CS235989B2 - Method of 4-oxo-1,2-benzothiazine-3-carboxamide-1,1-dio xides production - Google Patents

Description

The invention relates to an improved process for the preparation of benzothiazine carboxamide-based anti-inflammatory agents.

U.S. Pat. No. 3,591,584 describes two methods of synthesizing anti-inflammatory agents based on N-substituted benzothiazole-caboxamides. The first of these methods is used to prepare carboxamides in which the nitrogen substituent is not a heterocyclic residue. This process consists in reacting an organic isocyanate of the general formula

R ₃ NC0 in which

R 1 is, for example, a certain alkyl, phenyl or naphthyl group, with 4-oxo (or 3-oxo) -1,2-benzothiazine, resulting, for example, in the formation of a compound of formula V ⁰ . _{3 3} > r, <V)

Or the corresponding 3-oxo-4-carboxamide.

The latter is advantageous for the preparation of those amides in which the non-nitrogen substituent is a heterocyclic radical and consists in reacting the corresponding carboxylic acid ester with the corresponding amine of formula

235939 r ₂ nh in which

R ₂ represents a heterocyclic group, to give the desired benzothiazole-carboxamide. This reaction can be described, for example, by the following reaction scheme:

CONHRj (VII)

U.S. Pat. No. 3,891,637 describes a process for obtaining amides of formula VII, substituted on nitrogen by a heterocyclic radical, from the corresponding N-phenylamides by transamiration.

U.S. Pat. No. 3,853,862 describes a process for the preparation of 4-oxo-1,2-benstothiazine-3-carboxamides of formula VII by cyclization of the benzenesulfonylglycinamide of formula III below in the presence of a metal hydride, for example according to the following reaction scheme:

COjCHj

SO ₂ NCH ₂ CONHR ₂ ^R 1 _ * / VII, Ϊ -hydrogen /

U.S. Pat. No. 4,289,879 describes a process for the preparation of piroxicam / 4-hydroxy-2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide. via the corresponding 3- (2-methoxyethyl) ester.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of anti-inflammatory active 4-oxo-1,2-benzothiazine-3-carboxamide-1,1-dioxides of the general formula IV.

NR

CONHZ (IV) in which

R represents a hydrogen atom, a benzyl group or an alkyl group having 1 to 3 carbon atoms αχ

Z represents an optionally substituted 2-pyridyl radical, a 2-thiazolyl radical optionally substituted by one or two alkyl groups, or a 5-alkyl-3-isoxazolyl radical, all of the above-mentioned alkyl groups having from 1 to 4 carbon atoms, that is

a) an ester of the formula II

O ^ COOR ¹ _X NR 0 2 (II) wherein r 1 is a benzyl or C 1 -C 4 alkyl group, and R is as defined above reacted with an equimolar amount of an amine of the formula ZNHg, wherein R is as defined above in the presence of an inert organic solvent at a temperature of from 0 to 110 ° C, to form the intermediate of formula (I)

in which

R and R ¹ have the abovementioned meaning and

Z ¹ together with the group -C = N- form the radical Z as defined above,

b) and the intermediate is heated in the presence of an inert organic solvent to a temperature of about 20 ° C to 200 ° C to eliminate the compound of formula r'oh in which

R ¹ ;; is as defined above.

Particularly preferred radicals R, R ¹ and Z in the compounds of formula I are:

for R 1 is C 1 -C 3 alkyl.

for C 1 -C 4 alkyl, and for Z 2-pyridyl, 2-thiezolyl, 5-methyl-3-isosaxolyl, 1-methyl-2-pyridyl or 4,5-dimethyl-2-thiazolyl.

Particularly preferred radicals for the abovementioned substituents are:

for R 1 a methyl group, for R ^{1 a} methyl or ethyl group and for Z a 2-pyridyl, 2-thiazolyl or 5-methyl-3-isoxezolyl group.

The most preferred compound is a compound of formula I wherein R and R ¹ are each methyl and Z is 2-pyridyl. The corresponding anti-inflammatory agent of formula (IV) produced by the process of the invention is known under the common name of piroxacam (see, for example, Wiseman, Roy). Soc. Copper. Int. Cong. Symp. Ser. £,

11-23 (1978)].

