MXPA00004863A - Process for n-desmethylating erythromycins and derivatives thereof - Google Patents

Abstract

Disclosed is an improved and efficient process for N-desmethylating the 3'-amino nitrogen of erythromycins and for converting the 3'-N-desmethylated erythromycins into 3'-N-substituted derivatives of 8,9-anhydro-erythromycin 6,9-hemiketals.

Description

PROCESS FOR THE N-DEMETILATION OF ERYTHROMYCINES AND THEIR DERIVATIVES TECHNICAL FIELD The present invention relates to an improved and efficient process for the N-demethylation of 3'-amino nitrogen of erythromycins and to prepare their gastrointestinal prokinetic erythromycin compounds. More particularly, the invention relates to the N-demethylation of the 3'-amino nitrogen of erythromycin using 1-chloroethyl chloroformate and converting 3'-N-demethylated erythromycins to 3'-N-substituted derivatives of 8,9-anhydro -erythromycin-6,9-hemicetales.

BACKGROUND OF THE INVENTION Erythromycins A to D, represented by the formula (E), (AND) They are well-known and potent antibacterial agents, widely used to treat and prevent bacterial infection. Some erythromycin derivatives having formula I below possess an expected degree of prokinetic activity and are described in the U.S. patent. 5,578,579.

The preparation of these prokinetic compounds requires the preparation of the intermediate compounds, N-demethyl-4"-deoxy-erythromycin A and N-demethyl-4" -deoxy-erythromycin B. A process for the preparation of N-demethyl derivatives of Various macrolide antibiotics have been described in US Patent 3,725,385, issued April 3, 1993, which teaches that the methyl group can be removed through a one-step treatment with the only addition of iodide in a solution adjusted in its pH from -10 ° C to 50 ° C. The passage of N-demethylation with iodine generally does not come to an end, leaving a substantial amount of the starting material with the final product. Therefore, there is a need to provide a more efficient improved process for the manufacture of the 3'-N-substituted derivatives of 8,9-anhydro-erythromycin-6,9-hemiketals.

COMPENDIUM OF THE INVENTION The present invention relates to a process for preparing a compound having the formula I: and their pharmaceutically acceptable salts. In formula I, Rp is hydrogen or a hydroxy-protective group, R1 is independently hydrogen or hydroxy in each occurrence, and R2 is a lower alkyl. The method comprises the steps of: (a) treating a compound represented by the formula: with a hydroxy-protective group and 1-chloroethyl chloroformate to provide the compound of the formula: (b) heating the compound of step (a) with an alcohol to provide the compound of the formula: (c) alkylating the 3'-N with an alkylating agent in the presence of a base. The process of the invention is an efficient process as it provides demethylation and enol ether formation in a single step. Therefore, it is more economical and clearer than the processes known in the prior art.

