Process for n-acylating novenamine

Abstract

A process for preparing N-acylated novenamine having antibacterial activity comprising contacting novenamine with an acylating agent consisting of a derivative of the desired carboxylic or sulfonic acid in a nitrogen-containing organic base at a temperature of from about -80.degree.C. to about 0.degree.C., and allowing the reaction system to come to ambient temperature.

Description

BRIEF DESCRIPTION OF THE PRIOR ART

In U.S. Pat. No. 3,652,536, the preparation of novenamine, the portion of novobiocin which remains after cleavage of the amide bond, and novenamine N-acylates was disclosed. However, none of the acylation processes prepared the N-acylate selectively. When novenamine was acylated in aprotic solutions containing an acid binding agent, O-acylation occurred as well as N-acylation. The O-acyl group was removed by treatment with liquid ammonia, a process which is inconvenient, costly and potentially hazardous. To avoid the formation of novenamine O-acylates, the acylation reaction was alternatively carried out in a hydroxyl solvent such as water or ethanol. In this case, the solvent was also acylated and had to be separated from the N-acylated novenamine. Additionally, both of these processes suffered from the disadvantages of a tedious work-up of complex reaction mixtures and the final isolation of the N-acylated novenamine by column chromatography.

The process of this invention produces N-acylated novenamine selectively and allows rapid isolation and characterization of the N-acyl derivatives. The process is additionally advantageous in that the N-acylated products can be obtained from impure novenamine starting material as readily as from pure novenamine. The N-acylated novenamine compounds have anti-bacterial activity.

BRIEF SUMMARY OF THE INVENTION

A process is provided for preparing N-acylated novenamine having anti-bacterial activity comprising contacting novenamine with an acylating agent consisting of a derivative of the desired carboxylic or sulfonic acid in a nitrogen-containing organic base at a temperature of from about -80.degree.C. to about 0.degree.C., and allowing the reaction system to come to ambient temperature.

DETAILED DESCRIPTION OF THE INVENTION

Novenamine is readily prepared by the procedure of U.S. Pat. No. 3,652,356. Impure novenamine can be employed as readily in the instant process as further purified novenamine. "Impure novenamine" means a novenamine content of up to about 25 to 30 weight percent.

The novenamine, or its hydrochloride salt, is dissolved in a nitrogen-containing organic base with or without cosolvent. The solvent system should have the capability of solubilizing, but not necessarily completely, at least one of the reactants. Generally, the nitrogen containing organic base is selected from the group consisting of aromatic and non-aromatic heterocyclics, cyclic and acyclic tertiary amines, and cyclic and acyclic secondary amines having from 3 to 20 carbon atoms, preferably from 3 to about 6 carbon atoms most preferably amines which are liquid at room temperature. Illustrative examples of these amines are pyridine, imidazole, 2,4-lutidine, trimethylamine, triethylamine, diethylmethylamine, dimethylethylamine, dipropylmethylamine, dimethylpropylamine, methylpropylamine, piperidine, morpholine, quinuclidine, pyrrolidine, dicyclohexylamine, diethylamine, dipropylamine, and ethylpropylamine. (Examples of higher amines include cadaverine, quinoline, isoquinoline, decylamine, hexadecylamine, N-(p-chlorobenzhydryl)-piperazine and (di-n-nonylamine).

A cosolvent may be employed to retard freezing and to increase the solubility of the reactants if desired. Effective cosolvents include ethers, amides, alkanes, or esters. Illustrative examples of ethers are diethylether, tetrahydrofurane, pyrane, dipropylether, dodecylether and generally monoethers having from 4 to 20 carbon atoms, preferably from 4 to about 6 carbon atoms. Diethers including dioxane, 1,2-dimethoxyethane, diglyme, 1,3-dimethoxypropane, and higher ethers can be employed. In general, diethers having from 4 to 20 carbon atoms, preferably 4 to about 6 carbon atoms, can be used. Amides which can be employed are dimethylformamide, N-methylacetamide, N,N-dimethylacetamide, N,N-diethylpropionamide, 1-methyl-2-pyrrolidone and amides in general having from 2 to 19 carbon atoms, preferably from 3 to about 6 carbon atoms. Alkanes which can be employed include those alkanes and isomers thereof from 4 to about 10 carbon atoms, including butane, pentane, hexane, heptane, octane, nonane, decane, and isomers thereof. Esters which can be employed are methylformate, ethylacetate, butylformate, butyl acetate, and in general, esters having from 2 to 18 carbon atoms, preferably from 2 to about 6 carbon atoms. Also useful are nitromethane, acetonitrile, acetone, methylethylketone, chloroform, methylene chloride and dimethylsulfoxide.

