PROCESS OF PREPARING ESTERS OF PENICILLANIC ACID SULFOXIDE

Abstract: A new synthesis of penicillanic sulfoxide acid ester is claimed. The synthesis starts with 6-amino penicillanic acid and proceeds through conversion to a bromide via diazotization, esterification, reduction of the bromide, and oxidation of the resulting penicillanic ester.

Description: PROCESS OF PREPARING ESTERS OF PENICILLANIC ACID SULFOXIDE Field of the Invention The present invention relates to the field of organic chemistry. More specifically it relates to the fields of medicinal and pharmaceutical chemistry. Background of the Invention The discovery and mass production of penicillin in the 1940' s revolutionized the treatment of human disease. These early antibiotics saved countless lives by providing the first non-invasive treatment for bacterial infections. Unfortunately, the widespread use of antibiotics has not been free from costs. Numerous strains of drug resistant bacterial pathogens have emerged over the years, challenging the medicinal chemist's ability to redesign and/or engineer new antibiotics . An important class of building blocks often utilized in the design of antibiotics and β-lactamase inhibitors are the esters of penicillanic acid sulfoxide. Examples of antibiotics and β-lactamase inhibitors include cefaclor and cefuroxime. Esters of penicillanic acid sulfoxide are represented by compounds of formula (I) . The reported syntheses of this class of molecules is accomplished by segregated syntheses and purifications, which often entail laborious chromatographic separations (see Beels, C. M. D, et al . , J. Chem. Soc. Co mun. 665, 1979, Kemp, J. E. G, et al . , Tetrahedron Letters, 3785, 1979, Micetich, R. G., et al . , Heterocycles, 23, 325, (1985), and Johnson, G.; et al . , Spec . Publ . - R. Soc . Chem. 38, 170), (1980)). Low overall yields have been reported, due in part, to the sensitive nature of the β- lactam to ring opening events and losses in the multiple work-up process. The present invention provides a simple and efficient procedure for the synthesis of this important class of compounds. Summary of the Invention The present invention is a one-pot (one reaction zone, typically one-vessel) process for the preparation of a compound of the formula (I) : wherein R is a carboxy protecting group; comprising, conducting the following steps A, B, C, D, E and F in a single reaction zone: A) diazotizing 6-APA with nitrous acid to form a compound of the formula (II); B) reacting a compound of formula (II) with bromide or other halide anion to form a compound of the formula (III); C) alkylating a compound of formula (III) with an alkylating agent of the formula RX, where R is a monovalent radical and X is a leaving group comprising halide, hydroxy and the like to form a compound of the formula (IV) ; D) reducing a compound of formula (IV) to form a compound of the formula (V) ; E) oxidizing a compound of formula (V) to form a compound of the formula (I); and F) optionally, isolating the compound of formula (I) The compounds of formula (I) are valuable intermediates useful in the preparation of antibiotic compounds of the formula (IA) and the β-lactamase inhibitors of formula (IB) . Prior reported syntheses of the compounds of formula (I) have been unsatisfactory in that they require multiple steps and report low overall yields of the desired compounds. In addition, the reported syntheses require multiple isolation steps and accordingly the use of large volumes of solvents. The time required to perform these multiple isolations and handle the waste stream produced is a severe detriment to a commercial manufacture of these materials. The present invention overcomes many of the failings of the prior art. The novel single-pot synthetic process avoids numerous isolation steps that require large volumes of solvents. In addition, the present invention is robust, does not require extreme temperatures, utilizes cost effective reagents and solvents, and produces greatly reduced waste. As industrial production of antibiotics increases around the world, the advantages of the present process become increasingly valuable. This expedient, cost effective, environmentally conscious process allows cheaper and easier production of important antibacterial medicines . Detailed Description of the Invention The term "β-APA as used herein refers to the compound 6-aminopenicillanic acid. The term "carboxy protecting group" as used in the specification refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the condition of subsequent reaction (s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Suitable protecting groups are well known to chemists and chemical engineering practitioners of the art and are further set out in standard references such as T.W. Greene and P. Wuts, Protective Groups in Organi c Synthesis, John Wiley and Sons, New York, N.Y., 1991, Chapter 5. See also E. Haslam, Protective