DESCRIPTION OF THE INVENTION The term "lower alkyl", as used herein, refers to a saturated straight or branched chain hydrocarbon radical of C8 including, but not limited to, methyl, ethyl, N-propyl, isopropyl, N-butyl , sec-butyl, isobutyl, tert-butyl and the like. By "pharmaceutically acceptable salts" is meant those acid addition salts of the compounds of the formula I, which are, within the scope of medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like according to a reasonable benefit / risk ratio, and which are effective for their intended use. Pharmaceutically acceptable salts are well known in the art, for example, S.M. Berge, et al. Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977), 66: 1-19. Examples of non-toxic, pharmaceutically acceptable acid addition salts are the salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid., or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic or malonic acid or using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include salts of nitrate, bisulfate, borate, formate, butyrate, valerate, 3-phenylpropionate, camphorate, adipate, benzoate, oleate, palmitate, stearate, laurate, lactate, fumarate, ascorbate, aspartate, nicotinate, p- toluenesulfonate, camphorsulfonate, methanesulfonate, 2-hydroxyethanesulfonate, gluconate, glucoheptonate, lactobionate, glycerophosphate, pectinate, laurylsulfonate, alginate, cyclopentanpropionate, digluconate, dodecyl sulfate, ethanesulfonate, hemisulfate, heptonate, hexanoate, 2-naphthalenesulfonate, pamoate, persulfate, pivalate, propionate, undecanoate, and the like, and can be prepared according to conventional methods. Representative alkaline or alkaline earth metal salts include sodium, calcium, potassium, magnesium salts, and the like. Scheme 1 illustrates the process of the invention for preparing the compounds of formula I. According to Scheme 1, the 2'-hydroxy of erythromycin 1 is protected with a suitable hydroxy protecting reagent in an aprotic solvent, such as is described by TW Greene and PGM Wuts in Protective Groups in Organic Svnthesis. 2. ed., John Wiley &; Son, Inc., 1991. Hydroxy protecting reagents include, for example, acetic anhydride, benzoic anhydride, benzyl chloroformate, 1-chloroethyl chloroformate, hexamethyldisilazane, or a trialkylsilyl chloride in an aprotic solvent. Examples of aprotic solvents are dichloromethane, 1,2-dichloroethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone, dimethyl sulfoxide, sulfoxide. diethyl, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, acetone and the like . The aprotic solvents do not adversely affect the reaction, and are preferably dichloromethane, 1,2-dichloroethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof. Preferably, the 2'-hydroxy group is acetylated using acetic anhydride or acetyl chloride. Without processing the reaction mixture, the reaction mixture is treated with about 9 equivalents of 1-chloroethyl chloroformate. This reagent removes one of the two methyl groups in the 3'-nitrogen to provide compound 2, N-chloroethyl carbamate. The reaction is carried out in a solvent selected from the group consisting of ethyl acetate, acetone, toluene, acetonitrile, methyl t-butyl ether, dimethoxyethane and 1,2-dichloroethane. The most preferred solvent is 1,2-dichloroethane, since the product is more soluble in 1,2-dichloroethane than other solvents. Keeping the product in solution without resorting to large volumes of solvent makes the process much easier. If it is desired to isolate the crystalline intermediate, a solvent other than 1,2-dichloroethane can be used. The reaction is typically carried out at about 50 ° C. Compound 2, chloroethyl carbamate, is then converted to an enol ether compound 3, by heating with an alcohol such as methanol, ethanol, propanol and the like, at a temperature of about 20 ° C to about 65 ° C, and for about 2 to 12 hours. Preferably, the reaction temperature is from about 20 ° C to about 40 ° C. The enol ether of monomethylamine acetate 3 can be isolated and crystallized from ethyl acetate and any other suitable solvent as a solid. Compound 3 may not be isolated and the reaction mixture is treated with an alkylating agent to effect the alkylation of the 3'-N-demethyl derivative.

Scheme 1 1A Compound 3 is alkylated using N-methylpyrrolidinone (NMP), acetonitrile, dimethyl sulfoxide, or tetrahydrofuran as a solvent and an organic base such as a tertiary amine, for example, diisopropylethylamine ((DIEA) or Hunig base)) or a base inorganic such as sodium bicarbonate or potassium carbonate to provide a compound of formula I. Alkylating agents include, for example, alkyl halides, alkyl sulfates, alkyl sulfonates and the like. Preferably, the alkylating agent is selected from the group consisting of ethyl halides, ethyl sulfates and ethyl sulfonates. Most preferably, the alkylating agent is ethyl iodide. The protected 2'-hydroxy group in formula I is deprotected through the methods known in the art to obtain a compound of formula IA. It may be desirable to deprotect the 2'-hydroxy group of compound 2 before the alkylation step. "Alternatively, 1-chloroethyl chloroformate can be used to protect the 2'-hydroxy group and to effect 3'-N-carbamoylation in a single step to obtain 2'-chloroethylcarbonate-N-demethyl-N-chloroethyl carbamate, 2A When this compound is heated with an alcohol, both the chloroethyl carbonate and the chloroethyl carbamate groups will be removed to provide the 8,9-anhydro-6,9-hemicetal derivative, 3, where Rp is hydrogen. be more efficient since the deprotection of the 2'-hydroxy and the demethylation of the 3'-hydrogen are obtained in a single step.Alternatively, as illustrated in Scheme IA, the compound 2 can be demethylated using an alcohol such ethanol, methanol , propanol, isopropanol, and the like, and an organic base such as a tertiary amine, for example, as diisopropylethylamine ((DIEA) or Hunig's base)) or an inorganic base such as sodium bicarbonate or potassium carbonate to provide a compound of the formula a 4. Compound 4 is alkylated according to the procedure described above for compound 3 to provide compound 5. Compound 5 is heated in an organic solvent in the presence of an acid to provide a compound of formula I. Solvents organic include, for example, dimethylformamide (DMF), alcohols such as ethanol, methanol, isopropanol, and the like, acetonitrile, acetone, dioxane and tetrahydrofuran. Acids used include hydrochloric acid, trifluoroacetic acid, dichloroacetic acid, sulfuric acid, and the like. Preferably, the reaction is carried out using trifluoroacetic acid in DMF at 60 ° C for about 12 to 24 hours. Scheme 1A In a preferred embodiment, R1 in formula I is hydrogen, and R is ethyl.

