PREPARATION OF BETA-METHYL CARBAPENEM

INTERMEDIATES

BACKGROUND OF THE INVENTION

The invention disclosed herein concerns a process of making 1-Beta methyl carbapenems. 1-Betamethyl carbapenem antibiotics, particularly are well known for treating a broad spectrum of gram-negative and gram-positive bacterial infections. See for example U.S. 4,962,103 issued October 9, 1990; U.S. 4,933,333 issued June 12, 1990; U.S. 4,943,569 issued July 24, 1990; U.S. 5,122,604 issued June 16, 1992; U.S. 5,034,384 issued July 23, 1991, ('256) and U.S. 5,011,832 issued April 30, 1991.

Numerous routes to beta-methyl carbapenem intermediates of formula VI have been cited in the literature:

VI

Tetrahedron Letters. Vol. 26, No. 39, pp 4739-4742, 1985; J. Am. Chem. Soc. 1986, 108, 4673-4675; Tetrahedron Letters. Vol. 27, No. 19, pp 2149-2152, 1986; Tetrahedron Letters. Vol. 27, No. 51, pp 6241-6244, 1986; Can. J. Chem 65, 2140 (1987); J. Org. Chem. 1987, 52, 3174-3176; J. Org. Chem. 1987, 52, 2563-2567; J. Org. Chem. 1987, 52, 5491-5492; Tetrahedron Letters. Vol. 28, No. 1, pp 83-86, 1987; Tetrahedron Letters. Vol. 28, No. 5, pp 507-510, 1987; Tetrahedron Letters. Vol. 28, No. 17, pp 1857-1860, 1987; Tetrahedron Letters. Vol. 28, No. 52, pp 6625-6628, 1987; Can. J. Chem. 66, 1400 (1988); Can. J. Chem. Vol. 66, (1988); J. Chem. Soc.

Chem. Commun.. 1988; J. Org. Chem. 1988, 53, 2131-2132; J. Org. Chem. 1988, 53, 4154-4156; Tetrahedron Vol. 44, No. 8, pp 2149 to 2165, 1988; Tetrahedron Letters. Vol. 29, No. 1, pp 61-64, 1988; Tetrahedron Letters. Vol. 29, No. 49, pp 6461-6464, 1988; Tetrahedron Letters. Vol. 29, No. 48, pp 6345-6348, 1988; Chemistry Letters, pp 445-448, 1989; J. Chem. Soc. Perkin Trans. 1 1989; J. Org. Chem. 1989, 54, 2103-2112; Tetrahedron Letters. Vol. 30, No. 1 pp 113-116, 1989; Tetrahedron Letters. Vol. 31, No. 2, pp 271-274, 1990; Tetrahedron Letters. Vol. 31, No. 4, pp 549-552, 1990; Chem. Pharm. Bull. 39(9) 2225-2232 (1991); Tetrahedron Vol. 47, No. 16/17, pp 2801-2820, 1991; Tetrahedron: Asvmmetrv Vol. 2, No. 4, pp 255-256, 1991; Tetrahedron Letters. Vol. 32, No. 19, pp 2143-2144, 1991; J. Org. Chem. 1992, 57, 2411-2418; Tetrahedron Vol. 48, No. 1, pp 55-66, 1992;

Previous methods to stereoselectively prepare β-methyl carbapenems include:

(1) hydrogenation of a 4-(2-propenyl) substituted azetidinone.

(2) stereoselective protonation of an enolate ion.

(3) reaction of 4-acetoxy azetidinone with a chiral enolate.

These methods required difficult multistep preparation of intermediates (1) and/or reagents (3), tedious manipulation of highly reactive intermediates at low temperature (2), or the use of expensive reagents (2,3).

The invention disclosed herein provides a versatile route to β-methyl intermediates (VI Scheme 1 with high stereoselectivity from readily available starting materials in four steps.