The process according to the invention has the advantages over the known processes in that it results in better yields and higher productivity, resulting in a significantly higher weight of the product of formula IV per unit volume of solvent. The product of formula (IV) produced by the process of the invention also has better purity. ^J

A further advantage of the process according to the invention lies in the possibility of repeated recycling of the mother liquors to the next batch, whereby good results are obtained.

*

The isolation of the intermediate of formula (I) in the process according to the invention results in further purification which was not possible in the prior art processes. Thus, starting materials of lower purity can be used in the process of the invention, since purification occurs in the isolation of the intermediate of formula I. This represents a significant advantage since a contaminated amine of formula ZNHg can be used without reducing the purity of the anti-inflammatory agent. of formula IV. It is further known in the art that the amines of the formula ZNHg defined above are difficult to purify by the present methods.

The compounds of formula (I) of the present invention are prepared by reacting roughly equimolar amounts of a 4-oxo-1,2-benzothiazine-3-carboxylic acid ester of formula (II) and the corresponding amine of formula (II), wherein Z is as defined above. The reaction is carried out in the presence of an inert solvent at a temperature of about 0 to 110 ° C, with a reaction time of up to 24 hours. A particularly preferred temperature range for this reaction is about 20 to 90 ° C.

Within this temperature range, the reaction is usually complete in a few minutes to hours, for example in 15 minutes to about 4 hours. If desired, the desired product of formula (I) is then isolated, for example by cooling the reaction mixture to or below room temperature, the precipitated solid product is filtered off and dried.

The above-mentioned inert organic solvent is one which does not react to any significant extent with either the starting materials or the product under the reaction conditions used, and is capable of dissolving at least the bulk of the starting materials at or below the reaction temperature. Further, the desired product should be readily isolated from this solvent by standard techniques known in the art. Examples of inert organic solvents that can be used in the preparation of the desired compounds of formula (I) include hydrocarbons such as benzene, toluene, xylenes, ethylbenzene, tetralin and decalin, halogenated hydrocarbons such as chloroform, methylene dichloride, ethylene dichloride, ethyl bromide and ethylene dibromide, ketones such as acetone and methyl ethyl ketone, ethers such as ethyl ether, tetrahydrofuran, 1,2-dimethoxyethane and diethylene glycol dimethyl ether, dialkylamides such as dimethylformamide, dimethylacetamide and N-methyl-2-pyrrolidinone, dimethylsulfoxide and acetonitrile. Particularly preferred are those solvents mentioned above whose boiling point at atmospheric pressure is at least as high as the highest reaction temperature used. A commercial mixture of xylenes is particularly advantageous from an economic and efficiency point of view.

As mentioned above, the compounds of formula I are useful as intermediates for the preparation of anti-inflammatory agents of formula IV, which are formed by the elimination of the compound R OHOH from the compound of formula I. This process can be described by the following reaction scheme:

—RIqh

Y

CONHZ

NR (IV)

This reaction is also carried out in the presence of one of the above-mentioned particularly preferred inert reaction solvents, but at elevated temperature to remove the alcohol formed in the reaction. The preferred temperature for this reaction is about 120 to 200 ° C, especially about 135 to 145 ° C.

r

The inert organic solvents that can be used to produce the compounds of formula (IV) as described above are the same as those mentioned above for the preparation of the compounds of formula (1), except those boiling at a temperature substantially lower than the preferred reaction temperature range; which would therefore require the use of pressure equipment. Particularly preferred solvents for this reaction are toluene, xylenes, ethylbenzene, tetralin and decalin, and a mixture of xylenes is particularly preferred in terms of economy and efficiency. Obviously, the xylene mixture also has the advantage that its boiling point lies in

a particularly preferred reaction temperature range, thereby facilitating temperature control and removal of the by-product alcohol.

In the first reaction step of the process of the invention, the formation of a solid intermediate of formula I provides a purification method that was not possible in the prior art processes in which the ester of formula II and the amine of formula ZNHg reacted directly to give a compound of formula IV. Thus, relatively impure starting materials of formulas II and ZNH4 may be used in the process of the invention, and purification may be accomplished by isolating the novel intermediate of formula I prior to conversion to the anti-inflammatory compound of formula IV.

