PROCESS FOR PREPARING AZETIDINONE INTERMEDIATES

Abstract: Compounds of formula I wherein R₁ and R₂ is each H, halo or an organic group, R₃ is H or organic group, n=1 or 2, M is a heavy mono- or divalent metal, or M₂A wherein M₂ is a heavy divalent metal and A is an organic or inorganic group, are prepared by treating a starting penicillin in a solvent with a salt of M₁ or M₂A in the presence of a base at a temperature of from -70° to 100°C. The azetidinones of formula I are useful intermediates in the synthesis of β-lactam antibiotics, esp.penem.

Description: The present invention provides a process for preparing azetidinones which are useful intermediates in the synthesis of β-lactam antibiotics, esp. penems. Especially, the invention provides a a process for preparing a compound of formula (I) wherein R₁, R₂ are each independently hydrogen or halogen or a C 1-4 alkyl group or a protected 1-hydroxy ethyl group or a C 1-4 alkoxy group, or a residue of the formula NR'R", wherein R' is a hydrogen atom or a trimethyl silyl group and R" is trityl or R''' CO, wherein R''' is C 1-8 alkyl or alkenyl or a phenyl group; R 3 is hydrogen or a C 1-4 alkyl group, trichloroethyl or p-nitrobenzyl group; n is 1 or 2 and M represents a heavy metal M 1 in the +1 or +2 oxidation state, or a group M 2 A wherein M 2 is a heavy metal in the +2 oxidation state and A is an acetoxy, methoxycarbonyl or a phenyl group. When R 1 and R₂ are halogen, they are preferably bromo. R₃, which can be a C 1-4 alkyl group, is for example a methyl group or tert-butyl group. When M is a heavy metal M₁ in the +1 oxidation level, it is preferably Ag' , and in the compounds of formula (I) n represents 1. When M is a heavy metal M 1 in the +2 oxidation level, it is preferably Hg II , Cu II or Pb II , and r represents 2. A particularly preferred heavy metal M₁ in the +2 level is Hg II . A number of heavy metal salts of 4-mercaptoazetidinones are already known in the literature: R. Lattrell, Liebigs Ann. Chem ., 1974 , 1937; A Longo, P. Lombardi, C. Gandolfi and G. Franceschi, Tetrahedron Lett ., 22 , 355 (1981); A. Martel, P. Dextraze, J.P. Daris, R. Saintonge, P. Lapointe, T.T. Conway, I. Monkovic, G. Kavadias, Y. Ueda, P. Elie, S. Patil, G. Caron, J.L. Douglas, M. Menard, and B. Belleau, Can. J. Chem ., 60 , 942 (1982); F. Di Ninno, D.A. Muthard, R.W. Ratcliffe, and B.G. Christensen, Tetrahedron Lett ., 23 , 3535 (1982); W.J. Leanza, F. Di Ninno, D.A. Muthard, R.R. Wilkering, K.J. Wildonger, R.W. Ratcliffe, and B.G. Christensen, Tetrahedron Lett ., 39 , 2505 (1983); V.M. Girijavallabhan, A.K. Ganguly, P. Pinto, and R. Versace, Tetrahedron Lett ., 24 , 3179 (1983); V.M. Girijavallabhan, A.K. Ganguly, P. Pinto, and R. Versace, J. Chem. Soc ., Chem. Commun ., 908 (1983). The usefulness of the compounds of formula (II) as intermediates in the field of β-lactam antibiotics is self-evident and in part documented in the literature referred to above. In fact, these salts can be readily alkylated, acylated and converted into a number of 4-azetidinylthioderivatives, according to reaction known per se in the art. These derivatives, in turn, can be further manipulated on the azetidinone N-appendage to gave monocyclic β-lactam antibiotics, e.g. monobactams: or bicyclic β-lactam antibiotics, e.g. penems and cephems. A straightforward synthesis of compounds of formula (I) was still in demand, and it is now provided by the present invention. In fact, the methods known in the art and referred to above usually exploit an azetidinyl trityl sulphide