Groups in Organic Chemistry, J.G.W. McOmie, Ed., Plenum Press, New York, N.Y., 1973. Examples of carboxy protecting groups include for example, p-nitrobenzyl group, allylic groups, benzyl, butyl, and trichloroethyl groups. In general suitable carboxy protecting groups are groups that result in formation of readily hydrolyzable esters. A related term is "protected carboxy, " which refers to a carboxy- protecting group. The term "solvent" means a liquid reaction medium in which the selected reactant(s) has a solubility of at least 1% by weight. The terms "one-pot," "single-pot," "one reaction zone" or "one-vessel" as used herein are synonymous and mean a chemical synthesis in which the entire reaction sequence is performed in one reaction zone (typically in one reaction vessel without product removal or separation or purification until all essential reaction steps are completed) . The term "leaving group" as used herein defines the part of a substrate molecule that is cleaved in a reaction and comprises the groups halides, hydroxy, alkoxy sulfonate esters, triflates, phosphonates and the like . The term "diazotization" refers to the formation of a RN 2 + radical either by the treatment of a primary amine with nitrous acid or other nitrite source or the protonation of diazo compounds. Diazotization is well known to artisans in the field and may be found in general reference texts including for example J. March, Advanced Organic chemistry, John Wiley and Sons, New York, N.Y., 1985. General Process Conditions The reaction is carried out in a single reaction zone, typically a reaction vessel, having an input and an output means, an agitation means (electric stirrer) , heating and cooling means (heat exchange coils) , and is constructed of materials which are non-reactive with the reactants and products of the reaction (e.g. glass lined vessel) . The process may be conducted as a batch, semi-batch or continuous process, but batch operation is preferred. The process may be conducted at superatmospheric or subatmospheric pressure but ambient atmospheric pressure is preferred for convenience (e.g. about 101.3KPa). A preferred reaction medium is one or two phases where each phase is a solvent or mixture of solvents for the reactants and the reaction products at each step of the process. Solvents useful for the purpose of this invention include methylene chloride, water, lower (C ι -C 2 ) alcohols , chloroform, acetonitrile and the like. Particularly preferred solvents include methylene chloride and water. Scheme I Scheme I describes an efficient and practical one- pot synthesis of the compounds of formula (I). (V) (I) The starting material useful for the purpose of this invention is 6-aminopenicillanic acid , chemically known in the art as 6-amino-3, 3-dimethyl-7-oxo-4-thia-l- azabicyclo [3.2.0] heptane-2-carboxylic acid (6-APA). 6- APA is an item of commerce and is obtained from cultures of Penicillium Chrysogenum in the absence of side chain precursors: Batchelor et al . , Nature 183, 257 (1959). Synthetic methods for the preparation of 6-APA have been disclosed by Sheehan et al . , J. Am . Chem. Soc . 81, 5838 (1959), ibid. 84, 2983 (1962). Methods of preparation of 6-APA have also been disclosed in U.S. Patent Nos. 3,028,379; 2,934,540; and 2,941,995, the entire disclosures of which are incorporated by reference. 6- APA is also readily commercially available from the various chemical supply sources available to practitioners of the art. Step A: The diazotization of 6-aminopenicillanic acid (6-APA) can be performed by methods well known in the art including but not limited to treatment with nitrous acid in a suitable solvent such as ethanol. Numerous methods of preparing nitrous acid in si tu are known in the art. Alternatively, other nitrite sources can be employed including but not limited to alkylnitrites and the like. Most commonly a nitrite salt solution is added to a cooled solution of the amine and a mineral acid. The transformation can be preferably carried out by addition of aqueous sodium nitrite to a turbid ethanol/sulfuric acid solution of 6-APA. A skilled artisan will appreciate that the production of diazonium salts is a potentially dangerous operation that is most commonly performed at temperatures ranging from 0°C to 15°C. This reaction requires from 1 to 3 hours. Step B: The bromide displacement to form compounds of formula (III) can be performed by numerous methods known in the art. Most commonly the transformation is accomplished by addition of the diazonium solution to a solution (e.g., aqueous) of a periodic table group I or group II bromide salt. Potassium, sodium, or lithium bromide are preferred bromide anion sources. For the same reasons as outlined in the diazonium formation, the bromide addition is most often performed at reduced temperatures, preferably from 0°C to 15°C. This reaction step requires from 1 to 3 hours for