After placing the novenamine in the nitrogen-containing organic base and the cosolvent, if included, the temperature of this system is reduced to from about 0.degree.C. to about -80.degree.C., preferably from about -20.degree.C. to about -40.degree.C. This low temperature allows the ensuing reaction between the acylating agent and the novenamine to proceed selectively at the amino position of the novenamide. At this temperature, some of the solvent can be in its solid phase.

When the temperature of the system has been reduced to the desired level, stoichiometric quantities of the acylating agent calculated on the basis of the novenamine present, are added to the system. The acylating agent may go into solution or be in the solid phase at that temperature. The acylating agents employed are the usual acylating derivatives of carboxylic and sulfonic acids which can react with an amino grouping to form an acylated product. Examples of these agents include the following: Halides, anhydrides, mixed anhydrides, chloroformates, nitrophenylesters, and imidazoles. Examples of the halides are fluoride, chloride, bromide, and iodide. Anhydrides and mixed anhydrides include acetic anhdride, benzoic anhydride, and the mixed anhydride formed between isobutyl chloroformate and the N-carbobenzyloxy derivative of tyrosine. Nitrophenyl esters include the nitrophenyl esters of N-carbobenzyloxycarbonyl proline, of 1-methoxy-1-methyl-5-carboxychroman, and in general, for such acids where, according to the art, the nitrophenyl esters are known to be advantageously useful. Examples of suitable haloformates include methylchloroformate, cyclododecylchloroformate, and 4-cyclohexylcyclohexylchloroformate. Additionally, other usual acylating derivatives may also be used advantageously. These, in general, include imidazoles, carbodiimides, acylazides and Woodward's Reagent K. When the aforesaid acylating reagents are used under the low-temperature nitrogen-containing organic base solvent conditions of this invention, novenamine is N-acylated in a selective manner.

Operable carboxylic and sulfonic acyl donors can be the standard type usually employed. For example, the carboxylic and sulfonic acyls can be alkyl and aryl, branched or unbranched, cyclic or alicyclic, saturated or unsaturated acyls having from 2 to about 20 carbon atoms, preferably from about 10 to about 16 carbon atoms, and may be unsubstituted or substituted with a variety of radicals such as nitro, hydroxyl, alkoxyl, acyloxy, halogen, or combinations thereof. Examples include acetic, propionic, palmitic, oleic, 2-methylhexanoic, p-nitrobenzoic, phenoxyacetic, p-toluenesulfonic, acetylsalicylic, m-hexyloxybenzoic, pentaflurorbenzoic, 2-naphthoic, 1-adamantoic, chloroacetic, tetradecyloxyformic and the like. A preferred carboxylic grouping is a substituted benzoyl.

After addition of the acylating agents, the temperature of the reaction is allowed to gradually rise to room temperature, a time period which is generally from about 2 to about 20 hours. In general, the slower the temperature rise, the greater the selectivity of the amine acylation. For example, after addition of the acylating agent, the cooling means can be removed from contact with the reaction system and the reaction system allowed to stand overnight, that is, a period of 15-20 hours, while the system temperature is slowly rising to ambient. When this particular method is employed, N-acylation occurs to the essential exclusion of O-acylation.