or an azetidinyl tetrahydropyranil sulphide, which has to be synthesized through a multistep sequence either by total synthesis or from natural penicillins. Instead, the present invention allows a direct conversion of penicillins into the compounds of formula (I) under mild, non critical conditions. Moreover, the products (I) need not be isolated but can be further converted in situ to closer precursors of the target compounds. The present invention comprises treating a compound of formula (II) wherein R 1 , R 2 and R 3 are as defined above, with a strong, poorly nucleophilic base and an organic or inorganic salt of the heavy metal M 1 or of the M 2 A aggregate, wherein M 1 , M₂ and A are as defined above, in an aprotic organic solvent at a temperature of from -70 to 100°C. In several instances, the reaction is conveniently carried out at room temperature by which we mean 15-20°C. Protection from the light, an inert atmosphere and dry solvents are usually beneficial. If isolation of the product is desired, this can be usually performed by aqueous work-up; the compounds of formula (I) are usually extracted with standard organic solvents (e.g. ethyl acetate, dichloromethane). Alternatively, the heavy metal thiolates can be conveniently acylated or alkylated in situ, more preferably acylated. Alkylation of the heavy metal mercaptides of formula I can be performed with reactive halides, such as methyl iodide, alkyl bromide and benzyl bromide. Alkylation with α-halo acyl derivatives of formula III wherein Hal is bromo or chloro, R 4 is hydrogen or lower alkyl, esp. methyl, X is oxygen, sulphur or a bond, and R 5 is an organic group, gives azetidinyl derivatives formula IV wherein R₁,R₅ and X are as defined above, which are useful for the synthesis of classical and non-classical cephalosporin derivatives (see, for example J.H.C. Nayler et al., J. Chem. Soc., Chem. Commun., 1973, 57 and 59). The acylation of heavy metal mercaptides of formula (I) can be accomplished within a few minutes by the mere addition of an acylating agent of formula R 6 COY, wherein Y represents chlorine atom, OCOR₆, OCOR₆' or imidazolyl group, R 6 is an organic radical and R₆' is an organic radical different from R 6 . Preferably Y is chlorine atom, and R 6 is methyl or tert-butyldiphenylsilyloxymethyl group. The product thereby obtained is an azetidinyl thioester of formula (V) wherein R 1 , R 2 , R 3 , R 6 are as above defined. The importance of azetidinyl thioesters in the synthesis of penems is well known (see, for example, I. Ernest in "Chemistry and Biology of β-Lactam Antibiotics", Morin and Gorman ed., Academic Press, NY, 1982, vol. 2, pp 315-359); several routes from penams to these intermediates have been devised but they all suffer from major drawbacks (see M. Alpegiani et al., Tetrahedron Lett ., 1983, 1638, 1627, and references therein). On the contrary, preparation of azetidinyl thioesters of formula (V) from penams according to the present invention is a single, high-yield, stereoselective one-pot process, exploiting as reagents the acyl chlorides of formula R₆COCl, handy and often commercially available compounds. A particularly convenient procedure which for the first time elicits the synthesis of penem compounds of formula (VII) from penam compounds of formula (II) in a mere three-step process is herebelow described as illustrative of the merits of the present invention: In step (a), the penam compound of formula (II) is converted into the azetidinyl thioester of formula (V) as above described. Conversion