completion. Often, and most preferably, the displacement is performed by having the bromide anion present in the reaction mixture when the diazonium salt is being formed. In this way, the highly reactive diazonium species is immediately displaced with bromide prior to degrading. In addition, this procedure helps prevent the concentration of diazonium salts from reaching a level where a spontaneous and violent degradation is more likely. Step C: The alkylation of the carboxyl group to form compounds of the formula (IV), is well known in the art and can be effected by a wide variety of reagents. It is most often performed by reacting the carboxylate with a compound of the formula R-X; wherein, X is a leaving group including but not limited to halide, hydroxy, and phosphonate esters. A skilled artisan will appreciate that a wide variety of solvents and temperatures can be utilized in this transformation and that the specific choices will be determined by the reactivity of the alkylating agent, R-X. An especially preferred method is one wherein X is halide and the alkylation is carried out under phase-transfer catalysis conditions. Most preferred conditions include reaction of p-nitrobenzyl bromide with the compound of formula (III) in a biphasic reaction mixture of methylene chloride and water, at approximately neutral pH, and in - l i ¬ the presence of a phase-transfer catalyst. Appropriate phase-transfer catalysts are well known in the art and include but are not limited to tetralkylammonium salts, tetralkyl- phosphonium salts, and the like. Tetrabutylammonium bromide is one such preferred catalyst. This reaction step typically requires 2 to 20 hours for completion depending on the temperature which is typically from 0°C to 40°C. Step D: The reductive dehalogenation, to prepare compounds of formula (V) can be performed by reagents known in the art including but not limited to alkylphosphines, alkylphosphites, zinc, Al/Pb, alkyltin hydrides, hydrogen/Pd, and the like. A skilled artisan will appreciate that a wide variety of solvents and temperatures can be utilized in this and other transformations embodied in this invention and that the specific choices will be determined by the reactivity of the reducing agent. Preferred reducing agents are trialkylphosphines, especially tributylphosphine, which are added at 0°C to 30°C over a period of 20 to 60 minutes. A preferred solvent mixture is the mixture of dichloromethane and methanol. Step E: The sulfide oxidation, to prepare compounds of formula (I) can be performed by methods known in the art including but not limited to reacting the sulfide with peracids such as peracetic acid and m- chloroperbenzoic acid, OXONE® brand of potassium peroxymonosulfate, ozone, sodium periodate, hydrogen peroxide, and the like. These oxidations are most often but not always carried out at reduced temperature. The reaction is typically performed at from 0 to 10°C over a period of 1 to 4 hours depending on the rate of addition of the oxidizing agent. A wide variety of solvent can be utilized for the oxidizing agents as long as they are inert to the reaction conditions. Preferred solvents include lower alcohols, methylene chloride, chloroform, acetonitrile, water, and the like. In addition, these oxidations are often performed in mixtures of solvents. Especially preferred solvent mixtures include water/methanol, water/ethanol, and methylene chloride/methanol . Step F: The isolation of the final products of the formula (I) is optional and not necessary for the practice of this invention. The product mixture can be employed in a subsequent transformation without isolation. The isolation of the products of formula (I) if desired can be affected by a variety of known methods including but not limited to extraction, chromatography, crystallization, and the like. A skilled artisan would appreciate that the optimal isolation technique will be determined by the particular characteristics of the ester prepared by the present invention. A particularly preferred isolation technique is crystallization of the product. An especially preferred method is crystallization from hot methanol. Throughout the course of the reaction scheme, it may be preferable to add, change, or remove solvents. A skilled artisan would appreciate that the rate and efficiency of the process, as well as the purity of the product, can be affected by the choice of solvents. In addition, the ultimate purification of the compounds of formula (I) can be simplified if the reaction mixture is washed with an immiscible solvent, once or more than once, throughout the course of the process. Accordingly, this exchange, addition, or removal of solvents is within the scope of the present invention. A further embodiment of the present invention is the process scheme (I) wherein step (E) precedes step (D) . The oxidation and reduction steps may efficiently be performed in either order. Accordingly, the