After the reaction has reached its desired level of completion, the N-acyl novenamine is isolated in any convenient manner. A preferred method of isolation is to filter the reaction mixture if solids are present and concentrate in vacuo at about 20.degree.C. to about 60.degree.C. The residue is partitioned between a 0.01 to about 3N mineral acid such as hydrochloric, sulfuric, perchloric, or phosphoric acid and an immiscible organic solvent such as ethyl acetate, methylene chloride, chloroform, n-butanol or ether. The organic layer is washed successively with water and saturated NaCl solution, dried with MgSO.sub.4, filtered and concentrated. Any solid third phase present is collected by filtration and crystallized from a suitable solvent or solvent pair. The residue of the organic layer is crystallized from the same solvent combination as was the solid third phase, if present. Two crystallizations of the extracted product are usually required to obtain material of a purity level equivalent to that obtained from a single crystallization of the product which was present as a third phase above. Suitable crystallization solvents are combinations of lower alcohols or ketones of up to about 5 carbon atoms and water or a halogenated hydrocarbon such as methylene chloride and a hydrocarbon such as hexane, cyclohexane, ligroin or toluene.

The following examples are illustrative of the process and products of the present invention but are not to be construed as limiting. All percentages are by weight and all solvent mixture proportions are by volume unless otherwise noted.

EXAMPLE 1

N-(4-Nitro-3-n-pentyloxybenzoyl) Novenamine

Novenamine (13.5 g.) is dissolved in pyridine (250 ml) and the solution flushed with nitrogen and cooled to the point where solid begins to form on the wall of the flask (ca -30.degree.C.). 4-Nitro-3-n-pentyloxybenzoyl chloride (8.2 g.) is added in one batch. The mixture is stirred for 16 hr. during which time the temperature rises to 25.degree.C. The solvent is removed on a rotary vacuum evaporator (60.degree./18 mm) and the residue partitioned between ethyl acetate and 1 N hydrochloric acid. The organic layer is washed with water, dried with magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue is taken up in hot ethanol and cooled. The solution deposits 12.0 g. yellow solid, m.p. 175.degree.-177.degree..

______________________________________ Anal. Calcd. for C.sub.31 H.sub.37 N.sub.3 O.sub.13 : C, 56.44; H, 5.65; N, 6.37. Found: C, 55.83; H, 5.79; N, 6.91. ______________________________________

EXAMPLE 2

N-(3-n-Nonyloxybenzoyl) Novenamine

Novenamine (8.4 g.) is dissolved in 250 ml. pyridine and the solution flushed with nitrogen and cooled to -30.degree.. 3-n-Nonyloxybenzyol chloride (5.6 g.) is added in one batch. The mixture is stirred while the temperature slowly rises to 25.degree.. After 72 hr. the solvent is removed on a rotary evaporator. The residue is partitioned between ethyl acetate and 1 N hydrochloric acid. The residue is taken up in hot ethanol and water added so that the solution is cloudy at the boiling point. On cooling a total of 9.5 g. white solid deposits, m.p. 100.degree.-103.degree..

______________________________________ Anal. Calcd. for C.sub.35 H.sub.46 N.sub.2 O.sub.11 : C, 62.67; H, 6.91; N, 4.18. Found: C, 62.43; H, 7.07; N, 4.10. ______________________________________

EXAMPLE 3

N-(3-Benzyl-4-Hydroxybenzoyl) Novenamine

Novenamine (8.4 g.) is dissolved in 100 ml. pyridine and 100 ml. tetrahydrofuran. The solution is flushed with nitrogen and cooled to -35.degree.. 3-Benzyl-4-benzyloxybenzoyl chloride (from 6.4 g. of the acid and an excess of thionyl chloride) is added in one batch. The temperature rises to -28.degree. briefly and then returns to -35.degree.. Stirring is continued for 64 hr., during which time the temperature reached 25.degree.. The solution is concentrated on a rotary evaporator and the residue partitioned between ethyl acetate and 1 N HCl. The organic layer is washed with water, dried with magnesium sulfate, filtered, and concentrated on a rotary evaporator. This is taken up in ethyl acetate and filtered with suction over 400 g. silica gel. The first 650 ml. filtrate is concentrated to give 7.5 g. yellow solid. This has an R.sub.f using 10:1 ethyl acetate: methanol on a silica gel thin layer plate of 0.64. It is analyzed without further purification to give C, 66.89 and H, 5.75 (calculated for C.sub.40 H.sub.40 N.sub.2 O.sub.11 is C, 66.29 and H, 5.56).

