Method of preparing alkylated salicylamides via a dicarboxylate intermediate

ES 2 386 263 T3

DESCRIPTION

Method of preparing salicylamides alkylated by means of a dicarboxylate intermediate.

The present invention relates to a method of preparing alkylated salicylamides from salicylamides by means of a dicarboxylate intermediate. The alkylated salicylamides prepared by this method are suitable for use in compositions for administering active agents orally or other routes of administration to animals.

Carsalam (2H-1,3-benzoxazin-2,4 (3H) -dione) is known in the art as an analgesic (see Merck Index, 12^toedition, no. 1915).

Alkylated salicylamides, such as those disclosed in US Pat.^you 5,650,386, 5,773,647 and 5,866,536 are highly effective as delivery agents for active agents, particularly for oral administration of active agents. Typically, these alkylated salicylamides are prepared by modifying an amino acid or an ester thereof. For example, these alkylated salicylamides can be prepared by acylation of an amino acid or an ester thereof with agents that have a leaving group, such as a halogen, carbonyl group, or sulfonyl group, and an appropriate radical to provide the desired modification in the final product. . See, for example, US Patent No. 5,650,386.

International Publication No. WO 00/46182 discloses a method of preparing an alkylated salicylamide by alkylating a protected / activated salicylamide and deprotecting and deactivating the protected / activated salicylamide. The alkylating agent can be, for example, ethyl 10-bromo-decanoate and ethyl 8-bromo-octanoate.

WO 00/07979 discloses salicylic acid derivatives for delivering active agents.

GB 950,281 discloses the reaction of 2,4-dioxodihydro-1,3-benzoxazine in the form of its alkali metal salt with a compound of the general formula Z (CH2) nCOR1, in which Z indicates a halogen radical.

The preparation of dicarboxylated phthalimide derivatives by alkylation with a dicarboxylated alkylating agent is disclosed on page 2087, last paragraph, Method D of Itoh, K. et al., Chem. Pharm. Bull., Vol. 34, No. 5 (1986), pp. 2078-2089, and on page 195, col. 1, 2. paragraph, reaction steps ii) and iii) from Takechi, H. et al., Chem. Pharm. Bull., Vol. 42, No. 2 (1994), pp. 188-196.

Alternative methods of preparing alkylated salicylamides would be useful, especially when starting materials are expensive, yields are low, and reaction conditions are difficult.

Thus, there is a need for simpler and less expensive methods of preparing alkylated salicylamides.

The present invention relates to a method of preparing an alkylated salicylamide from a protected and activated salicylamide (hereinafter referred to as "protected / activated salicylamide") by means of a dicarboxylated salicylamide intermediate.

The present invention provides a method of preparing an alkylated salicylamide of the formula

<img file="ES2386263T3_D0001.tif" />

from a protected and activated salicylamide that is protected to prevent reaction of the hydroxyl moiety and is activated at the nitrogen atom of the amide group, the method comprising the steps of:

(a) renting a protected and activated salicylamide having the formula

ES 2 386 263 T3

<img file="ES2386263T3_D0002.tif" />

at the nitrogen atom of the amide group with a dicarboxylate alkylating agent of formula

<img file="ES2386263T3_D0003.tif" />

to form a protected and activated dicarboxylated salicylamide of formula

<img file="ES2386263T3_D0004.tif" />

in which

R¹, R², R³ and R⁴ they are independently hydrogen; halogen; C1-C4 alkoxy, optionally substituted with -OH or F; -OH; C1-C4 alkyl, optionally substituted with -OH or F; -COOH; -OC (O) CH3; -SO3H: nitrile; or -NR⁹R¹⁰;

R⁵ is a protecting group;

R⁶ it is an activating group; or

R⁵ and R⁶ combine to form a substituted or unsubstituted cyclic group;

R⁷ is a linear or branched C1-C20 alkylene;

R⁷ is optionally substituted with C1-C4 alkyl, alkenyl with up to 4 carbon atoms, oxygen, nitrogen, sulfur, halogen, -OH, C1-C4 alkoxy, aryl, heteroaryl or vinyl;

R⁷ is optionally interrupted with aryl, heteroaryl, vinyl, oxygen, nitrogen, or sulfur;

R⁸ and R¹¹ they are independently C1-C4 alkyl or C1-C4 haloalkyl;

R⁹ and R¹⁰ they are independently hydrogen, C1-C4 alkyl or oxygen;

R¹⁸ is hydrogen;

R¹⁹ is -COOH or a salt thereof;

X is a suitable leaving group; and (b) (i) deprotect, (ii) deactivate and (iii) decarboxylate the protected and activated dicarboxylated salicylamide to form the

ES 2 386 263 T3 alkylated salicylamide.