SUMMARY OF THE INVENTION

wherein R and P' are protecting groups Rl is a methylmalonic acid ester and Nu is a nucleophilic group. Process intermediates are also disclosed.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the invention concerns a process of making Beta-methyl carbapenem intermediates of formula VI

wherein

R is (a) hydrogen,

(b) methyl, or

(c) a hydroxy protecting group such as tri-organo- silyl including tri-Cl-4 alkyl silyl, phenyl di Cl-4 alkyl silyl and diphenyl mono Cl-4 alkyl silyloxy including tert-butyl-dimethylsilyl; and isopropyl dimethylsilyl and

P' is a nitrogen protecting group such as tri-organo-silyl, including tri-Ci-4 alkylsilyl, phenyl di Cl-4 alkyl silyl and diphenyl mono Cl-4 alkyl silyl including tert-butyl-dimethylsilyl; and isopropyldimethyl-silyl; compπsmg:

(a) contacting a compound of Formula I

Rl is (a) -0-C(0)-R" wherein R" includes Cl-6 alkyl, allyl and substituted phenyl wherein the substituent is hydrogen, Ci-3 alkyl, halo, nitro, cyano or Ci-3 alkyloxy, (b) -S(0)n-R2 wherein n is 1 or 2, and R2 is or an aromatic group such phenyl, biphenyl, naphthyl, said aromatic group optionally substituted with, for example halide, such as chloride or bromide, or Cl-4 alkyl, (c) halo, including Cl and Br in a non-reactive solvent with 2,2,5-trimethyl-l,3-dioxan-4,6- dione and a base to yield a compound of Formula HI:

For purposes of this specification protecting groups wherein R and P' are intended to include but are not limited to tri- organosilyl as defined above; suitable alternatives are cited in Protecting Groups In Organic Synthesis, Theodora W. Green, John Wiley and Sons 1981.

For purposes of this specification non-reactive solvents are defined to include a broad spectrum of non-reacting solubilizing agents including aromatic solvents such as benzene, toluene and xylene; etheral solvents including diethyl ether, di-n-butyl and diisopentyl ethers, anisole, cyclic ethers such as tetrahydropyran, 4-methyl-l,3-dioxane, dihydropyran, tetrahydrofurfuryl, methyl ether, ethyl ether, furan, 2- ethoxytetrahydrofuran and tetrahydrofuran (THF) ester solvents including ethyl and isopropyl acetate; halo carbon solvents including mono or dihalo Cl-4 alkyl; alcohols, including Cl-6 alkanol; and C6-10 linear, branched or cyclic hydrocarbon solvents including hexane and toluene; and nitrogen containing solvents including N ,N-dimethyl- acetamide, N^-dimethylformamide and acetonitrile.

For purposes of this specification bases are intended to include carbonates including alkali carbonates such as K2CO3 and tertiary Cl-4 alkyl amines including triethyl amine.

The molar ratio of compound of formula I to methyl Meldrum's acid should be approximately 1 to 1 or greater. The molar ratio of compound of formula I to base should be approximately 0.8 - 1.2 to 1. The reaction may be conducted from approximately 0 to 60°C preferably 40 to 50°C. The reaction is allowed to proceed until substantially complete in 1 minute to 20 hours, typically 14 hrs.

(b) contacting a compound of formula III in an aprotic solvent with a scavenging base, an alkali metal halide and a tri- organo halo silane to yield a compound of formula IV

For purposes of this specification, the aprotic solvent is intended to include N,N-diCl-6 alkylcarbonylamide such as N,N- dimethyl formamide (DMF), toluene, tetrahydrofuran and dichloro- methane. The scavenging base is intended to include pyrrole, pyridine, pyrrolidine, N,N diCi-3alkyl amino pyridine such as N,N-dimethyl amino pyridine tri-Ci-4alkylamine such as triethylamine and imidazole. The alkali metal halide may include sodium, potassium or lithium as the metal, and iodine, bromine, or chlorine as the halide. The tri-organo halo silane is intended to include tri-Ci-4 alkyl halo silane, such as Butyldimethyl silyl chloride; phenyl di Cl-4 alkyl halo silane, and diphenyl Cl-4 alkyl halo silane, wherein halo is intended to include chloride, bromide and iodide. The ratio of formula HI to silane should be approximately 1 to 1 or less. The molar ratio of silane to scavenging base should be approximately 1 to 1 or less. The ratio of silane to halide should be approximately 1 to 1 or less.

The reaction is conducted at 0 to 70°C, until essentially complete in 2-72 hours.

(c) contacting a compound of formula IV in a non- reactive solvent or Cl-6 alkanol with a base and

nucleophile of formula NuX to yield after acidification a compound of formula V

The non-reactive solvent is as defined above.

For purposes of this specification Cl-6 alkanol shall include methyl, ethyl, propyl, isopropyl, butyl and siobutyl alcohol. The base shall include alkali hydroxide such as potassium lithium or sodium hydroxide and shall include alkali carbonate such as sodium or potassium carbonate. Acidification may be accomplished with any suitable acid such as a mineral acid including HCl, H2SO4 or an organic acid such as acetic or formic acid.

