IMPROVED PROCESS FOR SYNTHESIZING CARBAPENEM

INTERMEDIATES

BACKGROUND OF THE INVENTION

The present invention relates to the synthesis of a beta methyl carbapenem intermediate of the formula:

This intermediate for carbapenem antibiotics has been disclosed in numerous patents and publications. For example, the intermediate is disclosed in U. S. Pat. No. 4,350,631 issued to Christensen, et al- on September 21, 1982 and in U. S. Pat. No. 4,994,568 issued to Christensen on February 19, 1991. In the process described in each of these patents, a diazo compound of the formula:

is cyclized using a catalyst or irradiation. These process steps generate a mixture of 1-α and 1-β methyl isomers, which in turn require separation prior to further chemical modification.

Likewise, a washing step has been utilized in the past, whereby the diazo compound is purified in an aqueous medium. The

diazo compound is washed with water, dried and then cyclized. This improves the yield of the 1-β methyl isomer, but introduces water into the reaction, thus necessitating the implementation of the drying step. Drying at this stage in the synthesis of carbapenems can be unpredictable and dangerous.

The present invention overcomes these difficulties, providing an unexpectedly low rate of formation of the 1-α methyl isomer, and thus eliminating the need for separation of the α and β isomers prior to further chemical synthesis. Moreover, even in relatively uncontrolled reactions, inclusion of the Lewis acid as described herein in detail can reduce epimerization to the 1-α methyl compound to less than about one percent.

SUMMARY OF THE INVENTION

A process for synthesizing a 1-β methyl compound of the formula:

1 is disclosed, in which M represents a carboxyl protecting group and P represents H or a hydroxyl protecting group,

wherein the compound:

is cyclized in the presence of a rhodium catalyst and a catalytic quantity of a Lewis acid which is effective for reducing the formation of the 1-α methyl isomer.

DETAILED DESCRIPTION OF THE INVENTION

The 1-β methyl isomer of the bicyclic ketoester 1 which is shown above is highly desired and useful as a carbapenem intermediate, due to the recognition in the art that 1-beta methyl final carbapenem compounds have a reduced tendency toward biological inactivation by the enzyme dehydropeptidase, when administered to treat bacterial infections. Generally, the 1-β methyl isomer of the final product is more resistant to deactivation than the 1H or the 1-α methyl isomer.

The 1-β methyl isomer of the bicyclic ketoester can further be reacted at the 2-position to establish a leaving group at this position, which can farther be reacted as described in numerous patents and published applications to form the appropriate carbapenem end product with a substituent group at position two.

The present invention is thus an improvement in the process of synthesizing the 1-β methyl bicyclic ketoester 1. The improvement in the process is comprised of the addition of a Lewis acid to the reaction mixture which effectively prevents the formation of the 1-α methyl isomer and further essentially prevents epimerization of the 1-β methyl isomer.

As used herein, the term "rhodium catalyst" refers to dimeric rhodium salts selected from the group consisting of rhodium octanoate

Rh2(Oct)4, rhodium acetate Rh2(Ac)4, rhodium acetamide Rh2(HNAc)4 and rhodium trifluoroacetate Rh2(θ2CCF3)4.

Illustrated below as a catalyst for use in the process described herein is Rh2(Oct)4, present in a catalytic amount which is effective for converting the diazo compound 2 to the bicyclic ketoester 1.

The term "Lewis Acid" is used herein to refer to those Lewis acids which are effective in forming the 1-beta methyl isomer upon cyclization, and for substantially preventing isomerization of the 1-beta methyl isomer to the less desirable 1 -alpha methyl isomer. Examples of suitable Lewis acids include but are not limited to the following: MgCl2, MgBr2, Mg(OAc)2, Mg(θ3SCF3)2, ZnCl2, ZnBr2, Zn(OAc)2- Zn(03SCF3)2, SnCl2, SnBr2, Sn(θ3SCF3)2, SnCl4, SnBr4, TiCH, Ti(OiPr)4,TiCl _n (OiPr)4-n, with n = 0, 1, 2, 3 or 4, CaCl2, CaS04, GaCl3, FeCl2, FeCl3, CuCl, CuBr, CuCl2, CuBr2, PdCl2, Pd(OAc)2, BF3-OEt2, BC13, R2B(θ3SCF3), with R = Cl-4 alkyl), BBr3, B(OPh)3, B(OCH3)3, AICI3, LiCl and UCIO4.