In another embodiment, the present invention relates to a compound having the formula

<img file="ES2386263T3_D0005.tif" />

in which

R¹, R², R³ and R⁴ they are independently hydrogen; halogen; C1-C4 alkoxy, optionally substituted with -OH or F; -OH; C1-C4 alkyl, optionally substituted with -OH or F; -COOH; -OC (O) CH3; -SO3H; nitrile; or -NR⁹R¹⁰;

R⁵ is a protecting group selected from the group consisting of -C (O) CH3, -C (O) CF3, -S (O2) CH3, -S (O) 2CF3, benzyl, silyl, tetrahydropyranyl, and methylene alkoxy;

R⁶ is an activating group selected from the group consisting of -C (O) CH3, -C (O) CF3, -S (O2) CH3, and -S (O) 2CF3; or

R⁵ and R⁶ combine to form a substituted or unsubstituted cyclic group;

R⁷ is a linear or branched C1-C20 alkylene,

R⁷ is optionally substituted with C1-C4 alkyl, alkenyl with up to 4 carbon atoms, oxygen, nitrogen, sulfur, halogen, -OH, C1-C4 alkoxy, aryl, heteroaryl or vinyl;

R⁷ is optionally interrupted with aryl, heteroaryl, vinyl, oxygen, nitrogen, or sulfur;

R⁸ and R¹¹ they are independently C1-C4 alkyl or C1-C4 haloalkyl; Y

R⁹ and R¹⁰ they are independently hydrogen, C1-C4 alkyl or oxygen.

Preferred embodiments are set forth in the dependent claims.

The dicarboxylated salicylamide intermediate can be prepared by alkylating a protected / activated salicylamide with a dicarboxylate alkylating agent. In one embodiment, the alkylated salicylamide is prepared by (a) deprotecting and deactivating the salicylamide, and (b) optionally, hydrolyzing the deprotected and deactivated salicylamide. In another embodiment, the alkylated salicylamide is prepared by (a) deprotecting and deactivating the salicylamide, (b) optionally hydrolyzing the deprotected and deactivated salicylamide; and (c) decarboxylating the salicylamide. Steps (a) and (b) can be carried out before or after step (c). Preferably, step (c) is carried out after steps (a) and (b). According to one embodiment, the deactivation and hydrolysis steps occur simultaneously and after deprotection. The alkylated salicylamides prepared by this method are suitable for use in compositions for administering active agents orally or other routes of administration to animals.

Many of the alkylating agents disclosed in the prior art, such as ethyl 10-bromo-decanoate and ethyl 8-bromo-octanoate as disclosed in International Publication No. WO 00/46182, are prepared from the dicarboxylate alkylating agents of the present invention. The process for converting dicarboxylated compounds to alkylating agents of the prior art is often expensive and time consuming. For example, ethyl 8-bromo-octanoate is prepared from 2- (6-bromohexyl) malonic acid diethyl ester by a multi-step process that includes an expensive distillation step. The process of the present invention reduces the number of synthetic steps required to prepare alkylated salicylamides and, therefore, reduces their cost and manufacturing time.

The terms "alkynyl", "alkenyl" and "alkyl" as used herein include linear and branched alkynyl, alkenyl and alkyl substituents, respectively.

The term "substituted" as used herein refers to compounds substituted with one or more of C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 alkynyl.

The term "protected salicylamide" is defined herein as a salicylamide in which the remainder

ES 2 386 263 T3 hydroxyl of the salicyl group has been protected to prevent reaction of the hydroxyl moiety. The term "activated salicylamide" is defined herein as a salicylamide in which the nitrogen atom of the amide group has been activated so that the nitrogen atom is in a more reactive condition, that is, more prone to reaction. .

Any of the protected / activated salicylamides in International Publication No. WO 00/46182 can be used in the process of the present invention. Suitable protected / activated salicylamides include, compounds having the formula

<img file="ES2386263T3_D0006.tif" />

in which

R¹, R², R³ and R⁴ they are independently hydrogen; halogen; C1-C4 alkoxy, optionally substituted with -OH or F; -OH; C1-C4 alkyl, optionally substituted with -OH or F; -COOH; - OC (O) CH3; -SO3H; nitrile; or -NR⁹R¹⁰;

R⁹ and R¹⁰ they are independently hydrogen, C1-C4 alkyl or oxygen;

R⁵ is a protecting group;

R⁶ it is an activating group; or

R⁵ and R⁶ combine to form a substituted or unsubstituted cyclic group, i.e., R⁵ and R⁶ they form a single group that forms a heterocycle with the oxygen atom and the nitrogen atom of the amide moiety.

Preferred halogens for R, R, R, and R are chlorine, bromine, and fluorine. Preferred alkoxy groups for R, R, R, and R⁴ include methoxy and ethoxy.

Protecting and activating groups can be the same or different. Protecting and activating groups can be separate moieties (each attached to one of the hydroxyl or amide moieties) or a single moiety (attached to both the hydroxyl and amide moieties).