The ratio of formula IV to base should be approximately 1 to 1 or less, and approximately 1 to 2 acid may be used for acidification.

The ratio of formula IV to nucleophile should be approximately 1 to 1 or greater. The reaction is allowed to proceed at -20 to 25°C until substantially complete in 10 to 100 minutes.

As appreciated by those of skill in the art, the particular nucleophile selected is a non-essential aspect of the invention disclosed herein. Any of a vast array of nucelophile may be selected. For example, Nu X is intended to include alkali metal salts of alkoxides, thiolates and enolates. Thus, X is intended to include Na, K, Li, and Cs. Similarly, Nu is intended to include R2θ- where hydrogen, Ci-6alkyl and substituted Ci-6alkyl and phenyl;

(enolate of t-butylacetate), or

(enolate of allyl acetate).

Moreover, with particular regard to R2S-, R2 is intended to include substituents at position-2 of the carbapenem, as found in commercially available or other active carbapenem antibiotics.

Thus in one aspect applicants anticipates the use of their compounds and process, as illustrated in Schemes 1 and 2, shown below. As shown in Scheme 1, compound a undergoes a stereoselective decarboxylation to give compound b. Compound b is then converted to active antibiotic as is well known in the art. See Shih, D. H. et al., Heterocycles 1984, 21, 79. Similarly, as shown in Scheme

2, compound a undergoes a stereoselective decarboxylation to give the thio ketone b' which is converted to active antibiotic as is well known in the art. See Greenlee, et al-, Heterocycles 1989, 28, 195 and references therein.

SCHEME 1

β-methyl --- _* - carbapenem antibiotics

30

30

Thus, for purposes of this specification Nu is intended to include, but not be limited to CH2C02t-Bu, sulfur or oxygen containing groups -SR2 and -OR2 wherein R2 is selected from the group consisting of hydrogen; straight and branched loweralkyl having from 1 to 10 carbon atoms; alkenyl, alkynyl, having from 2 to 10 carbon atoms; cycloalkyl having from 3 to 6 carbon atoms; cycloalkylalkyl wherein the cycloalkyl moiety comprises 3 to 6 carbon atoms and the alkyl moiety comprises 1 to 10 carbon atoms; alkylcycloalkyl wherein the alkyl moiety comprises 1 to 6 carbon atoms and the cycloalkyl moiety comprises 3 to 6 carbon atoms; aryl such as phenyl and naphthyl; aralkyl such as benzyl, phenethyl and the like; heterocyclyl (saturated and unsaturated) comprising mono- and bicyclic structures having from 5 to 10 ring atoms wherein one or more of the hetero atoms is selected from oxygen, nitrogen or sulphur, such as thiophene, imidazolyl, tetrazolyl, furyl and the like; heterocyclylalkyl which comprises the immediately preceding heterocyclyl moieties and the alkyl moiety comprises from 1 to 10 carbon atoms; the substituent (or substituents) relative to the above-named radicals is selected from the group consisting of amino, hydroxyl, cyano, carboxyl, nitro, chloro, bromo, fluoro, lower alkoxy having from 1 to 6 carbon atoms, mercapto, perhaloloweralkyl such as trifluoromethyl, loweralkylthio, guanidino, amidino, sulfamoyl, and N-substituted; sulfamoyl, amidino and guanidino wherein the N-substituent is loweralkyl having from 1 to 6 carbon atoms or aryl having 6-10 carbon atoms.

To illustrate, the aryl group includes but is not limited to R2 as defined in U.S. 4,962,103, issued October 9, 1990, wherein -SR2 is defined as

those defined in U.S. 4,933,333, U.S. 4,943,569, and U.S. 5,122,604 wherein -SR^ is defined as

those defined in U.S. 4,866,171 issued September 12, 1989 wherein -SR2 is defined as

those defined in U.S. 5,034,384, issued July 23, 1991,

wherein R2 is

those defined in U.S. 5,011,832 issued April 30, 1991, wherein R2 is

all of which are hereby incorporated by reference. Specific substituted on these aryl groups can be illustrated by the following species disclosed in the above references

(d) contacting a compound of formula V in an ester or ether solvent with a mild acid to yield a compound of formula VI

For purposes of this specification, the ester solvent is intended to include ethyl and isopropyl acetate and etheral solvents as defined above including methyl t-butyl ether. Mild acid are intended to include acetic and formic acid. The molar ratio of formula V to acid should be 1 to 1 or greater. The reaction may be allowed to proceed at from 10 to 150°C until substantially complete in 10 to 120 minutes. In a second embodiment, the invention concerns intermediate compounds of formulas HI, IV and V.