EXAMPLES Example 1 8,9-Anhydro-4"-deoxy-3'-N-demethyl-3'-ethyl-erythromycin B-6,9-hemiketal (ABT-229) Step 1: 2'-acetyl-4" - deoxy-3'-N-desmethyl-3'-N - ((1-chloroethyl) carbamate)) erythromycin BA a 500 ml three-necked flask was charged with 20 g (28.5 mmol) of 4"-deoxy-erythromycin B , available from Abbott Laboratories, 35.9 g (427.4 mmoles, 15 equiv.) of sodium bicarbonate and 140 ml (7 ml / g) of dichloroethane.The slurry was stirred at room temperature, while 3.0 ml (31.3 mmoles, 1.1) was added. equiv.) of acetic anhydride The reaction was heated to 50 ° C and stirred for 1 hour.The reaction was sampled and checked for completion through thin layer chromatography (TLC) .The acetylation was completed. The reaction mixture was then stirred at 50 ° C, 21.5 ml (199.4 mmol, 7.0 equiv.) of 1-chloroethyl chloroformate was added dropwise, The reaction mixture exothermed at 54 ° C for the first part of the reaction mixture. the addition, and then returned to 50 ° C. The reaction was sampled after 1 hour and verified for completion through TLC. Carbamylation was completed. After cooling the reaction mixture in an ice / water bath, the reaction was quenched with 200 ml of 1.5 N of ammonium hydroxide. The mixture was stirred for 30 minutes, then it was sedimented and in the upper part the washed layer was removed. The organic layer was washed with 100 ml of 1.5 N of ammonium hydroxide, then with 2 x 100 ml of water. The dichloroethane solution was separated on a rotary evaporator to give 37.0 2 g of a thick oil. This was diluted with 100 ml of heptane and the resulting solution was separated to give 26.85 g of a white solid.

Step 2: 8, 9-anhydro-2'-acetyl-4"-deoxy-3'-N-demethyl-erythromycin B-6,9-hemiketal The white solid obtained from step 1 above was dissolved in 160 ml of methanol and it was heated to 40 ° C. The solid dissolved after approximately 30 minutes The reaction was sampled and checked for completion after 4 hours at 40 ° C. The reaction was terminated.The methanol was removed on the rotary evaporator to give 23.93 g of the solid This material was made into a slurry in 100 ml of heptane at 40 ° C. After separation of the heptane, the solid weighed 23.15 kg.

Step 2A: 3'-N-demethylation-4"-deoxy erythromycin B: Alternatively, to a 400 ml round bottom flask containing 21 g of 2'-acetyl-4" -deoxy-3'-N-desmethyl-3 '-N ((1-chloroethyl) carbamate)) crude erythromycin B was charged with 210 ml of methanol and 13.4 ml (3.3 equivalents) of diisopropylethylamine. The reaction mixture was heated to 60 ° C and stirred overnight, then cooled to room temperature. The methanol was removed on the rotary evaporator to give 22.7 g of a foam. The foam was dissolved in 250 ml of toluene and concentrated on the rotary evaporator to produce a slurry. The solid was filtered, washed with 100 ml of toluene and dried in a vacuum oven at 45 ° C. The dry product weighed 12.95 g. The product thus obtained was ethylated as described in step 3 below. The resultant 3-N-desmethyl-3'-N-ethyl-4"-deoxy-erythromycin B was treated with an acid in the presence of an organic solvent to provide ABT-229 according to step 4 below.