Suitable protecting groups include -C (O) CH3; -C (O) F3; -S (O) 2CH3; -S (O) 2CF3; benzyl; silyl; tetrahydropyranyl; and methylene alkoxy, such as methylene methoxy and methylene ethoxy. Suitable activating groups include, -C (O) CH3; -C (O) CF3; -S (O) 2CH3; and -S (O) 2CF3. Preferably R⁵ and R⁶ they combine to form a cyclic group that protects the hydroxyl moiety and activates the nitrogen atom of the amide moiety. More preferably, the R⁵ and R⁶combined are -C (O) - or -S (O) 2-,

Preferred protected / activated salicylamides include carsalam and derivatives thereof having the formula

<img file="ES2386263T3_D0007.tif" />

in which R¹, R², R³ and R⁴ they are as defined above. A preferred carsalam derivative has the above formula, where R¹, R², R³ and R⁴ they are independently hydrogen, C1-C4 alkoxy or halogen. Another preferred carsalam derivative has the above formula, where R¹, R², R³ and R⁴ they are independently hydrogen, methoxy or chlorine. Still another preferred carsalam derivative has the above formula, in which R¹, R³ and R⁴are hydrogen and R² it is methoxy. Still another preferred carsalam derivative has the above formula, in which R¹, R² Y

ES 2 386 263 T3

R⁴ are hydrogen and R³ it is chlorine.

Carsalam has the formula

<img file="ES2386263T3_D0008.tif" />

Carsalam can be prepared by methods known in the art, such as those described in Shapiro et al., JACS, 79: 2811 (1957), and DN Dhar, AK Bag, Indian J. Chem., 21 B: 266 (1982) . The above-mentioned derivatives of carsalam can be prepared by known methods for preparing carsalam by substituting appropriate starting materials. These carsalam derivatives can also be prepared by adding the appropriate substituents to carsalam by methods known in the art.

A method of preparing the protected / activated salicylamide of the present invention comprises protecting the hydroxyl moiety of a salicylamide and activating the amide moiety of the salicylamide, as described in International Publication No. WO 00/46182. The protection and activation steps can be performed in any order, but are preferably performed simultaneously. Alternatively, the protection step can be performed prior to performing the activation step.

Suitable salicylamides (unprotected and deactivated) include those of the formula

<img file="ES2386263T3_D0009.tif" />

in which R¹, R², R³ and R⁴ they are as defined above. Representative unprotected and deactivated salicylamides include salicylamide, 4-methoxysalicylamide, and 5-chlorosalicylamide.

The hydroxyl moiety of the salicylamide can be protected by methods known in the art. For example, the hydroxyl moiety is protected by reacting salicylamide with a protective agent, such as an activated halide. The resulting salicylamide has a protecting group attached to the oxygen atom of the hydroxyl moiety. Examples of activated halides include acyl halides; silyl halides, such as silyl chlorides; benzyl halides; and methylene alkoxy halides, such as methylene methoxy halides and methylene methoxy halides. Preferably, the reaction with an activated halide is carried out in the presence of a base, such as potassium carbonate, triethylamine or pyridine.

Another example of a protective agent is an activated ether. Examples of activated ethers include dihydropyranyl ether. Preferably, the activated ether is reacted with the salicylamide under acid catalyzed conditions, such as with sulfuric acid, paratoluenesulfonic acid, or camphorsulfonic acid in methylene chloride, tetrahydrofuran, or toluene.

The amide moiety of salicylamide can be activated by methods known in the art. For example, the amide moiety can be activated by reacting the salicylamide with an activating agent, such as an acyl halide, acyl anhydride, sulfonyl halide, or sulfonyl anhydride. The resulting salicylamide has an activating group attached to the nitrogen atom of the amide moiety. Suitable acyl halides include those described above to protect the hydroxyl moiety of salicylamide. Preferably, the activating moiety is reacted with the salicylamide in the presence of a base, such as potassium carbonate, triethylamine, or pyridine.

In the preparation of carsalam and the aforementioned derivatives thereof, the protection and activation steps are usually performed simultaneously and the protecting and activating groups are a single group attached to both hydroxyl and amide moieties. A method of preparing carsalam and its derivatives is

ES 2 386 263 T3 by reacting the corresponding salicylamide (deprotected and deactivated) with an alkyl chloroformate, such as ethyl chloroformate; a phenyl chloroformate; or a carbonylalkoxyimidazole.

Alkylation

The protected / activated salicylamide is alkylated with a dicarboxylate alkylating agent to form the dicarboxylated salicylamide. Dicarboxylate alkylating agents have the formula

<img file="ES2386263T3_D0010.tif" />

in which R⁷, R⁸, R¹¹ and X are as defined in claim 1.

Suitable leaving groups include halogens and alcohols. Two preferred leaving groups are chlorine and bromine.

811 811 7

Preferably R and R are independently C1-C4 alkyl. Preferably R and R are the same. R is preferably C4-C12 alkylene and more preferably C7-C9 alkylene.

A preferred dicarboxylate alkylating agent has the formula

<img file="ES2386263T3_D0011.tif" />

in which

R¹² and R¹³ are independently C1-C4 alkyl;

X is a suitable leaving group; and n is an integer from 2 to 12.

Preferably, n ranges from 3 to 10, more preferably 4 to 8, and most preferably 6 to 8. Examples of dicarboxylate alkylating agents include 2- (6-bromohexyl) -malonic acid diethyl ester and 2- (8-bromooctyl) malonic acid, which are available from Allied Signal, Inc. of Morristown, NJ.