of the compound of formula (V) into a trialkoxyphosphorane of formula (IV), step (b), is simply accomplished by ozonolysis and quenching of the ozonide with excess trialkylphosphite P(OR₇)₃, wherein R₇ is a lower alkyl group, preferably ethyl or methyl, according to what described by E. Perrone et al., Tetrahedron Lett ., 1984 , 2399. Plain heating of the intermediates of formula (VI) then affords the desired penem of formula (VII). Example 1 Silver 3,3-dibromo-2-oxo-1-(trichloroethoxycarbonyl-2-methylprop-1-enyl)-(4R)-azetidinylthiolate A solution of trichloroethyl 6,6-dibromopenicillanate (1.01 g; 2.04 mmol) in acetonitrile (12 ml) was stirred at room temperature under argon in the presence of silver nitrate (0.41 ml, 2.4 mmol) and diazabicyclononene (0.29 ml, 2.4 mmol). After 3 hours all the starting material was converted into the title silver salt (TLC monitoring). Isolation of the latter was performed by partition between ethyl acetate and water. The organic layer was dried (MgSO₄), the solvent removed and the residue triturated in isopropyl ether to give a powder (700 mg); m.p. 160° (dec.) IR= γ max (KBr) 1790, 1730 cm⁻¹ NMR= δ(CDCl₃) 2.10 and 2.40 (each 3H, s, Me), 4.90 (2H, ABq, J= 12 Hz, CH₂), 6.15 (1H, s, 4-H) ppm. MS (FD)= 593 m/z. By following a similar procedure, but starting from p-nitrobenzyl 6,6-dibromopenicillanate, there was obtained silver 3,3-dibromo-1-(p-nitrobenzyloxycarbonyl-2-methylprop-1-enyl)-2-oxo-(4R)-azetidinylthiolate as a fine yellowish powder; m.p. 115-120°C (dec.). IR= γ max (KBr) 1790, 1725 cm⁻¹ NMR= δ(CDCl₃) 2.05 and 2.25 (each 3H, s, Me), 5.25 (2H, m, CH₂), 5.87 (1H, s, 4-H), 7.5 and 8.15 (each 2H, d, 8.5 Hz, Ar) ppm. Example 2 (4R)-acetylthio-3,3-dibromo-1-(trichloroethoxycarbonyl-2-methylprop-1-enyl)azetidin-2-one. A solution of trichloroethyl 6,6-dibromopenicillanate (1 g) in acetonitrile (15 ml) was treated under argon with silver nitrate (416 ml) and diazabicyclononene (292 µl). After 3 hours at room temperature, acetyl chloride (174 µl)was added. A white precipitate of AgCl immediately appeared. After 10 minutes, the reaction mixture was filtered and poured into ethyl ether - aqueous 2% NaHCO₃ solution. The organic layer was dried and evaporated to afford the crude title compound in quantitative yield. This material could be purified by silica gel chromatography; 0.89 g (82%); m.p. 87°C IR= γ max (KBr) 1795, 1745, 1720 cm⁻¹ NMR= δ (CDCl₃) 2.05, 2.39, 2.45 (each 3H, s, Me), 4.88 (2H, s, CH₂CCl₃), 6.40 (1H, s, 4-H) ppm. MS (FD)= 529 m/z. By following a similar procedure, but starting from p-nitrobenzyl 6, 6-dibromopenicillanate, there was obtained (4R-acetylthio-3,3-dibromo-1-(p-nitrobenzyloxycarbonyl-2-methylprop-2-enyl)azetidin-2-one , white powder; m.p. 110-112°C; IR= γ max (KBr) 1790, 1720, 1707 cm⁻¹ NMR= δ (CDCl₃) 2.0, 2.31, 2.43 (each 3H, s, Me) 5.4 (2H, s, OC H ₂Ar), 6.15 (1H, s, 4-H), 7.55 and 8.23 (each 2H, d, j=8.5 Hz, Ar) ppm; and starting from methyl 6,6-dibromopenicillanate, there was obtained (4R)-acetylthio-3,3-dibromo-1-(methoxycarbonyl-2-methylprop-1-enyl)azetidin-2-one ; syrup; IR= γ max (CHCl₃) 1790, 1725, 1710 sh. cm⁻¹; NMR= δ(CDCl₃) 1.98, 2.30, 2.43 (each 3H, s, Me), 3.83 (3H, s, OMe), 6.22 (1H, s, 4-H) ppm; and starting from tert -butyl 6,6-dibromopenicillanate, there was obtained (4R)-acetylthio-3,3-dibromo-1-(tert-butoxycarbonyl-2-methylprop -1-enyl)azetidin-2-one ; white powder; m.p. 180 °C (dec.); IR= γ max (KBr) 1785, 1710 br cm⁻¹; NMR= δ (CDCl₃) 1.55 (9H, s, C₄H₉), 1.95, 2.27, 2.43 (each 3H, s, Me), 6.30 (1H, s, 4-H) ppm; and