/

A further advantage of the process according to the invention is that the desired product of formula (IV) can be lured at a higher yield and at a higher throughput than the most advantageous process known from the prior art of U.S. Pat. No. 3. No. 591,584, which, as mentioned above, provides benzothiazine-3-carbo-. xamides using the corresponding 3-carboxylic acid ester and heterocyclic amine of formula ZNH ₂ , wherein Z is as defined above. In this known process, when the total concentration of the reactants exceeds about 3 g per 100 ml of solvent, a relatively high amount of decomposition products and colored materials is formed in the reaction mixture which makes it difficult to isolate the desired product of formula IV. the inclusion of other costly cleaning operations is not suitable for pharmaceutical use.

However, the process according to the invention can be carried out in such a way that the efficiency in step (b), expressed by the concentration of the reactants in the reaction solvent, can be increased to 6-8 g / 100 ml or more without detrimentally affecting product yield or purity. This is accomplished by isolating the novel intermediate of formula (I) obtained in step (a) and adding it in portions to the heated reaction solvent used in step (b), where a portion of the alcohol molecule of formula S ¹ OH is eliminated and formation of the product of formula IV in high yield and purity.

Another advantage of the process according to the invention is the possibility of repeated recycling of the mother liquors to the next reaction batch. Even after repeated recycling of mother liquors in this way, high yields and high purity of the product are achieved, so that losses of the product contained in the mother liquor are eliminated. On the other hand, recycling of mother liquors in the prior art process results in so much accumulation of impurities that after only a few uses of mother liquor in the following batch, the desired product cannot be isolated at all or can be very difficult to isolate.

The invention is illustrated by the following non-limiting examples.

Example 1

Standard Preparation of Piroxicam

O O

To a 5-liter flask equipped with a thermometer, filled with a distillation column, condenser and stirrer, was added, under a nitrogen atmosphere, 3,300 mL of a xylene mixture, 80 g (0.297 mol) of methyl-3,4-dihydro-2-methyl-4-oxo-2H-1. 2-benzothiazine-3-carboxylate-1,1-dioxide, 32 g (0.340 mol) of 2-aminopyridine and 8 g of activated carbon. The mixture was heated at reflux (about 140 ° C) for 28 hours, and methanol and xylene were slowly distilled off for about the first 8 hours at a rate of about 25 mL per hour and for the remainder of the reflux period. at a rate of 5 to 10 ml per hour, fresh xylene is added to the reaction mixture to maintain a volume of about 3: 500 ml. After Ϊ8 hours, the reaction mixture is cooled gently (to approx

235989 6

100 ° C) β activated carbon is filtered off. The filter cake is washed with 100 ml of warm xylene and the filtrate and the wash liquid are slowly cooled to 25-50 ° C under vigorous stirring under nitrogen. Stirring is continued for 1 hour to complete the crystallization, then the crystals are filtered off, the mother liquor is concentrated to a volume of about 1500 ml, cooled to 0-5 ° C under nitrogen, filtered, and the filter cake is washed with 100 ml of cold xylene. the crystalline material was dried under vacuum at a temperature below 60 ° C for several hours. Yield: 76.7-84.6 g (78-86% of theory). The efficiency of the process, expressed as a solids concentration in the solvent, averaged 24.4 g / liter.

Example 1 a d 2

An improved process for the preparation of piroxicam preparations using an intermediate of formula I wherein R and R * are methyl and Z is a 2-pyridyl group.

A. In a one liter flask purged with nitrogen, place 300 ml of the xylene mixture,

120 g (0.446 mol) of methyl 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 48 g (0.510 mol) of 2-aminopyridine. The mixture is heated to 90 ° C, stirred vigorously at this temperature for 1 hour, and then allowed to cool under a nitrogen atmosphere.

A 5 liter flask containing 3 300 ml of xylene is charged with 12 g of activated carbon and the mixture is heated to reflux with azeotropic distillation of the xylene / water mixture. Half of the above prepared suspension of the intermediate of formula I in xylene is added to the mixture, the reaction mixture is heated to reflux and a mixture of methanol and xylene is distilled off at a rate of 25 ml per hour, maintaining the reaction mixture at about 3 by adding fresh xylene. 500 ml. After 4 hours, a third of the remaining intermediate suspension is added and the methanol / xylene mixture is distilled off at the same rate. The remaining portions of the intermediate (one-third each of the above residue) were added after 8 and 10 min respectively. 12 hours and the methanol / xylene mixture was distilled off at 25 ml / hour for a total of 16 hours. After these 16 hours, the distillation rate was reduced to 12.5 ml per hour and maintained at this level for a total of 34 hours.

