CA2058223A1 - Process for preparing beta-lactams - Google Patents

Abstract

ABSTRACT
A wide range of compounds having a .beta.-lactam (2-azetidinone) ring are prepared by the condensation reaction of cerium (III) ester enolates with both enolizable and non-enolizable imines in good yields and with high (usually cis) stereoselectivity.

Description

FIELD OF THE INVEN~ION 2 0 ~ 8 2 2 ~

This invention relates to a process for the production of ~-lactams from the condensation reactions of metal ester enolates with imines.

BACKGROUND OF THE INVENTION

The group of compounds possessing the B-lactam (2-azetidinone) ring has the following general chemical structural formula:

¦2'N
( 1 ) 0~ ~R5 in which the various R groups represent organic radicals described more fully below.

Many of these compounds possess desirable medicinal properties and fall into the family of compounds known as ~-lactam antibiotics. Penicillins and cephalosporins are examples of classes of well known ~-lactam antibiotics.

Due to the importance of this class of compounds, considerable efforts have been directed towards the development of processes for the synthesis of B-lactams.
The condensation reaction of metal ester enolates with imines is one of the better methods for the synthesis of B-lactams.

Until now, lithium ester enolates have been the most generally applicable of these reagents for ~-lactam synthesis. Equation I shows the condensation of lithium ester enolate (2) and imine (3) to give B-lactam (1).

Rl R2 ~ ~ R~ R2 RoO X oLi R5 (2) (3) (1) 20S8~2~

The various R groups represent organic radicals more fully described below.

When R1 is different from R2, the 3 position (C3) in the B-lactam ring is a chiral centre. Similarly, when F~
and R4 are different, the 4 position (C4) of the B-lactam ring is a chiral centre. Many desirable B-lactams have chiral centres at C3 and C4 and may have only one useful stereoisomer. Therefore, it is important that the condensation reaction be stereoselective. The condensation reaction shown in Equation I is highly cis-stereoselective.
An R group at C3 of B-lactam (1) is cis to an R group at C4 when both are located on the same side of the plane defined by the B-lactam ring. Also, good enantioselectivity is observed when an R qrOup of the lithium ester enolate has a chiral centre. However, the high basicity and poor nucleophilicity of lithium ester enolates limit the applicability of this process. It has been found that lithium ester enolates generally do not react well with enolizable imines, i.e. where R3, R4, or F~ in imine (3) has a hydrogen atom to the carbon or nitrogen of the imino group. In this case the lithium ester enolate simply removes the proton of the imine, seriously diminishing the yield of B-lactam. An exception to this general case - is that lithium ester enolates will react with both enolizable and non-enolizable N-trimethylsilyl imines to give N-unsubstituted B-lactams in good yields. Lithium ester enolates are poor nucleophiles, and therefore they do not react well with sterically hindered imines. Because imines are often unstable, decomposition of the imine may occur before it reacts with the lithium ester enolate.

The use of other metal ester enolates has produced mixed results. Zinc and aluminum ester enolates generally react with both enolizable and non-enolizable imines and may produce good yields of B-lactams, however generally with lower stereoselectivity than lithium ester enolates.

, 20~8223 Boron, tin (II) and zirconium enolates may also produce good yields of B-lactams under certain conditions, stereospecifically producing cis or trans *-lactams, however, a separate ring closure step is required.

The limitations of the above reagents in producing B-lactams means that all of the above B-lactam syntheses lack generality.

SUMMARY OF THE INVENTION

The present invention provides a new and useful general process for the preparation of B-lactams via the condensation reaction of imines with cerium ester enolates.

Thus, according to the present invention, there is provided a process for preparing B-lactams of general formula (1) by reacting a cerium ester enolate of formula (4):

R~ R2 (4) X
RoO OCeX2 wherein X is halide or the conjugate base of a strong acid;
ORo is a leaving group where R~ represents a saturated or unsaturated hydrocarbon group which may contain any functionality whatever, so long as it is unreactive with the ester enolate; and R1 and R2 represent non-anion-stabilizing groups selected from hydrogen, lower alkyl, aryl, alkaryl, lower dialkylamino, di(trialkylsilyl)amino, diarylamino, dialkarylamino, alkoxy, phenoxy, aryloxy, and alkaryloxy, or R1 and R2 taken together with the C3 carbon of the B-lactam ring form an aliphatic ring; with an imine of general formula (3):

F~ ~ R~

(3) N~

wherein R3, R4 and F~ represent non-electron-donating, saturated or unsaturated, hydrocarbon groups, optionally substituted with one or more functional groups at positions electronically isolated (i.e. unconjugated) from the site of attachment to the B-lactam ring. Rs may also represent a lower trialkylsilyl group.

The cerium ester enolates are prepared by a known method from esters of the following general formula:

R1 ~ R~

(5) RbO ~ o wherein Fb, R1 and F~ are as defined above.