starting from trichloroethyl 6α-bromo-6β[(1R)-tert-butyldimethylsilyloxyethyl] penicillanate, there was obtained (4R)-acetylthio-(3S)-bromo-(3S)-[(1R)-tert-butyldimethylsilyloxyethyl]-1-(trichloroethoxycarbonyl-2-methylprop-1-enyl) azetidin-2-one; IR= γ max (CHCl₃) 1780, 1730, 1700 cm⁻¹; NMR= δ(CDCl₃) 0.13, 0.16 (each 3H, s, SiMe₂), 0.91 (9H, s, C₄H₉), 1.51 (3H, d, J=6 Hz, C H ₃ . CH), 2.02, 2.30, 2.36 (each 3H, s, Me), 4.83 (2H, s, CH₂CCl₃),6.10 (1H, s, 4-H) ppm. Example 3 ( 4R)-tert-butyldiphenylsilyloxyacetylthio-3,3-dibromo-1-(trichloroethoxycarbonyl-2-methylprop-1-enyl)azetidin-2-one. A solution of tert -butyldiphenylsilyloxyacetic acid (1.57 g) and thionyl chloride (0.72 ml) in dry benzene (25 ml) was kept at 25°C for 24 hours. The reaction mixture was thoroughly evaporated and freed from the excess reagent and volatile by-products. In a separate vessel, trichloroethyl 6,6-dibromopenicillanate (2 g) in acetonitrile (12 ml) was sequentially treated in a nitrogen atmosphere with silver nitrate (0.83 g) and diazabicyclononene (0.584ml). After 3 hour stirring at room temperature, a solution of the above-described acyl chloride in dry acetonitrile (10 ml) was dropped in under stirring; a white precipitate of silver chloride soon appeared. After a further 15 min., the reaction mixture was filtered and partitioned between water and ethyl acetate. The organic layer was washed with water, dried and evaporated to a syrup which was purified by flashchromatography; 2.5 g (78%). IR= γ max 1795, 1740, 1710 cm⁻¹; NMR= δ(CDCl₃) 1.06 (9H, s, C₄H₉), 2.00 and 2.32 (each 3H, s, Me), 4.25 (2H, s, OCH₂CO), 4.80 (2H, s, OCH₂CCl₃), 6.30 (1H, s, H-4), 7.2-7.8 (10 H, m, Ar) ppm. EXAMPLE 4 (3 S )-[(1 R )-tert-Butyldimethylsilyloxethyl]-(4 R )-te r t-butyldiphenylsilyloxyacetylthio-1-(1-trichloroethoxycarbonyl-2-methylprop-1-enyl)azetidin-2-one. By following the experimental procedure described in Example 3, a solution of trichloroethyl 6α[(1 R )-tert-butyldimethylsilyloxyethyl] penicillinate in MeCN was reacted with silver nitrate and diazabicyclononene (1 mol equiv. of each, 48 h, 0°C in the dark, N₂), and the reaction mixture then treated with tert-butyldiphenylsilyloxyacetyl chloride (1.1 mol equiv.,1H, 20° C) to afford to the title product (55% after silica gel chromatography). IR= γ max (CHCl₃) 1760, 1725, 1695 cm⁻¹ NMR= (200 MHz, CDCl₃)δ 0.07, 0.10 (each 3H, s), 0.87, 1.06 (each 9H, s), 1.32 (3H, d, J = 6.3 Hz) 2.03, 2.26 (each 3H, s) 3.35 (1H, dd, J = 2.6 and 6.7 Hz), 4.19 (2H, s), 4.33 (1H, dq, J = 6.7 and 6.3 Hz), 4.47, 4.85 (2H, each d, J = 12.0 Hz), 5.76 (1H, d, J = 2.6 Hz), 7.3-7.8 (10 H , m). EXAMPLE 5 (4 R )-Acetylthio-(3 S )-[(1 R )-tert-butyldimethylsilyloxyethyl]-1-(1-trichloroethoxycarbonyl-2-methylprop-1-enyl)azetidin-2-one. A solution of trichloroethyl 6α-[(1 R )-tert-butyldimethylsilyloxyethyl] penicillinate (450 mg; 0.92 mmol) in acetonitrile (15 ml) was added to a mixture of phenylmercuric chloride (313 mg; 1 mmol) and diazabicyclononene (0.118 ml; 0.95 mmol) in the same solvent (20 ml). After stirring for 2 h at room temperature, acetyl chloride (0.2 ml) was added, and the mixture was stirred for an additional hour, then partitioned between ethyl acetate and water. The organic layer was sequentially washed with 4% HCl, sat. NaHCO₃, H₂O, dried (Na₂SO₄) and evaporated, The residue was extracted with CCl₄ (15 ml); the insoluble salts were filtered off, and the solution was evaporated to give the title product in almost quantitative yeld; IR = γ max (CHCl₃) 1760, 1725, 1695 cm⁻¹ NMR = (60 