Step 3: 8,9-anhydro-2'-acetyl-4"-deoxy-3, -N-desmethyl-3'-ethyl-erythromycin B-6,9-hemicetal The solid from step 2 was dissolved in 60 ml of N-methyl pyrrolidinone (NMP) at 40 ° C. To this solution at 40 ° C was added 14. 9 ml (85.5 mmoles, 3.0 equivalents) of diisopropylethylamine and 6.9 ml (85.5 mmoles, 3.0 equivalents) of ethyl iodide. The reaction was stirred at 40 ° C for 4 hours, and then overnight at room temperature. A sample was taken in the morning and checked to complete the reaction. The reaction is over. The reaction solution was diluted with 60 ml of water and extracted with 2 x 200 ml of heptane. The reaction was then extracted with 200 ml of 10% ethyl acetate in heptane. The extracts were combined and extracted again with 20 ml of acetonitrile. The heptane solution was then washed with 2 x 100 ml of water and 1 x 100 ml of 10% aqueous ammonium chloride. The heptane solution was separated on the rotary evaporator to give 19.17 g of a white solid.

Step 4: 8,9-anhydro-4"-deoxy-3'-N-desmethyl-3, -ethyl-erythromycin B-6,9-hemiketal (ABT-229) The white solid from step 3 was dissolved in 200 ml of methanol The resulting solution was heated to 40 ° C and stirred for 4 hours, then cooled to about 20 ° C and stirred over the weekend, checked through TLC for the morning term. The reaction was terminated and separated on the rotary evaporator to give 17.29 g of a white foam, the crude product ABT-229.

Example 2 8, 9-anhydro-2'-acetyl-3'-N-demethyl-3'-ethyl-erythromycin B-6,9-hemiketal Step 1: 2'-acetyl-3'desmethyl-3'N- ( (1-chloroethyl) carbamate)) erythromycin BA a 500 ml three neck flask was charged with 17.9 g (25.0 mmoles) of erythromycin B, available from Abbott Laboratories, 31.5 g (374.7 mmoles, 15 equivalents) of sodium bicarbonate and 125 ml of 1,2-dichloroethane. The mixture was heated to 45 ° C and 2.8 ml (30.0 mmol, 1.2 equivalents) of acetic anhydride were added. The reaction mixture was stirred for 1 hour and 15 minutes. The reaction was sampled and verified for the end of TLC. The acetylation was completed. While continuing to stir the reaction mixture at 45 ° C, 18.9 ml (174.9 mmol, 7.0 equivalents) of 1-chloroethyl chloroformate was added dropwise. The reaction mixture was made exothermic at 54 ° C during the first part of the addition, then returned to 50 ° C. The reaction was sampled after about 50 minutes and verified for completion through TLC. The carbamylation was completed. After cooling the reaction in an ice / water bath, the reaction was quenched with 175 ml of 1.5 N of ammonium hydroxide, keeping the temperature of the mixture below 10 ° C during the addition. The ice bath was stirred and the mixture was stirred for 30 minutes. Another 100 ml of 1,2-dichloroethane was added and the mixture was stirred. The mixture was then allowed to settle. The organic layer was washed with 100 ml of 1.5 N of ammonium hydroxide, then with 2 x 100 ml of water. The dichloroethane solution was separated on the rotary evaporator to give 24.9 g of a white foam.

Step 2: 8,9-anhydro-2'-acetyl-3'-N-demethyl-erithromycin B-6,9-hemiketal 10.9 g of the white foam obtained in step 1 above was dissolved in 120 ml of methane and warmed to 40 ° C. The reaction mixture was maintained at that temperature for 4 hours. The reaction mixture was then allowed to stand overnight. The reaction was completed as determined through TLC. The methanol was removed on the rotary evaporator to give 10.48 g of the solid. The solid was dissolved in 100 ml of ethyl acetate, transferred to a separatory funnel and washed with 3 x 100 ml of saturated aqueous NaHCO3. Approximately 50 ml of the aqueous layer was extracted. 100 ml of water were added and the mixture was stirred very well. The ethyl acetate layer settled completely well, but the aqueous layer contained a batch of white solid. The mixture was filtered and the ethyl acetate layer was separated from the aqueous layer in the filtrate. The ethyl acetate layer was concentrated to approximately 20 ml of a white slurry and filtered. The total solid weighed 9.47 g.