Cerium ester enolates are much more nucleophilic and have much lower basicity than their lithium analogs. This allows cerium ester enolates to react with most non-enolizable and enolizable imines to give B-lactams. As mentioned above, lithium ester enolates generally do not react with enolizable imines to produce B-lactams. It has been found according to the present invention that the higher nucleophilicity of cerium ester enolates allows them to react with sterically hindered imines and with unstable imines before they can decompose. Since cerium ester enolates are more nucleophilic than their lithium counterparts, they are reactive with imines at temperatures as low as -78C, whereas lithium ester enclates are generally not very reactive below 0C. Since many imines are not stable at or above O~C, it is advantageous to carry out the reaction at as low a temperature as possible. The reaction is highly stereo selective, usually producing the cis B-lactam exclusively in good yields, without a separate ring closure step. Good enantioselectivity is also observed when the starting cerium ester enolate (4) or the imine (3) contains a chiral centre.

Cerium, the first element in the lanthanide series of metals, is cheap, plentiful and has low toxicity. Several cerium (III) salts are commercially available, so that the process of the present invention is commercially attractive.

Equation (II) shows the general condensation reaction of imines with cerium ester enolates.

R2 R~,R~
II ~O ~ OCeX2 N~Rs ~ N~

(4) (3) (1) DESCRIPTION OF THE PREFERRED EMBODIMENTS

Good yields of B-lactams are obtained using a wide variety of substituents X and R~-R~, with most reactions yielding 90 to 100% of the theoretical yield of B-lactam.

The choice of groups R1 and R2 is largely determined by the requirement that the acidity constant, pKa, of the ~
hydrogen atom shown in starting ester (5) should be maintained at a high level, i.e. the pXa of the ~ hydrogen should not be lower than about 20-25. Accordingly, R~ and R2 may be hydrogen, lower alkyl, aryl, alkaryl, lower dialkylamino, di(trialkylsilyl)amino, diarylamino, dialkarylamino, alkoxy, phenoxy, aryloxy, alkaryloxy, or R1 and R~, taken together with the C3 carbon of the B-lactam ring, may form an aliphatic ring. R1 and R2 should not be anion-stabilizing groups, which have the effect of lowering the pKa of the hydrogen. Nitro, carbonyl and cyano groups are examples of common anion-stabilizing groups which should not be used.

The choice of appropriate R3, R4 and ~ groups is largely determined by the requirement that they should not unduly diminish the electrophilicity of the imino group.
The steric bulk of these groups is not of so much concern because sterically hindered imines will react with cerium ester enolates. Accordingly, appropriate choices of R3, R4 and F~ include lower alkyl, aryl or alkaryl. F4, which is attached the imino nitrogen, may also be an acyl or lower trialkylsilyl group. Groups such as alkoxy and amino are electron-donating and tend to make the imine less electrophilic, and therefore should not be used.

Because ORb is merely a leaving group and is not near the reaction site, the identity of Fb has little effect on the reaction. Thus F~ may generally be defined as any alkyl, aryl or alkaryl group, substituted or unsubstituted, so long as it is unreactive with the ester enolate.

Similarly, the identity of X has little effect on the reaction. X may be halide or the conjugate base of a strong acid, examples of conjugate bases being oxalate, sulfate, and trislate.

The cerium ester enolates may be prepared by treatment of the starting ester (5) with lithium (di-lower alkyl) amine, followed by transmetallation with the cerium (III) 20~8223 salt. Both steps are suitably carried out at low temperatures, e.g. -78C, in a coordinating solvent such as an ether, as exemplified by tetrahydrofuran (THF), in the absence of water and under an inert atmosphere, suitably an argon atmosphere. The resulting product mixture may be used directly in the condensation reaction.

A solution of the imine in a solvent such as THF is then suitably added slowly to the pre-formed cerium ester enolate suspension and the resulting mixture is stirred until completion of the reaction. The ratio of cerium ester enolate to imine is preferably about 2:1, however higher and lower ratios may also produce good yields of B-lactam. The B-lactam is then isolated from the product mixture, suitably by acidification of the mixture followed by extraction of the product in a suitable organic solvent.
The crude product may then be purified, suitably by flash chromatography on silica gel or by recrystallization.

As can be seen from formula (6), which shows a general formula for penicillins, and formula (7), which shows a general formula for cephalosporins, the B-lactam ring forms an integral part of these classes of B-lactam antibiotics.
Many of these compounds may be prepared from B-lactams produced according to the present invention.

RCOt~ <CH3 RCONH ,S
2S (7) O

20~8223 DESCRIPTION OF THE MOST PREFERRED EMBODIMENTS

Preparation of methyl 2-(dichlorocerio)-3-methylbutanoate Powdered cerium trichloride heptahydrate (1.00 g, 2.70 mmol) was dried at 100C (0.1 mmHg) for 10 h, then at 150C
(0.1 mmHg) for 2 h. The dried cerium chloride was cooled to room temperature under vacuum and vented to an argon atmosphere. Dry THF (5.5 mL, ca. 2 ml for 1 mmol of CeCl3) was added and the resulting suspension was stirred vigorously for 2 h under argon to get a fine suspension of cerium chloride in THF. To a stirred solution of diisopropylamine (0.42 mL, 304 mg, 3.0 mmol) in dry THF (10 mL) was added n-BuLi (1.3 mL, 2.5 M in hexane, 3.3 mmol) dropwise at -78C and the resulting solution was stirred for 20 min. Methyl 3-methylbutanoate (325 mg, 2.80 mmol) in dry THF (2 mL) was added to lithium diisopropylamide (LDA) solution at -78C dropwise and stirred for 30 min.
This solution of lithium ester enolate in dry THF was transferred to the cerium chloride suspension in THF, precooled to -78C, via a cannula. ~he resulting mixture was stirred for 2 h at -78C to generate methyl 2-(dichlorocerio)-3-methylbutanoate.