MHz, CDCl₃) δ 0.10 (6H,s), 0.90 (9H,s), 1.30 (3H, d J = 6.2 Hz), 2.03, 2.27, 2.32 (each 3H, s) 3.23 (1H, dd, J = 2.5 and 6.5 Hz), 4.30 (1H, m), 4.80 (2H, s) 5.72 (1H, d, J = 2.5 Hz). Mass spectrum = 531 (M⁺), 475 (M⁺ - 56, base peak). EXAMPLE 6 (4 R -Acetylthio-(3 R )-[(1 R )-tert-butyldimethylsilyloxyethyl]-1-(1-trichloroethoxycarbonyl-2-methylprop-1-enyl) azetidin-2-one. By following the experimental procedure described in Example 5, but starting from trichloroethyl 6β-[(1 R )-tert-butyldimethylsilyloxyethyl] penicillinate, the title product was obtained in quantitative yield; IR = γ max (CHCl₃) 1760, 1730, 1690 cm⁻¹ NMR = (200 MHz,CDCl₃) δ 0.09, 0.13 (each 3H, s,), 0.87 (9H, s) 1.39 (3H, d, J = 6.4 Hz), 1.98, 2.21, 2.28 (each 3H, s), 3.58 (1H, dd, J = 2.9 and 5.7 Hz), 4.10 (1H, qd, J = 2.9 and 6.4 Hz), 4.76, 4.84 (2H, each d, J = 12.0 Hz), 5.93 (1H, d, J = 5.7 Hz).

Claims: A process for preparing a compound of formula (I) wherein R 1 , R₂ are each independently hydrogen or halogen or a C 1-4 alkyl group or a protected 1-hydroxy ethyl group or a C 1-4 alkoxy group, or a residue of the formula NR'R", wherein R' is a hydrogen atom or a trimethyl silyl group and R" is trityl or R'''CO, wherein R''' is C₁ - ₈ alkyl or alkenyl or a phenyl group; R₃ is hydrogen or a C 1-4 alkyl group, trichloroethyl or p-nitrobenzyl group; n is 1 or 2 and M represents a heavy metal M₁ in the +1 or +2 oxidation state, or a group M₂A wherein M₂ is a heavy metal in the +2 oxidation state and A is an acetoxy, methoxycarbonyl or a phenyl group, which comprises treating a compound of formula (II) wherein R₁, R₂ and R₃ are as defined above, with a strong, poorly nucleophilic base and an organic or inorganic salt of the heavy metal M 1 or of the M₂A aggregate, wherein M₁, M₂ and A are as defined above, in an aprotic organic solvent at a temperature of from -70 to 100°C. A process according to claim 1, wherein said strong, poorly nucleophilic base is selected from diazabicyclononene, 1,4-diazabicyclo octane and diazabicycloundecene. A process according to claim 1 , wherein said organic or inorganic salt of the heavy metal M₁ is silver nitrate, silver perchlorate, silver acetate or mercury acetate. A process according to claim 1 wherein said organic salt of the M₂A aggregate is methoxycarbonylmercury (II) acetate, or phenyl mercury (II) chloride. A process according to claim 1 wherein said aprotic organic solvent is acetonitrile, dimethylformamide, benzene or dichloromethane. A process according to claim 1 wherein the reaction is carried out at 15-25°C. A process according to claim 1, in which R₁, R₂ are each independently bromo or hydrogen atom or protected 1-hydroxy ethyl group and R₃ is methyl, t-butyl, trichloroethyl or p-nitrobenzyl group. A process for preparing a compound of formula (V) comprising the step of acylating a compound of formula (I) obtained by a process according to any of claims 1 to 7 with a compound of formula R₆COY, wherein Y represents chlorine atom, OCOR₆, OCOR₆' or imidazolyl group, R₆ represents an organic radical and R₆' is an organic radical different form R₆, to give an azetidinyl thioester of formula: where R₁, R₂ and R₃ are as defined in claim 1 and R₆ is as defined above. A process according to claim 8,in which Y represents chlorine atom and R₆ is methyl or tert-butyldiphenylsilyloxymethyl group.

Inventors: ALPEGIANI, MARCO, BEDESCHI, ANGELO, PERRONE, ETTORE
Applicants: FARMITALIA CARLO ERBA S.R.L.
Application year: 1986
Main classification: C07D205
IPC codes: C07D499, C07F7, C07D205