As used above, the abbreviation Ac means acetate (CH3C(0)-); Et means ethyl, Ph means phenyl and OiPr means isopropoxide (-OCH(CH3)2). With respect to the titanium catalyst noted above, Ti(OiPr)4 refers to titanium isopropoxide (Ti(OCH(CH3)2)4.

The term Cl-4 alkyl means -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3 and -C(CH3)3-

A subset of the Lewis acids for use in the process described herein is comprised of ZnBr2 and MgCl2 .

Illustrated below is the Lewis acid ZnBr2 used in the process described herein.

The Lewis acid is typically used in a catalytic amount, which is an amount that is effective for forming the 1-β methyl isomer, and for preventing the epimerization of the 1-β methyl isomer to the 1-α methyl isomer. This amount typically ranges from about 0.1 to about 10 mole %, with the preferred concentration being around 1 mole %.

In the process described above, the hydroxyl group of the hydroxyethyl side chain can be unprotected or in protected form. Hence,

P represents hydrogen or a hydroxyl protecting group. Examples of suitable hydroxyl protecting groups P are: t-butylmethoxyphenylsilyl, t- butyldimethylsilyl (TBDMS), t-butoxydiphenylsilyl, trimethylsilyl (TMS), triethylsilyl (TES), o-nitrobenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl, 2,2,2- trichloroethyloxycarbonyl and allyloxycarbonyl.

A subset of the hydroxyl protecting groups used in the present invention is comprised of TES, TMS and TBDMS.

Likewise, in the process, the carboxyl group is typically in protected form. Examples of suitable carboxyl protecting groups M are: benzhydryl, o-nitrobenzyl, p-nitrobenzyl (PNB), 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl, t- butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl, 2- (trimethylsilyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, p- methoxyphenyl, 4-pyridylmethyl and t-butyl.

A subset of the carboxyl protecting groups is comprised of TBDMS and PNB. The carboxyl protecting group PNB is illustrated below.

Many other suitable hydroxyl and carboxyl protecting groups are known in the art. See, e.g., T.W. Greene, Protective Groups in Organic Synthesis. John Wiley & Sons, Inc., 1981 (Chapters 2 and 5).

The invention is further described in connection with the following non-limiting examples.

EXAMPLE 1

1a C0 ₂ PNB

Compound 2a (43.2 g, 0.111 mol) is slurried in MeOAc (987 mL). A solution of ZnBr2 (246.8 mg) in THF (24.68 mL) is added, followed by a solution of Rh2θct4 (259 mg) in MeOAc (130 mL). The mixture is heated at reflux for 90 minutes, followed by liquid chromatography with 40:60 CH3CN:H2θ (0.1% H3PO4), 1.5 mL/min, YMC-AQ C-18, 260 nm, Retention Time (RT) 2a = 7.6 min., RT of la = 3.2 min., RT of the 1-α methyl isomer = 3.3 min.

Liquid Chromatography assay showed 87.5% yield of 1-β- methyl compound la, and no detectable 1-α methyl isomer.

EXAMPLE 2

Using the procedure set forth in Example 1, the Lewis acid ZnBr2 is replaced with MgCl2-

EXAMPLE 3

The procedure set forth in Example 1 is repeated, except that the triethylsilyl (TES) substituted compound 2b is reacted in place of compound 2a, producing compound lb.

EXAMPLE 4

1c C0 ₂ -TBDMS

The procedure set forth in Example 1 is repeated, except that the TBDMS -substituted compound 2c is reacted in place of compound 2, producing compound lc.

EXAMPLE 5

For purposes of comparison, Rhodium octanoate (1.05 mg) in methyl acetate (0.525 mL) was added to compound 2a (175 mg) in methyl acetate (4 mL). The solution was refluxed for 2.0 h. LC analysis showed the presence of la and the 1-α-methyl compound in a molar ratio of 4:88.

Using the same lots of materials as above, rhodium octanoate (1.05 mg) in methyl acetate (0.525 mL) and MgCl2 (0.42 mg) in THF (0.1 mL) were added to compound 2a (175 mg) in methyl acetate (4 mL). The solution was refluxed for 2.0 h. LC analysis showed the presence of la and the 1-α-methyl compound in a molar ratio of 93:1.