The reaction mixture was cooled to about 100 ° C, freed from charcoal by filtration, and the filter cake was washed with 100 mL of warm xylene. The filtrate was purged with nitrogen and cooled to 25-50 ° C with vigorous stirring. Stirring was continued for 1 hour to complete the crystallization. The crystals are filtered off, the mother liquor is concentrated to about 1500 ml, cooled to 0-5 ° C under nitrogen, filtered, the filter cake is washed with 100 ml cold xylene and the crystalline product is dried under vacuum at a temperature below 60 ° C. The yield of piroxicam is 121-132.8 g (82-90% of theory), the average efficiency of the process, expressed as the solids concentration in the solvent, is 38.5 g / liter.

B. The above procedure is repeated with the following variations. To 600 ml of the xylene mixture was added, under a nitrogen atmosphere, 60 g (0.594 mol) of methyl 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 60 g (0.637 mol) of industrial 2-aminopyridine.

The mixture was heated at 85-90 ° C for two hours, then cooled to 20-25 ° C and stirred at this temperature for 2 hours. The crystalline intermediate formed is filtered off and washed with 100 ml of cold xylene. A weighed sample of solvent-moistened crystals is dried under vacuum. Differential calorimetry of the dry sample yields a single sharp signal at 132.9 ° C. From the weight of the dried sample, it can be found that the yield of the intermediate of formula I in which R ¹ and R ¹ known on its methyl groups and Z represents a 2-pyridyl group is 215.9 g (98%).

3 g of 2-aminopyridine, 8 g of activated carbon are introduced into 3,300 ml of the xylene mixture, the mixture is heated to gentle reflux and the reaction system is dehumidified by distilling off the azeotropic mixture of xylene and water. 81 g (based on dry compound) (0.223 mol) of the above-prepared crystalline intermediate mixed with 50 ml of xyl ether were then added to the mixture. The mixture was heated to reflux while a mixture of methanol and xylene was distilled off at 25 ml / h. An additional 17 g of intermediate was added every 2 hours until a total of 215.9 g of the above product was consumed. Refluxing the methanol / xylene mixture at 25 ml / hour was continued for a total of 20 hours, after which the distillation rate was reduced to 12-13 ml / hour. If necessary, the volume of the reaction mixture is maintained between 3.3 and 3.7 liters by the addition of xylene. After a total of 34 hours, the reaction mixture was cooled and the product isolated in the same manner as in Part A. 165.3 g (84%) of piroxicam were obtained. The efficiency of the process, expressed as the solids concentration in the solvent, is 50 g per liter.

Example 1 and d .3

Comparison of the standard process for the production of piroxicam with the improved process using recycle mother liquors

The standard procedure (Example 1) and the improved procedure (Example 2) are repeated four times, with the second, third and fourth embodiments always adding mother liquors from the previous embodiment. The results are summarized as follows:

batch yield in% standard procedure with recycling yield improved recycling process 1 81 83 2 90 87 3 93 96 4 93 average of 4 batches 66 90

At each stage of this experiment, by recycling the mother liquors, the batches prepared by the standard procedure are more colorful, with this color progressively increasing. In the fourth batch prepared by the standard procedure, only a syrupy material is obtained which cannot be crystallized. By working with the improved process, on the other hand, a yield of 93% is obtained in the fourth batch. The experiment was terminated at this time because the standard procedure is no longer to whistle any product. After the fourth batch in an improved process, the mother liquor is still clear and is expected to be successfully used in other batches.

Example 4

If the procedures described in Examples 2 and 3 were repeated using the appropriate starting materials, the following products of the formula IV were obtained, also in higher yield and 8 higher efficiency (I; Z = 2-pyridyl) --->

Ύ

NR

O-NH (IVj Z = 2-pyridyl)

CH, C ₂ H ₅ Cl 2 Cl 2 Hy

C _e H ₅ CH ₂

Example 5

Using the corresponding starting materials in the paddle procedure of Example 2 and the recycle procedure of Example 3, the following products of Formula IV are obtained in improved yield and efficiency.