present invention includes such alternative processes. The reaction temperature of all reaction steps is within the freezing point and boiling point of the reaction medium, and preferably from 0°C and 50°C, with comparable reaction times of 1 minute to 100 hours. Each reaction step is performed for a time sufficient to convert a major portion of the penicillanic acid precursor, that is at least about 50 mole percent and preferably at least 95 mole percent. The reaction at each stage may be monitored by conventional means such as withdrawal of an aliquot sample and analyzing for a product and or by-product or disappearance of a starting material, to determine completeness of the reaction. Examples Example 1 p-Nitrobenzyl Penicillanate Oxide Aqueous sulfuric acid (281 mmol, 1.25 M, 225 mL) and 168 mL of ethanol were mixed in a 3-necked, 1 liter flask equipped with a thermometer, mechanical stirrer and an addition funnel connected to a gas bubbler. 6-Aminopen- icillanic acid (222 mmol, 48.1 g) was added at 5°C to give a cloudy solution, which was vigorously stirred with 54.0 g of KBr (454 mmol) . A solution of NaN0 2 (21.8 g, 316 mmol) in 56 mL of H 2 O was added at such a rate so as to keep the temperature below 13 °C. Nitrogen gas generated was let out through the bubbler. The addition took 40 min and the resulting mixture was stirred at ice- bath temperature for additional 50 min, during which the pH rose from 0.97 to 1.97. Dichloromethane (250 mL) was added and the resulting mixture was stirred for 15 min. The top aqueous layer was removed and replaced with 112 mL of water. To this was added 9.3g (28.8 mmol) of nBu4NBr, 48.1 g of p-nitrobenzyl bromide (223 mmol), and approximately 95 mL of 45% aqueous K 3 PO 3 to bring the pH to 7.3. The resulting mixture was stirred at room temperature (22 °C) for 17 h, while keeping the pH at 7.0-7.3 using 45% aqueous K 3 P0 4 and an automatic titrator. The top aqueous layer was removed by suction and replaced with 168 mL of MeOH. The CH 2 Cl 2 -MeOH solution was cooled to 8°C, treated with dropwise addition of nBu 3 P (77mL, 310 mmol), stirred at room temperature for 30 min, and then cooled to 0°C. Peracetic acid (92 mL, 32% in dilute acetic acid, 437mmol) was added over 55 min, maintaining the temperature below 6°C. The mixture was stirred at 5°C for 20 min, washed sequentially with 100 mL of 5 % NaHS0 3 (to give a negative peroxide test) , 100 L of 5 % NaHC0 3 , and 100 mL of brine, and concentrated to give 152 g of a thick slurry, which was crystallized from 150 mL of hot MeOH. After cooling down to 0°C, the solid was filtered, washed with 150 mL of cold MeOH, and dried in vacuo at 45°C to give 33.8 g (43%) of the title compound as a white solid. IR (KBr) : n = 3000, 1791, 1755, 1526, 1348, 1182 cm "1 . ! H NMR (d 6 DMSO) : d = 1.17 (s, 3H) , 1.57 (s, 3H) , 3.04 (dd, 1H, J = 16, 2 Hz), 3.46 (dd, 1H, J = 5, 16 Hz), 4.42 (s, 1 H) , 5.34 (dd, 1H, J = 2, 5 Hz), 5.39 (s, 2H) , 7.72 (d, 2 H, J = 8 Hz), 8.27 (d, 2 H, J= 8 Hz). 13 C NMR (d 6 DMSO) : d = 15.39, 17.78, 35.50, 64.93, 65.83, 70.43, 72.97, 123.62, 124.90, 142.81, 147.31, 167.89, 171.70. C 15 H 16 N 2 0 6 S calc. C 51.13H 4.58N, 7.95S 9.10 (352.37) found 51.12 4.65 7.86 8.83 The principles, preferred embodiments and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed as limited to the particular forms disclosed, since they are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art without departing from the spirit of the invention.

Claims: I Claim: 1. A one-pot process for the preparation of a compound of the formula (I) : comprising conducting the following steps A, B, C, D, E and F in a single reaction zone: diazotizing 6-APA with nitrous acid to form a compound of the formula (II); b) reacting a compound of formula (II) with bromide anion to form a compound of the formula (III) ; C0 2 H c) alkylating a compound of formula (III) to form a compound of the formula (IV) ; d) reducing a compound of formula (IV) to form a compound of the formula (V) ; e) oxidizing a compound of formula (V) to form a compound of the formula (I) f) optionally, isolating the compound of formula (I) . 2. A process according to Claim 1 wherein R is a carboxy protecting group comprising any one of p- nitrobenzyl, benzyl, allyl or p-methoxybenzyl groups. 3. A process according to Claim 1 wherein R is p- nitrobenzyl group. 4. A process according to claim I comprising the step of isolating the compound of formula (I) . 5. A process according to Claim 1 for the manufacture of a pharmaceutical intermediate or drug substance composition comprising the compound of formula (I) or derivatives thereof.

Inventors: GARDNER JOHN PAUL, ZHANG TONY YANTAO, GARDNER, JOHN, PAUL, ZHANG, TONY, YANTAO
Applicants: GARDNER JOHN PAUL, LILLY CO ELI, ZHANG TONY YANTAO, ELI LILLY AND COMPANY, GARDNER, JOHN, PAUL, ZHANG, TONY, YANTAO
Application year: 1999
Main classification: C07D499
IPC codes: C07D499