Step 3: 8,9-anhydro-2'-acetyl-3'-N-desmethyl-3'-ethyl-erythromycin B-6,9-hemicetal The solid from step 2 was dissolved in 56 ml of N-methyl pyrrolid? nona (NMP). To this solution were added 2.8 ml (16.0 mmoles, 1.25 equivalents) of diisopropylethylamine and 1.3 ml (16.0 mmoles, 1.25 equivalents) of ethyl iodide. The reaction was stirred to 40 ° C for 4 hours, then at room temperature and during the weekend. A sample was verified through TLC, indicating that the reaction was completed. The reaction mixture was transferred to a separatory funnel with ethyl acetate. The reaction solution was diluted with 100 ml of ethyl acetate and washed with 100 ml of water. The aqueous layer was extracted with 50 ml of ethyl acetate. The extracts were combined and washed with 2 x 100 ml of water. The solvent was separated on the rotary evaporator to give 9.14 g of foam. It should be understood that the foregoing detailed description and the appended examples are merely illustrative and should not be construed as limitations on the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the described modalities will be apparent to those skilled in the art. Said changes and modifications, including without limitation those in relation to the chemical structures, stereochemistry, substituents, derivatives, intermediates, syntheses, formulations and / or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims (12)

1. CLAIMS A process for preparing a compound represented by the formula: and their pharmaceutically acceptable salts, wherein: Rp is hydrogen or a hydroxy-protective group; R1 is independently of each occurrence hydrogen or hydroxy in each occurrence; and R2 is a lower alkyl; the method comprises the steps of: (a) treating a compound represented by the formula: with a hydroxy-protective group and 1-chloroethyl chloroformate to provide the compound of the formula: (b) heating the compound of step (a) with an alcohol to provide the compound of the formula: (c) alkylating the 3'-N with an alkylating agent in the presence of a base.
2. 2. The process according to claim 1, wherein the protected 2'-hydroxy group of the compound of step (b) is deprotected before the alkylation in step (c).
3. 3. The process according to claim 1, wherein the protected 2'-hydroxy group of the compound is deprotected after the alkylation in step (c).
4. 4. The process according to claim 1, wherein R1 is hydrogen.
5. 5. The process according to claim 1, wherein the alkylating agent is selected from the group consisting of alkyl halides, alkyl sulfates and alkylsulfonates.
6. 6. The process according to claim 1, wherein the alkylating agent is ethyl iodide.
7. 7. The process according to claim 1, wherein the solvent in step (a) is selected from the group consisting of acetone, ethyl acetate, toluene, acetonitrile, methyl t-butyl ether, dimethoxyethane and dichloroethane.
8. 8. The process according to claim 6, wherein the solvent is 1,2-dichloroethane.
9. 9. The process according to claim 1, wherein the temperature of the reaction mixture in step (a) is from about 20 ° C to about 65 ° C.
10. 10. The process according to claim 1, wherein the solvent in step (c) is N-methyl pyrrolidinone, dimethyl sulfoxide, tetrahydrofuran or acetonitrile and the base is NaHCO3, K2CO3 or diisopropylethylamine.
11. 11. The process according to claim 1, wherein the compound is 8,9-anhydro-4"-deoxy-3'-N-demethyl-3'-N-ethyl erythromycin B-6,9-hemicetal.
12. 12. The process according to claim 1, wherein: (b) the compound obtained in step (a) is heated with a base in an organic solvent to provide a compound of the formula: (c) the compound obtained in step (b) is alkylated in the presence of a base to obtain a compound of the formula: (d) the compound obtained in step (c) is heated in an organic solvent in the presence of an acid to obtain the compound of formula I.