This material (3.6 g.) is hydrogenated at 38 psi hydrogen in 150 ml. methanol with 1.5 g. 10% Pd/C on a Parr hydrogenation apparatus. The solution is filtered and concentrated on a rotary evaporator. The residue is dissolved in hot ethyl acetate, filtered and treated with hexane to cloudiness. The first crop amounts to 2.7 g. white solid, m.p. 158.degree.-160.degree. (sealed tube).

______________________________________ Anal. Calcd. for C.sub.33 H.sub.34 N.sub.2 O.sub.11 : C, 62.45; H, 5.59; N, 4.20. Found: C, 62.03; H, 5.41; N, 4.22. ______________________________________

EXAMPLE 4

N-(4-Cyclohexylcyclohexyloxycarbonyl) Novenamine

4-Cyclohexylcyclohexanol is stirred in toluene while phosgene is bubbled through the solution. After 2 hr. the solvent is removed to give a clear liquid. Infrared analysis shows this to be the chloroformate free of the alcohol. This material (4.89 g.) is added in one batch to a solution of novenamine (8.4 g.) in 250 ml. pyridine at -30.degree.. After 16 hr. the temperature has reached 25.degree. and the solvent is removed on a rotary evaporator. The residue is partitioned between ethyl acetate and 1.0 N HCl. The organic layer is washed with water, dried with magnesium sulfate, filtered, and then concentrated on a rotary evaporator. The residue is taken up in hot ethanol and water was added to cloudiness. The first crop amounts to 7.7 g. white solid, m.p. 142.degree.-147.degree..

______________________________________ Anal. Calcd. for C.sub.32 H.sub.44 N.sub.2 O.sub.11 : C, 60.74; H, 7.01; N, 4.43. Found: C, 60.80; H, 7.23; N, 4.40. ______________________________________

EXAMPLE 5

In a manner similar to Examples 1-4, the following exemplary N-acylated novenamine compounds are prepared. ##SPC1##