The invention is further detailed in Scheme 3 and the Examples thereafter.

4-acetoxyazetidinone I (Scheme 3) was reacted with methyl Meldrum's acid, II (2,2,5-trimethyl-l,3-dioxan-4,6-dione), giving β- lactam HI. Silylation of El with t-butyl dimethylsilylchloride/triethyl- amine/sodium iodide gave the N-silylated adduct IV. Reaction of IV with a nucleophile gave the carboxylic acid derivative V which underwent stereoselective decarboxylation giving the β-methyl azetidinone VI, a precursor to β-methyl carbapenem antibiotics. Use of intermediate VI is illustrated in Schemes 1 and 2, Supra.

SCHEME3

EXAMPLE 1

Preparation of Meldrum's acid adduct III

2,2,5-trimethyl-l,3-dioxan-4,6-dione II (17.4 g, 110 mmol), 4-acetoxy-azetidinone I (28.7 g, 100 mmol) and K2CO3 (15.2 g, 110 mmol) were mixed in dry acetonitrile (150 mL, KF=5.6 mg/mL), and the mixture was aged at 45-50° for 14 hours. Upon completion, the reaction mixture was cooled to room temperature and water (150 mL) was added. The organic layer was separated and the aqueous layer was back extracted with acetonitrile (100 mL). Combined organic extracts were washed with brine (100 mL) and concentrated to ca. 50 mL in volume. The mixture was then diluted with heptane (200 mL) and concentrated to 50 mL. Additional heptane (150 mL) was added and the mixture was aged at room temperature for crystallization. The resulting product was collected by filtration, washed with heptane (50 mL) and dried under vacuum at 40-50 for 15 hours to give an off-white crystalline solid (30.9 g, 80.2 mmol). A second crop was obtained by concentrating the combined filtrate and washed to ca. 50 mL in and aging at room temperature to give a white, fluffy solid (2.07 g, 5.4 mmol). Combined yield was 85.6%. Melting Range (°C) 78-83 d.

IH NMR (in CDCI3) 6.19 (IH, broad, NH), 4.20 (IH, dq, J=3.7 & 6.4Hz), 4.15 (IH, d, J=2.1Hz), 3.54 (IH, dd, J=2.1 & 3.7Hz), 1.77 (3H, s, CH3), 1.73 (3H, s, CH3), 1.62 (3H, s, CH3), 1.17 (3H, d, J=6.4Hz), 0.85 (9H, s, Si-t-Bu), 0.06 & 0.05 (6H, 2 s, 2 Si-CH3);

13C NMR (CDC13) 168.91, 168.51, 167.72, 105.47, 64.70, 61.22, 55.63, 50.99, 30.04, 28.28, 25.78, 22.82, 18.60, 17.95, -4.32, -4.94.

EXAMPLE 2

Preparation of IV

Azetidinone UI (7.7 g, 20 mmol) was dissolved in dimethylformamide (100 mL, KF=10 mg/mL) and Nal (6.6 g, 44 mmol), triethylamine (8.4 mL, 60 mmol) and N,N-dimethylamino-

pyridine (0.25 g, 2 mmol), were added consecutively. The mixture was stirred for 5 minutes and t-butyldimethylsilyl chloride (6.6 g, 44 mmol) was added in one portion. The mixture was stirred for 48 hours at room temperature and 50-60° for 15 hours. Upon completion, the reaction mixture was cooled to room temperature and water (100 mL) was added. The mixture was extracted with hexanes (100 mL x 2). The combined extracts were washed with 1 N aqueous HCl solution (100 mL) and water (100 mL) and concentrated to dryness. The resulting oily residue was dissolved in 2-propanol (40 mL) and water (40 mL) was added dropwise. It was seeded and additional water (40 mL) was added dropwise and aged at room temperature for crystallization. The resulting product was collected by filtration and dried under vacuum at 40-50°C 15 hours to give a pale orange crystalline solid (8.4 g, 16.8 mmol). Yield was 84.1%. Melting Range (°C) 73-73 d. IH NMR (in CDC13) 4.32 (IH, d, J=2.2Hz), 3.96 (IH, dq, J=5.9 & 9.4Hz), 3.66 (IH, dd, J=2.2 & 9.4Hz), 1.79 (6H, s, 2 CH3), 1.71 (3H, s, CH3), 1.34 (3H, d, J=5.9Hz), 0.95 & 0.91 (18H, 2 s, 2 Si-t-Bu), 0.25, 0.14, 0.12 & 0.11 (12H, 4 s, 4 Si-CH3);

13C NMR (CDCI3) 173.72, 168.56, 167.44, 105.43, 68.39, 63.13, 60.92, 50.45, 29.80, 28.09, 26.67, 25.95, 23.61, 23.03, 19.06, 18.02, -4.09, -4.38, -4.76, -4.90.