In a more preferred embodiment, R¹, R², R³ and R⁴ of the protected / activated salicylamide are hydrogen and n of the dicarboxylate alkylating agent is 6 or 8. According to another preferred embodiment, R¹, R² and R⁴ of the protected / activated salicylamide are hydrogen, R³ is chlorine and n of the dicarboxylate alkylating agent is 2 or 6. According to yet another preferred embodiment, R¹, R³ and R⁴ of the protected / activated salicylamide are hydrogen, R² is methoxy and n of the dicarboxylate alkylating agent is 6.

Many of the alkylating agents disclosed in the prior art, such as ethyl 10-bromo-decanoate and ethyl 8-bromo-octanoate as disclosed in International Publication No. WO 00/46182, are prepared from the dicarboxylate alkylating agents of the present invention. The process for converting the dicarboxylated compounds to the prior art alkylating agents is often expensive and time consuming. For example, ethyl 8-bromo-octanoate is prepared from 2- (6-bromohexyl) malonic acid diethyl ester by a multi-step process that includes an expensive distillation step. The process of the present invention reduces the number of synthetic steps required to prepare alkylated salicylamides and, therefore, reduces their cost and manufacturing time.

The reaction between the dicarboxylate alkylating agent and the protected / activated salicylamide is preferably carried out in the presence of a slight molar excess of protected / activated salicylamide over the dicarboxylate alkylating agent. Generally, the molar ratio of protected / activated salicylamide to dicarboxylate alkylating agent ranges from 1: 1 to 1: 0.5, preferably from 1: 0.99 to 1: 0.8, and most preferably 1: 0 , 95.

ES 2 386 263 T3

The alkylation reaction is preferably carried out in the presence of a suitable base, such as pyridine, picoline, tetramethylguanidine, triethylamine, diisopropylethylamine, sodium or potassium bicarbonate, sodium or potassium carbonate, or any combination of any of the foregoing. According to a preferred embodiment, the base is sodium carbonate. Generally, the reaction is carried out in the presence of a slight molar excess of base over the protected / activated salicylamide.

The reaction can be carried out in solvents, including dimethylacetamide (DMAC); dimethylformamide (DMF); ketones, such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; and any combination of any of the above. Preferably the solvent is non-aqueous.

The alkylation reaction is generally carried out at a temperature of from 40 to 80 ° C. The reaction is preferably carried out at a temperature of from 60 to 80 ° C and most preferably at 70 ° C. The reaction is normally carried out at atmospheric pressure under full vacuum and preferably from 74.5 to 81.3 kPa (22 to 24 inches Hg vacuum).

The reaction mixture before and during the reaction preferably contains less than 5%, more preferably less than 3%, and most preferably less than 1% by weight of water, based on the 100% total weight of the reaction mixture.

The reaction is generally carried out for a time sufficient to ensure complete reaction of the alkylating agent. The duration of the reaction can vary depending on the starting materials. Generally, the reaction is allowed to run for a sufficient time so that at least about 90% and preferably at least about 99% of the limiting reagent, i.e., the dicarboxylate alkylating agent, has been consumed, but is stopped sooner. significant side reaction product accumulates. This reduces or eliminates the need for purification of the final product. Preferably, the reaction is carried out for from about 2 to about 18 hours, more preferably from about 3 to about 5 hours, and most preferably for about 4 hours.

Carsalam and carsalam derivatives are preferably alkylated in the presence of a slight molar excess of base. A preferred base for such an alkylation reaction is sodium carbonate. A molar excess of sodium carbonate over carsalam or derivative of carsalam is generally used. More preferably, the carsalam or the carsalam derivative is alkylated by sequentially adding sodium carbonate to a solvent, such as those described above (eg, DMAC); adding carsalam or the derivative of carsalam to the dissolution; and adding a dicarboxylate alkylating agent to the solution. The alkylating agent is preferably added to the solution immediately after the addition of carsalam or carsalam derivative and more preferably within about 10 seconds after completion of the addition of carsalam or carsalam derivative. When the base, in this case sodium carbonate, is reacted with the carsalam or derivative of carsalam, it forms carsalam sodium or derivative of carsalam sodium and sodium bicarbonate. Although carsalam has a solubility of approximately 30% in DMAC, carsalam sodium only has a solubility of approximately 6% in DMAC. Sodium bicarbonate can react with the carsalam or derivative of carsalam resulting in the formation of carbonic acid, which can further react to form water. Generally, water significantly reduces the effectiveness of the alkylating agent. In order to minimize the reaction of sodium bicarbonate with the carsalam or derivative of carsalam, the carsalam or derivative of carsalam is preferably reacted with a molar excess of sodium carbonate. The water content of the reaction mixture can also be reduced by conducting the reaction in a low pressure atmosphere (eg, under vacuum).

According to another embodiment, the sodium carsalam or derivative of sodium carsalam is isolated before being reacted with the alkylating agent in order to reduce the water content.