Following the procedure described in Example 1 but substituting for methyl 3-methylbutanoate an ester described in Table l, there are produced the cerium ester enolates described in Table 1.

20~8223 Example Ro Rl R2 3 -CH3 CH2CH3 CHzCH3 4 -CH3 -CH2CH2CH2cH2 --CH3 --CH2CHzCH2cH2cH2 6 -CH3 -CH2CH ( CH3 ) 2 -H

9 -CH3 -N ( CH3 ) 2 -H
-CH3 -CH3 ~ (C6H5) Example ll Preparation of cis-3,4-diisopropyl-1-phenyl-2-azetidinone A solution of aniline N-isobutylidene (180 mg, 1.22 mmol) in THF (4 mL) was added dropwise with a syringe to the pre-formed methyl 2-(dichlorocerio)-3-methylbutanoate (2.70 mmol) as described in Example 1 in THF (20 mL) at -78-C. The resulting mixture was stirred at -78C for 3 h under an atmosphere of argon. Saturated aqueous NH4C1 was added to the mixture at -78C and the resulting mixture was extracted with Et20-hexane (3 x 20 mL). The combined organic extracts were washed with water and brine and dried over MgSO4. Removal of the solvent in vacuo gave the crude product which was purified by flash chromatography on silica gel (5% EtOAc in hexane) to give cis-3,4-diisopropyl -1-phenyl-2-azetidinone in 98% yield (276 mg) as a white crystal: mp 91-92~C (hexane).

Employing the procedure substantially as described in Example 11 but substituting for methyl-2-(dichlorocerio)-3-methylbutanoate and aniline N-isobutylidene (for Examples 12 and 22 only) the cerium ester enolates and imines identified in Examples 12-22 of Table 2, there are produced the 2-azetidinones described in-Table 2. R1 and R3 are cis to each other in the B-lactam products of Table 2.

~D

.

N N N N N N N N N N ~
U~UUUUU~UU Z
~^_____---------- a~
pl~l U U ~ U ~ 5 ~ 5 U ~ ~ C

~ O

U U U N ,~

UUUUOUOOSU~) ii æ~ U U C) U U , ~ , I I I c While the inventlon has been de~cribed with particular reference to certain variables in the proceas conditions and compound substituents, it is to be understood that the invention embraces related processe~ and substituents which S are obvious extensions of those disclosed.

' ' :
~' , :
'' ` ,`'~ ' ~ ~ `

Claims (10)

1. A process for preparing .beta.-lactams of the general formula:

(I) wherein R1 and R2 are the same or different and both represent non-anion-stabilizing groups selected from; hydrogen, lower alkyl, aryl, alkaryl, lower dialkylamino, di(trialkylsilyl)amino, diarylamino, dialkarylamino, alkoxy, phenoxy, aryloxy, and alkaryloxy or R1 and R2 taken together with the carbon atom at the C3 position of the .beta.-lactam ring may form an aliphatic ring;
R3, R4 and R5 are non-electron-donating, saturated or unsaturated, hydrocarbon groups, optionally substituted with one or more functional groups at positions remote from the site of attachment to the .beta.-lactam ring; and R5 may additionally represent lower trialkylsilyl or acyl:

which comprises reacting a cerium ester enolate of the general formula:

(II) wherein X is halide or the conjugate base of a strong acid;

R0 represents a non-anion-stabilizing, saturated or unsaturated, hydrocarbon group; and R1 and R2 are as defined in formula (I);

with an imine of the general formula (III) wherein R3, R4 and R5 are as defined in formula (I); in an appropriate organic solvent under an inert atmosphere.

2. The process of claim 1 wherein R1 and R2 are selected from hydrogen, lower alkyl, dimethylamino and phenoxy; or R1 and R2 together with the carbon atoms at the C3 position of the .beta.-lactam ring form a 5 or 6 membered saturated hydrocarbon ring.

3. The process of claims 1 or 2 wherein R3 is isopropyl or phenyl.

4. The process of any one of claims 1-3 wherein R4 is hydrogen.

5. The process of any one of claims 1-4 wherein R5 is phenyl or trimethylsilyl.

6. The process of any one of claims 1-5 wherein R0 is lower alkyl.

7. The process of any one of claims 1-6 wherein X is chloride.

8. The process of any one of claims 1-7 wherein the organic solvent is an ether.

9. The process of any one of claims 1-8 wherein the organic solvent is tetrahydrofuran.

10. The process of any one of claims 1-9 wherein the ratio of molar equivalents of cerium ester enolate (II) to imine (III) is 2:1.