EXAMPLE 3

Hydrolysis of silylated adduct IV

Adduct IV (2.5 g, 5 mmol) was dissolved in THF (10 mL) and the solution was cooled to 0°C. 1 N Aqueous NaOH solution (10 mL, 10 mmol) was added dropwise while the internal temperature was kept below 5°C. The mixture was aged for 1 hour at 0°C and additional NaOH solution (2 mL, 2 mmol) was added dropwise. Upon completion, the mixture was acidified with formic acid (1.1 mL, 30 mmol) and extracted with ethyl acetate (40 mL). The solution was used for the next step. The diacid can be isolated by concentration of the solvent

followed by crystallization of the resulting solid from a mixture of methanol/water. Melting Range (°C) 97-99 d.

IH NMR (in CDCI3) 4.39 (IH, s), 4.07 (IH, q, J=6.5Hz), 3.29 (IH, d,

J=6.2Hz), 1.28 (3H, d, J=7.6Hz), 0.95 & 0.90 (18H, 2 s, 2 Si-t-Bu),

0.28, 0.14 & 0.11 (12H, 3 s, 4 S1-CH3);

13C NMR (CD3OD) 176.79, 173.78, 67.94, 62.15, 57.81, 27.21, 26.59,

22.31, 20.14, 19.01, 17.71, -3.77, -4.46.

EXAMPLE 4

Methanolvsis of silylated adduct IV

Adduct IV (1.50 g, 3 mmol) was dissolved in methanol (20 mL) and the solution was cooled to 0°C. K2CO3 (0.86 g, 6.2 mmol) was added in 3 portions and the mixture was aged for 1 hour at room temperature. Upon completion, the mixture was quenched with water (10 mL) followed by aqueous HCl solution (10 mL, IN) and extracted with ethyl acetate (20 mL). The organic layer was washed with water (20 mL) and concentrated to dryness to give a white foam (1.18 g, 2.5 mmol) in 80% yield. The foam was further purified by crystallization from a methanol/water mixture to give a white crystalline solid. Melting Range (°C) 125-135 d.

IH NMR (in CDCI3) 8.5 (IH, broad, CO2H), 4.34 (IH, d, J=2.4Hz), 4.09 (IH, q, J=6.4Hz), 3.76 (3H, s, OCH3), 3.11 (IH, dd, J=2.4 & 6.8Hz), 1.50 (3H, s, CH3), 1.22 (3H, d, J=6.2Hz), 0.96 & 0.89 (18H, 2s, 2 Si-t-Bu), 0.29, 0.12, 0.09 & 0.08 (12H, 3 s, 4 Si-CH3); 13C NMR (CDCI3) 174.57, 174.20, 171.26, 67.37, 61.33, 56.88, 56.54, 53.05, 26.54, 26.02, 22.52, 19.32, 18.34, 18.12, -3.99, -4.43, -4.60, -4.74.

EXAMPLE 5

Decarboxylation of the diacid V

From the base hydrolysis step, the diacid in ethyl acetate was refluxed with additional formic acid (1.10 mL, 30 mmol) for 2

hours. Aliquot assay showed a mixture of 95:5 ratio of β:a methyl product VI. The mixture was cooled to room temperature and concentrated to an oil. The resulting oil was dissolved in aqueous NaOH solution (1 N, 10 mL, 10 mmol) and aged for 2 hours at room temperature. The solution was acidified with aqueous HCl solution (1 N, 15 mL, 15 mmol) and extracted with ethyl acetate (30 mL). The extract was washed with water and concentrated to ca. 5 mL in volume. To it was added hexanes (60 mL) and aged at room temperature. A white crystalline solid was collected by filtration followed by washing with hexanes (10 mL) to give pure β-methyl formula VII (0.96 g, 3.18 mmol). Overall yield from intermediate IV is 64%. Melting Range (°C) 144-146 d.