The dicarboxylate-salicylamide intermediate has the formula

<img file="ES2386263T3_D0012.tif" />

qq / c λ 7 q * | * | wherein R, R, R, R, R, R, R, R and R are as defined above. Examples of dicarboxylate-salicylamide intermediates of the present invention are

ES 2 386 263 T3

<img file="ES2386263T3_D0013.tif" />

<img file="ES2386263T3_D0014.tif" />

<img file="ES2386263T3_D0015.tif" />

Cl

<img file="ES2386263T3_D0016.tif" />

where Y is -C (O) - oi 'WVX.

<img file="ES2386263T3_D0017.tif" />

<img file="ES2386263T3_D0018.tif" />

<img file="ES2386263T3_D0019.tif" />

R¹⁴ and R¹⁵ they are independently C1-C4 alkyl; Y

R¹⁶ and R¹⁷ they are independently hydrogen, C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl.

According to one embodiment, Y is -CH2-. According to another embodiment, Y is -C (O) -. R¹⁴ and R¹⁵ they are preferably methyl or ethyl.

The dicarboxylate-salicylamide intermediate is then (a) deprotected and deactivated, (b) optionally hydrolyzed, and (c) optionally decarboxylated to provide the alkylated salicylamide. Steps (a) and (b) can be carried out before or after step (c). Preferably, step (c) is carried out after steps (a)

ES 2 386 263 T3 and (b). Typically, this procedure involves the removal of the protecting and activating groups and optionally one of the carboxylate moieties. Optionally, the carboxylate moiety (s) of the alkylated salicylamide can be hydrolyzed to form a carboxylic acid moiety or carboxylic acid moieties or carboxylate salt. The protecting and activating groups and one of the carboxylate groups can be removed and the remaining carboxylate group can be hydrolyzed by acidic, basic and / or neutral hydrolysis as is known in the art. Neutral hydrolysis can be carried out, for example, with superheated water at a temperature of from 100 to 250 ° C.

Vulnerability

Salicylamide can be deprotected by any method known in the art, such as acidic, basic, or neutral hydrolysis. The deprotection is preferably carried out by basic hydrolysis. The basic hydrolysis can be carried out, for example, with aqueous sodium carbonate or aqueous sodium hydroxide. According to one embodiment, the basic hydrolysis is carried out with aqueous sodium hydroxide at a temperature of from 78 to 98 ° C.

Another method of deprotection is by acid hydrolysis. Acid hydrolysis can be carried out, for example, with aqueous hydrochloric acid or aqueous trifluoroacetic acid. For example, acid hydrolysis can be carried out with aqueous hydrochloric acid in acetone at a temperature of from 25 to 65 ° C. According to one embodiment, the acid hydrolysis is carried out at a pH of 3.5 to 4.5 and preferably 4. The acid hydrolysis process can also deactivate salicylamide.

Deactivation

The activating group can be removed by any method known in the art. When acidic or basic hydrolysis is performed to deprotect salicylamide, the activating group can be removed by neutralization. For example, when deprotection is carried out by basic hydrolysis, salicylamide can be deactivated by adding an aqueous acid, such as aqueous hydrochloric acid or trifluoroacetic acid. When deprotection by acid hydrolysis is performed, salicylamide can be deactivated by adding an aqueous base.

Hydrolysis

Optionally, the alkylated salicylamide can be further reacted to modify the terminal group of the alkylating moiety, i.e., R⁸ or R¹¹as well as the oxygen group attached to the phenyl ring. For example, the terminal group -CN or -C (O) OCH2-CH3 can be modified to give -COOH or a salt thereof. This can be accomplished by methods known in the art, such as acidic, basic, and neutral neutralization and hydrolysis. Generally, the hydrolysis of salicylamide is carried out by neutralizing the unprotected and deactivated salicylamide. When salicylamide is deprotected by basic hydrolysis, the free acid of salicylamide, for example, is recovered by neutralization with an aqueous acid, such as hydrochloric acid.

Decarboxylation

If a monocarboxylic salicylamide is desired, the prepared alkylated salicylamide can be decarboxylated. The decarboxylation step is performed either before or after the deprotection and deactivation steps and the optional hydrolysis step. Preferably, decarboxylation is performed after the deprotection and deactivation steps and the optional hydrolysis step.

The decarboxylation step removes one of the carboxylate moieties from the alkylated salicylamide (i.e., one of the two carboxyl groups at the end of the R chain⁷). Decarboxylation can be carried out by any method known in the art, such as acid hydrolysis as discussed above. In order to control foaming due to the release of carbon dioxide, the reaction can be carried out in the presence of acetone.

Decarboxylation can also be performed by heating the alkylated salicylamide in a high-boiling organic solvent, such as xylenes, toluene, heptane, dimethylacetamide (DMA or DMAC), dimethylformamide (DMF), methyl sulfoxide, isoparaffins (eg isopar-G, isopar -H, isopar-L and isopar-K available from Exxon Chemicals of Houston, TX), and any combination of any of the above. The organic solvent preferably has a boiling point of at least 110 ° C and more preferably at least 140 ° C. The decarboxylation reaction is preferably carried out at a temperature ranging from 140 to 200 ° C and more preferably ranging from 140 to 160 ° C. The temperature at which the reaction is carried out must be sufficient to eliminate one of the carboxylate groups at the end of the R chain⁷.

