-42 ° C for 4 hours, then poured into 700 ml of 5% hydrochloric acid and extracted seven times with 100 ml of methylene chloride each time. The combined extracts were washed with 5% hydrochloric acid solution and saturated sodium chloride solution, dried over magnesium sulfate and the solvent was evaporated in vacuo. 21 g of product are obtained in the form of a thick oil which solidifies on standing.

some of this material gave a white solid after trituration with isopropanol, m.p. 122-125 ° C.

NMR (LMSG-d6): signals at 8.1-7.6 (m, 5H), 5.05 (s, 1H), 3.45 (s, 3H) and 2.7 (s, 3H) ppm. For C ^ HH ^O ON NSClCl requires C, 43.2; H, 3.9; N, 4.6;

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

B. Methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide

Κ 63 mg (0.001 3 mol) of dehydrated sodium hydride by washing with pentane, 400 ml (0.001 3 mol) of methyl 2- (2-methyl-3-hydroxy-2,3-dihydro-1,2) are added in 8 ml of dry dimethyl sulphoxide (benzisosulfonazol-3-yl) -2-chloroacetate in 8 mL of dimethyl sulfoxide.

The reaction mixture is heated at 35 ° C for 1 1/4 hour and then poured into 80 ml of cold 5% hydrochloric acid solution. The precipitate formed is filtered off and dried, yielding 280 mg (80.56) of the desired product melting at 162-163 ° C. The product obtained is identical to the product described in U.S. Pat. No. 3,591,584.

Example 4

AND.

Using the procedure of Example 3A, the following 1,2-benzisosulfonazoles were obtained using N-methylsaccharin and the corresponding alkyl haloacetate as starting materials:

X ^R 1 Cl -OCH ₂ CH ₃ Cl -O (CH ₂ ) ₂ CH ₃ Cl -OCH _{(CH3) 2} Cl -O (CH ₂ ) ₃ CH ₃ Cl -OC (CH3) ₃ Cl -0CH ₂ CU Br -0CH ₃ Br -OCH ₂ CH ₃ Br -0 (ch ₂ ) ₂ ch ₃ Br -O (CH ₂ ) ₃ CH ₃ Br -0CH ₂ CHÍCH,) _? AND -och ₃ AND -OCH ₂ CH ₃ AND -OCH _{(CH3) 2} AND -O (CH ₂ ) ₃ CH ₃ AND -OCH ₂ CH (CH ₃ ) ₂ AND -OC (CH3) ₃

B.

The procedure is as described in Example 3B, using the appropriate one below. said 1,2-benzisosulfonazole, metal hydride, reaction temperature and solvent. The corresponding alkyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxides were prepared.

X ^R 1 metal hydrides temperature (° C) solvent ¹ Cl -OCH ₃ KH 25 DMF Cl -OCH ₂ CH ₃ NaH 30 DMAC Cl -O (CH ₂ ) ₂ CH ₃ NaH 35 DMF Cl -OCH _{(CH3) 2} CaH ₂ 50 MSO Cl -0 (CH ₂ ) ₃ CH ₃ NaH 45 DMAC Cl -OC (CH3) ₃ KH 30 HMPA Cl -OCH ₂ CH (CH ₃ ) ₂ KH 25 1-M-2-P Br -OCH ₃ NaH 35 DMF Br -OCH ₂ CH ₃ KH 35 DMF Br -O (CH ₂ ) ₃ CH ₃ KH 25 DMAC Br -O (CH ₂ ) ₂ CH ₃ CaH ₂ 45 Dt (SO Br -0CH _? CH (CH ₂ ) ₂ NaH 50 1-M-2-P AND -OCH ₃ KH 40 DMF AND -OCH ₂ CH ₃ NaH 40 HMPA AND -OCH (CH ₃₎ KH 35 MSO AND -0 (ch ₂ ) ₃ ch ₃ CaH ₂ 50 MSO AND -OCH ₂ CH (CH ₃ ) NaH 30 DMAC AND -OC (CH3) ₃ KH 25 IMF

Legend: 1) the solvents used are indicated by the following abbreviations: DMF = dimethylformamide DMAC = dimethylacetamide MSO = dimethylsulfoxide HMPA = hexamethylphosphoramide

1-M-2-P = 1-methyl-2-pyrrolidone

Claims (3)

SUBJECT OF THE INVENTION A process for the preparation of 1,1-dioxide alkyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxilates of the general formula I (I) in which: R ¹ represents an alkoxy group having 1 to 4 carbon atoms or 2-methoxyethoxy, wherein the compound of formula II (Π), wherein R ¹ meaning stated above and X is chlorine, bromine or iodine, reacted with one equivalent of a metal hydride in a polar inert solvent at a temperature of from 25 ° C to 50 ° C. 2. A method according to claim 1, wherein the polar inert solvent is selected from the group consisting of dimethylformamide, dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoramide and t-ethyl-2-pyrrolidone. 3. The process of claim 2 wherein the inert solvent is dimethylsulfoxide or dimethylformamide and sodium hydride metal hydride.