Melting Point .degree.C (Accompanied by R decomposition) ______________________________________ 4-nitrobenzoyl 255 (dec) 4-chlorobenzoyl 255-7.degree. 4-methoxybenzoyl 257-9.degree. phenoxyacetyl 183-5.degree. n-propyloxycarbonyl 136-8.degree. diethylaminocarbonyl 126-32.degree. 1-adamantanoyl 190-2.degree. 4-n-dodecyloxybenzoyl 178-9.degree. 4-tert-butylbenzoyl 275 (dec) 4-[3-tert-amylphenoxy]-benzoyl 163-5.degree. 2-ethoxybenzoyl 163-5.degree. 4-phenylbenzoyl 253-4.degree. 1-naphthoyl 223-7.degree. 2-naphthoyl 263-4.degree. pentafluorobenzoyl 230-5.degree. 9-anthranoyl 193-5.degree. 3-(2-chlorophenyl)-5-methyl-4- isoxazoyl 151-4.degree. 3-coumaranoyl 335 (dec) 3,4-methylenedioxybenzoyl 260-1.degree. 3-fluorobenzoyl 228-9.degree. 2-chlorobenzoyl 147-50.degree. 2,4-dichlorobenzoyl 215-8.degree. trichloromethylsulfonyl 195-7.degree. 3,4,5-trimethoxybenzoyl 235-7.degree. 2-nitrophenylsulfonyl 200-3.degree. n-tetradecyloxycarbonyl 128-31.degree. 4-n-hexadecyloxybenzoyl 149-52.degree. 4-acetoxy-3-methoxybenzoyl 259-1.degree. 3-n-butoxy-4-nitrobenzoyl 212-3.degree. 4-methoxy-3-nitrobenzoyl 226-9.degree. 4-hydroxy-3-methoxybenzoyl 300-1.degree. 3,4,5-triethoxybenzoyl 128-31.degree. 3,5-ditert-butyl-4-hydroxybenzoyl 174-7.degree. N-methyl-N-phenylaminocarbonyl 146-50.degree. 2-phenylbenzoyl 148-52.degree. n-decyloxycarbonyl 164-7.degree. n-dodecyloxycarbonyl 87-91.degree. 2-(2-ethoxyethoxy)-ethoxycarbonyl 100-3.degree. 2-(2-n-butoxyethoxy)-ethoxycarbonyl 98-100.degree. 3-ethoxy-1-propanoxycarbonyl 105-9.degree. 4-cyclohexylcyclohexyloxycarbonyl 142-7.degree. cyclododecyloxycarbonyl 145-6.degree. 4-n-octyloxybenzoyl 197-9.degree. 3-(3-ethoxy-1-propanoxy)-benzoyl 149-53.degree. 3-(3-phenoxy-1-propanoxy)-benzoyl 119-21.degree. 3-n-(4-methyl-1-pentyloxy)-benzoyl 144-7.degree. 3-n-hexyloxybenzoyl 171-4.degree. 3-n-heptyloxybenzoyl 127-9.degree. 3-n-octyloxybenzoyl 133-5.degree. 3-n-nonyloxybenzoyl 100-3.degree. 3-n-dodecyloxybenzoyl 85-9.degree. 3-n-(2-methyl-1-pentyloxy)-benzoyl 110-4.degree. 3-n-(3-methyl-1-butyloxy)-benzoyl 150-4.degree. 3-n-pent-4-enyloxybenzoyl 136-8.degree. 3-hydroxy-4-nitrobenzoyl 247-50.degree. 3-allyloxy-4-nitrobenzoyl 246-7.degree. 4-nitro-3-n-pentyloxybenzoyl 175-7.degree. 3-n-(3-methyl-1-butyloxy)-4-nitro- benzoyl 139-41.degree. 3-n-(1-methyl-1-butyloxy)-4- nitrobenzoyl 138-40.degree. 4-nitro-3-n-(1-pent-4-enyloxy)- benzoyl 120-4.degree. 3-(2-ethoxyethoxy)-4-nitrobenzoyl 187-91.degree. 4-nitro-3-n-octyloxybenzoyl 118-22.degree. 4-allyloxy-3-nitrobenzoyl 155-7.degree. 4-n-butoxy-3-nitrobenzoyl 147-50.degree. 3-n-butylbenzoyl 140-3.degree. 3-n-pentylbenzoyl 134-5.degree. 3-n-hexylbenzoyl 119-24.degree. 2-acetoxybenzoyl 164-6.degree. 3,5-diisopropyl-2-hydroxybenzoyl 142-7.degree. 2-quinoxazoyl 258-60.degree. 4-cinnolinoyl 190-5.degree. 3-piperidinoyl 214-5.degree. 6-methyl-2-pyridinoyl 162-5.degree. 1-methyl-2-pyrroloyl 162-6.degree. 2-pyrroloyl 225-7.degree. 2-acetamido-4-methyl-5-thiazolesulfonyl 179-80.degree. 3-methyl-4-nitrobenzoyl 257-8.degree. 4-methyl-3-nitrobenzoyl 197-9.degree. N-carbobenzyloxy-tyrosinoyl 197-8.degree. 4-acetoxy-3-benzylbenzoyl 151-5.degree. 3-benzyl-4-hydroxybenzoyl 158-60.degree. 