Preferably, any amount of water in the reaction mixture is removed prior to heating. Water can be removed from a reaction mixture containing the free acid of the alkylated salicylamide (which forms if the alkylated salicylamide is hydrolyzed as described in the "Hydrolysis" section above) as follows. The alkylated salicylamide is mixed with an organic solvent in which it is soluble, such as xylenes. The aqueous phase, which in this case is the lower phase, is then removed, leaving the xylenes alkylated salicylamide. The reaction mixture can then be heated to decarboxylate the alkylated salicylamide.

ES 2 386 263 T3

The reaction mixture before and during the decarboxylation reaction preferably contains less than 5%, more preferably less than 3%, and most preferably less than 1% by weight of water, based on the total weight of 100% of the mixture of reaction.

The decarboxylation step can also be carried out cleanly (ie without a solvent) by heating the deprotected, deactivated and optionally hydrolyzed alkylated salicylamide to a temperature ranging from 140 to 200 ° C.

The deprotection, deactivation, hydrolyzation and decarboxylation steps can be carried out at a temperature of from 20 to 200 ° C.

Suitable solvents for the protected / activated alkylated salicylamide in the deprotection, deactivation, decarboxylation and hydrolyzation step include organic solvents, such as ethanol, dimethylacetamide (DMAC), dimethylformamide (DMF), ketones (for example acetone, methyl ethyl ketone and methyl isobutyl ketone), and any combination of any of the above.

When the protected / activated salicylamide is carsalam or a derivative thereof, the alkylated salicylamide can be deprotected by hydrolysis, such as basic hydrolysis. This causes the bonds between the carbonyl group and adjacent oxygen atoms to be cleaved, thereby deprotecting the hydroxyl moiety. The hydrolysis can be carried out under conditions known in the art.

After hydrolysis of the carsalam or carsalam derivative, the activated salicylamide can be deactivated by methods known in the art. For example, hydrochloric acid can be added to the activated alkylated salicylamide until the pH of the reaction mixture is 3.5 to 4.5 or until the pH is less than 4. This causes the bond between the carbonyl moiety and the nitrogen atom of the amide moiety of the salicylamide and carbon dioxide is released. Hydrochloric acid can also remove one of the carboxylate moieties and hydrolyze the remaining carboxylate moiety.

Alternatively, after hydrochloric acid is added to deactivate the alkylated salicylamide, the alkylated salicylamide can be decarboxylated by heating in xylenes or other high-boiling organic solvent, such as those discussed above, to or near reflux. For example, when xylene is used as the solvent, the mixture is preferably heated to a temperature ranging from 105 to 140 ° C.

Salts of the alkylated salicylamide can be formed by any method known in the art. For example, the acid form of alkylated salicylamide, that is, when the alkylated salicylamide has a -COOH moiety, can be converted to the corresponding sodium salt by reacting it with sodium hydroxide. Suitable salts include organic and inorganic salts, for example alkali metal salts, such as sodium, potassium, and lithium; alkaline earth metal salts, such as magnesium, calcium or barium; ammonium salts; basic amino acids, such as lysine or arginine; and organic amines, such as dimethylamine or pyridine. Sodium salts include mono-, di-salts, and other multivalent sodium salts. A preferred salt is the disodium salt. The salts can also be solvates, including ethanol solvates, and hydrates. The term "solvate" as used herein includes a molecular or ionic complex of molecules or ions of a solvent, such as ethanol, with ions or molecules of the compounds of the present invention.

The present method can be used to prepare alkylated salicylamides having the formula

<img file="ES2386263T3_D0020.tif" />

in which

R¹, R², R³, R⁴, R⁷, R¹⁸ and R¹⁹ are as defined in claim 1.

According to a preferred embodiment, R¹⁹ it is hydrogen. Examples of such compounds include N- (8- [2-hydroxybenzoyl] -amino) caprylic acid, N- (9- [2-hydroxybenzoyl] -amino) nonanoic acid, N- (10- [2-hydroxybenzoyl] amino) decanoic acid, N- (5-chlorosalicyloyl) -8-aminocaprylic acid, N- (4-methoxysalicyloyl) -8-aminocaprylic acid and salts, solvates and hydrates thereof. Additional examples are N- (2-hydroxybenzoyl) -7amino) heptanoic, N- (2-hydroxy-5-chlorobenzoyl) -4-amino) butyric acid or a salt thereof.

ES 2 386 263 T3

The alkylated salicylamides of the present invention can be purified by recrystallization or fractionation on one or more chromatographic supports. Fractionation can be carried out on suitable chromatographic supports, such as silica gel or alumina, using solvent mixtures such as acetic acid / butanol / water as the mobile phase; reverse phase column supports using trifluoroacetic acid / acetonitrile mixtures as the mobile phase; and ion exchange chromatography using water as the mobile phase. The alkylated salicylamides can also be purified to remove impurities, such as inorganic salts, by extraction with a lower alcohol, such as methanol, butanol, or isopropanol.

The method of the present invention uses cheap and readily available starting materials and provides a cost-effective method for preparing and isolating alkylated salicylamides. The method is simple to perform and is capable of industrial scale expansion for commercial production.