O

R OF ch ₃ ^C 6 ^H 5 ch ₃ 2-thiazolyl c ₂ h ₅ 2-pyridyl n-CjHy 2-thiazolyl - ₄ H ₉ 5-methyl-2-thiazolyl CH ₃ 4-ethyl-2-thiazolyl c ₆ h ₅ ch ₂ 5-n-Butyl-2-thiazolyl ch ₃ 5-Methyl-3-isoxazolyl ^C 2 ^H 5 5-methyl-2-pyridyl CHj 4-Methyl-2-pyridyl Objective ₃ 1-methyl-2-pyridyl fcítj 6-n-propyl-2-pyridyl CH ₃ 6-isobutyl-2-pyridyl ^C 2 ^H 5 5-ethyl-3-isoxazolyl c ₂ h ₅ 5-Isopropyl-3-isoxazolyl and 5-n-Butyl-3-isoxazolyl Η 4-methyl-2-thiazolyl Sa ₃ 4,5-dimethyl-2-thipzolyl ěn ₃ 4,5-di-n-butyl-2H-thiazolyl

Example

An improved process for preparing sudoxicam using an intermediate of formula I wherein R and R * are methyl and Z is 2-thiazolyl

The reaction flask is charged with 30 ml of xylene and 0.5 g of the crystalline intermediate 2-thiazolylderivative of formula I, which has been prepared beforehand, and the contents of the flask are slowly distilled to remove the distillate at 5 ml in 2.5 hours. 5 ml of xylene and 0.25 g of intermediate are added and the distillation is repeated as above. This procedure is repeated once more and the mixture is refluxed for a total of 7 hours. The reaction mixture was stirred at room temperature over Saturday and Sunday (ca. 60 hours) and the product was filtered off.

Yield 65% (590 mg) of sudoxicam, a 2-thiazolyl analogue of piroxicam, melting at 245-247 ° C with decomposition.

The starting material of the formula (I) used for the reaction described above is prepared as follows:

To a mixture of 2.69 g (10 mmol) of methyl 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 50 mL of xylene was added with stirring under nitrogen, 1.05 g (10.5 mmol) of 2-aminothiazole was added, the resulting mixture was heated at 85-90 ° C for 3 hours, then cooled to room temperature, filtered and the brown crystalline product dried in vacuo. 2.3 g (62.3%) of the title compound melting at 131-142 ° C are obtained.

The crystalline product is dissolved in 20 ml of methylene chloride, the solution is decolorized with charcoal and filtered. The filtrate was added to hexane with vigorous stirring, stirred for 1 hour and then filtered. 1.35 g of white crystalline product, mp 140-145 ° C (I; R = R ¹ = CH, Z = 2-thiazolyl.

Claims (7)

A process for the preparation of 4-oxo-1,2-benzothiazine-3-carboxamide-1,1-dioxide of the general formula IV in which: R represents hydrogen, benzyl or alkyl having 1 to 3 carbon atoms, ^L '.a. Z represents an optionally substituted 2-pyridyl radical, a 2-thiazolyl radical optionally substituted by one or two alkyl groups, or a 5-alkyl-3-isoxazolyl radical, all of the above alkyl groups having from 1 to 4 carbon atoms, The compound of formula (II) is (a) O. .COOR ¹ South dl) * ·, ··. ° 2 in which R ¹ is benzyl or C 1 -C 4 alkyl, and R is as defined above, reacted with an equimolar amount of an amine of formula ZNH 2 wherein Z is as defined above in the presence of an inert organic solvent at a temperature of 0 to 110 ° C, yielding an intermediate of formula 1 COR (I) in which r R ¹ and R ¹ are as defined above and z 1 together with the group -C = N- form the radical Z as defined above, b) and the intermediate of formula (1) is heated in the presence of an inert organic solvent to a temperature of 120 to 200 ° C to give a compound of formula (IV). 2. The process of claim 1, wherein the corresponding compounds of formula II and ZNHg are used as starting materials to give compounds of formula IV wherein R is methyl and Z is 2-pyridyl, 2-thiazolyl, a methyl-3-isoxazolyl, 6-methyl-2-pyridyl or 4,5-dimethyl-2-thiazolyl residue. 3. Process according to claim 1 or 2, characterized in that the corresponding compounds of the formula II and ZNHgI are used as starting materials to give a compound of the formula IV in which Z represents a 2-pyridyl radical and R represents a methyl group. 4. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out in step a) at a temperature of from 20 to 90 ° C and in step b) at a temperature of 135 to 145 ° C. 5. A process according to any one of claims 1 to 4, wherein the intermediate product of step a) is isolated. 6. A process according to any one of claims 1 to 5, wherein the product of step b) is isolated and the mother liquor is recycled. r 7. A process according to any one of claims 1 to 6, wherein xylene is used as the inert organic solvent.