4-acetoxy-3-(4-fluorobenzyl)-benzoyl 131-5.degree. 3-(4-fluorobenzyl)-4-hydroxybenzoyl 156-9.degree. 3-(4-hydroxybenzyl)-4-hydroxy- benzoyl 184-6.degree. 4-acetoxy-3-(4-methylbenzyl)- benzoyl 142-5.degree. 4-hydroxy-3-(4-methylbenzyl)- benzoyl 220-4.degree. 4-hydroxy-3-phenylbenzoyl 140-3.degree. 3-n-hexyloxy-4-hydroxybenzoyl 203-5.degree. 4-hydroxy-3-n-(3-methylbutyloxy)- benzoyl 174-5.degree. 4-hydroxy-3-(3-oxobutyl)-benzoyl 143-5.degree. 3 (1-oxo-n-pentyl)-benzoyl 139.degree. 3 (1-hydroxy-n-pentyl)-benzoyl 197.degree. benzoyl 245.degree. 4-acetoxy-3-allylbenzoyl 120-22.degree. 3-allyl-4-hydroxybenzoyl 168-70.degree. 4-acetoxy-3-n-propylbenzoyl 220-4.degree. 4-hydroxy-3-n-pentylbenzoyl 148-51.degree. 4-hydroxy-3-n-propylbenzoyl 134-9.degree. 4-acetoxy-3-n-hexylbenzoyl 120-22.degree. 3-n-hexyl-4-hydroxybenzoyl 138-140.degree. 3-n-heptyl-4-hydroxybenzoyl 138-42.degree. 4-hydroxybenzoyl 256-8.degree. isobutyryl 144-8.degree. n-heptanoyl 146-8.degree. n-nonanoyl 173-8.degree. n-dodecanoyl 148-52.degree. n-tetradecanoyl 124-7.degree. 2-furanoyl 122-30.degree. cinnamoyl 228-31.degree. 4-hydroxycinnamoyl 137-43.degree. 4-methoxycinnamoyl 231-5.degree. 4-allyloxycinnamoyl 205-7.degree. 3-(4-n-propyloxyphenyl)-propionoyl >80.degree. (dec.) 3-(4-n-pentyloxyphenyl)-propionoyl 4-hydroxy-3-methoxycinnamoyl 165-7.degree. 4-acetoxy-3-methoxycinnamoyl 165-8.degree. 3,4-dimethoxycinnamoyl 264-7.degree. 3-phenylpropionoyl 220-4.degree. 3-aminobenzoyl 258-9.degree. 4-amino-3-n-butoxybenzoyl 166-8.degree. 3-amino-4-methoxybenzoyl 267-8.degree. 4-amino-3-hydroxybenzoyl 189-92.degree. 4-amino-3-n-propyloxybenzoyl 135-7.degree. 4-amino-3-n-pentyloxybenzoyl 138-41.degree. 4-amino-3-(3-methylbutoxy)-benzoyl 137-40.degree. 4-amino-3-(1-methyl-1-n-butoxy)-benzoyl 150-55.degree. 4-amino-3-(2-ethoxyethoxy)-benzoyl 159-62.degree. 4-amino-3-n-octyloxybenzoyl 123-6.degree. 3-amino-4-n-butoxybenzoyl 156-60.degree. 4-amino-3-methylbenzoyl 197-8.degree. 3-amino-4-methylbenzoyl 187-94.degree. 11-bromodecanoyl 131-5.degree. N-methylanthranoyl 150-55.degree. anthranoyl 212-17.degree. cyclohexylphenylacetyl 134-9.degree. ______________________________________

The novenamine N-acylates selectively prepared by the process of this invention are useful in the same manner as the uses of novenamine and N-acylates of novenamine described in U.S. Pat. No. 3,652,536 at Column 7, lines 25-37. They are particularly useful as a disinfectant on various dental and medical equipment contaminated with S. aureus.

Claims

I claim:

1. A process for preparing N-acylated novenamine having anti-bacterial activity which comprises contacting novenamine with an acylating agent consisting of a derivative of the desired carboxylic or sulfonic acid in a nitrogen-containing organic base solvent at a temperature of from about -80.degree.C. to about 0.degree.C. and allowing the reaction system to come to ambient temperature.

2. A process in accordance with claim 1 wherein the temperature is from about -40.degree. to about -20.degree.C.

3. A process in accordance with claim 2 wherein the solvent is pyridine.

4. A process in accordance with claim 1 wherein said carboxylic or sulfonic acid has two to about 20 carbon atoms, inclusive.