The invention will now be illustrated in the following examples. All percentages are by weight unless otherwise indicated.

Example 1

Preparation of N- (2-hydroxybenzoyl) -10-amino) -decanoic acid

20 g (0.123 mole) of carsalam (available from Sigma-Aldrich of Shiboygan Falls, WI), 43.16 g (0.123 mole) of 2- (8-bromooctyl) malonic acid diethyl ester (available from Allied Signal, Inc. of Morristown, NJ), 15.52 g (0.137 mol) of sodium carbonate (available from Sigma-Aldrich of St. Louis, MO) and 100 ml of dimethylacetamide (DMA) (available from Sigma-Aldrich) to approximately 75 ° C for about 5 hours. The solids were filtered off and the filtrate was stirred in 2N sodium hydroxide at 45 ° C for a total of about 9 hours to form N- (2-hydroxybenzoyl) -10-amino) -decanoic acid. The formation of decanoic acid was evident. It was then heated to about 100 ° C to determine if decanoic acid was indeed forming. HPLC of the reaction showed the 9.09 peak to transform to 8.79, 7.23, 5.78 min. The last HPLC showed an area% of 49.6 of the peak at 5.78 min, indicating the formation of approximately 50% (w / w) of the decanoic acid.

In a separate reaction, the same reagents described above were heated to about 100 ° C for about 2 hours. The solids were filtered off and washed with ethanol. Water was added to the filtrate and the DMA was removed in vacuo. The aqueous phase was extracted with ethyl acetate (3x 150 ml), combined, and concentrated in vacuo. The resulting oil was stirred in 2N sodium hydroxide at 45 ° C for about 4 hours.

HPLC was performed by dissolving approximately 1 mg of the product per ml of solution in 50% aqueous acetonitrile. The injection size was 20 ml. The HPLC parameters were as follows:

<td>Column: Higgins Kromasil 100 C18</td><td>Particle size: 5 pm</td>

<td>Column length: 5 cm</td><td>Column diameter: 4.6 mm</td>

Mobile phase A: water, acetonitrile, acetic acid (950: 50: 1

Mobile phase B: water, acetonitrile, acetic acid (50: 950: 1

<td>Gradient: 0 to 100% mobile phase B, 10 minutes</td><td>Flow rate: 3 ml per minute</td>

<td>Back pressure: 7,583 kPa (1,100 psi)</td><td>Column temperature: ambient</td>

Detector: UV 220 nm

HPLC of the reaction showed the peak at 8.9 to transform in 8.6, 7.0, 5.7 min. Final HPLC showed an area% of 35% of the peak at 5.7.

Example 2

Preparation of N- (8- [2-hydroxybenzoyl] amino) caprylic acid

N- (8- [2-Hydroxybenzoyl] amino) caprylic acid was prepared by the procedure described in Example 1 with the appropriate starting materials.

Below is a flow chart of this procedure.

ES 2 386 263 T3

<img file="ES2386263T3_D0021.tif" />

Blocked Amine

EtOCOCt pyridine

CH₃CN 5O-80OC

OR

<img file="ES2386263T3_D0022.tif" />

+ + C₂H₅Oh

H-1,3-Benzoxazin-2,4 (3H) -dione (Carsalam)

Alkylation

<img file="ES2386263T3_D0023.tif" />

+ NaHCO₃

Sodium salt of carsalam

<img file="ES2386263T3_D0024.tif" />

74.5 to 81.3 kPa (22-24 inches Hg vacuum)

Br- (CH)_toCH (COOCiH_s)_to.

OMAC

<img file="ES2386263T3_D0025.tif" />

N- (CH)₆CHtCOOC₂H₅) 2 + NaBr

<img file="ES2386263T3_D0026.tif" />

N- (CH)_andCH (COOC_sH_sh + 4NaOH

Hydrolysis ^!0

78-9B ° C

H₂cT

<img file="ES2386263T3_D0027.tif" />

ONa

N- (CH₃)_andCH (GOONa)₂⁺H₂OR

<img file="ES2386263T3_D0028.tif" />

N-ÍCH₃)₆CH (COONah

ONa + 4HCI

H_ZOR

25-65 ° C

Acetone

<img file="ES2386263T3_D0029.tif" />

NH- (CH_s)₇&lt;pQQH + 4NaC1 + CO_S

<img file="ES2386263T3_D0030.tif" />

<img file="ES2386263T3_D0031.tif" />

+ NaOH

Sodium salt

1) EtOH / HgO

2) Heptane

30 ° C

<img file="ES2386263T3_D0032.tif" />

NH- (CI-) 2) 7COONa + h₂or

Example 3

Preparation of N- (2-hydroxybenzol) -10-amno) -decanoic acid

55.6 g (0.123 moles) of carsalam (available from Nipa Laboratories of Wilmington, DE), 116.7 g (0.123 moles) of diethyl 8-bromooctylmalonate (available from Allied Signal, Inc. of Morristown, NJ) were heated. ) and 400 ml of dimethylacetamide (DMA) (available from Sigma-Aldrich) up to about 75 ° C. 39.26 g (0.137 mol) of sodium carbonate (available from JT Baker of Phillipsburg, NJ) was added in 5 portions over 40 minutes and the reaction was heated for an additional 4 hours. The solids were filtered off at 50 ° C and the filtrate was diluted with 477.5 ml of deionized water for 45 minutes. The mixture was cooled to 20.5 ° C and the resulting solids were filtered off, washed with additional water and dried under vacuum at 48 ° C.

This sample was combined with other samples prepared by the above procedure for the next step.

323.9 g of the diethyl ester were stirred with 299 g of 50% (w / w) sodium hydroxide (available from JT Baker) and 650 ml of deionized water. The mixture was heated to 82.5 ° C for 9 hours and monitored by HPLC. This hydrolysis solution was slowly added to a mixture of 368.9 g of concentrated hydrochloric acid (available from JT Baker) and 1 liter of deionized water. The mixture was cooled to 25 ° C and the resulting solids were filtered off and air dried.

ES 2 386 263 T3

90.0 g of the diacid produced above and 500 ml of xylenes (available from Sigma-Aldrich) were heated to reflux for 18 hours. Any residual water was removed by distillation before reflux was reached. At 107.5 ° C, evolution of gas was evident. The reaction was monitored by collecting carbon dioxide in a sodium hydroxide trap. The solution was cooled to room temperature and the resulting crystals were collected by filtration. The structure of the final compound was confirmed by¹HRMN.

Analytical data:

A sample was prepared for HPLC analysis by dissolving approximately 1 mg of the sample per ml of 60% (w / w) aqueous acetonitrile. The injection size was 20 µl. A retention time of 20.75 minutes was observed under the following conditions.

Column: Higgins CLIPEUS Phenyl Particle size: 5 pm

Column length: 15 cm Column diameter: 4.6 mm

Mobile phase A: methanol, water, acetic acid (350: 650: 5)

Mobile phase B: methanol, water, acetic acid (950: 50: 5)

Flow rate: 0.7 ml per minute Column temperature: ambient

Detector: UV 244 nm

Program: The HPLC program started with 100% mobile phase A for an 8 minute wash period, then the sample was injected. At the same time as the sample was injected, a linear gradient was started which changed to 100% mobile phase B over a 30 minute period. 100% mobile phase B was held for 5 minutes, then a linear gradient was used to return to 100% mobile phase A in 2 minutes. The 8 minute wash cycle was repeated before the next sample was injected.

Analysis by ¹H-NMR: (d6-DMSO), 300 mHz: δ 12.40, s, 1H (COOH); δ 8.8, t, 1H (NH); δ 7.85, dd, 1H (H ortho to hydroxyl); δ 7.4, dt, 1H, (H in para to amide); δ 6.9, t, 1H, (H para to hydroxyl); δ 3.25, q, 2H (CH2 adjacent to NH); δ 2.20, t, 2H (CH2 adjacent to COOH); δ 1.51, m, 4H (CH2 aliphatic in beta with respect to NH and CH2 in beta with respect to COOH); δ 1.29, m, 10H (remaining aliphatic CH2).

Below is a flow chart of this procedure.

ES 2 386 263 T3

<img file="ES2386263T3_D0033.tif" />

<img file="ES2386263T3_D0034.tif" />

Blocked Amine

EtOCOCI pyridine CHgCN 5 ° -86 &lt;&gt; C

<img file="ES2386263T3_D0035.tif" />

2H-1, 3-Beneoxfl 2 ^ -2,4 ^) -dione (Carsalam)

<img file="ES2386263T3_D0036.tif" />

Alkyl ation from 74.5 to 01.3 kPa _N1_l (22-24 inches Hg vacuum _οΛ_ο^ίΜ^ ° 'WE^uu DMAC

<img file="ES2386263T3_D0037.tif" />

N-Na + NaHCO,

Sodium salt of carsalam

<img file="ES2386263T3_D0038.tif" />

(22-24 inches le ^ lg³Jetado * Br ^ CHzhCHÍCOOCjHsJj

7ü^andC OMAC

<img file="ES2386263T3_D0039.tif" />

OR

N-ÍCHj ^ CHÍCOOCzHsJs + NaBr

Hydrolysis fíjl N-íCHjieCHtCQOCjHsk

1) 5NaOH

2) 5HCl '

7B-3S ° C

<img file="ES2386263T3_D0040.tif" />

NH4CH;} j¿H (COCH)&gt; ^{+ 2C}!^h5OW ^r +5 NaCl + CO2 + H₂OR

Decarfoxylation

<img file="ES2386263T3_D0041.tif" />

NH-fCHjJaCHtCOQHk xi logs

105-140 ° C

<img file="ES2386263T3_D0042.tif" />

NH-tCHiJjfCOOH + CO₇

OR

<img file="ES2386263T3_D0043.tif" />

NH- (CH2) gcoOH + NaOH

Sodium salt

1) EtOHH_toOR

2) heptane 26-35OC

<img file="ES2386263T3_D0044.tif" />

NH- (CH2)₉CODNa + H₅OR