Enantioselective synthesis of azetidinone intermediate...

Details Enantioselective synthesis of azetidinone intermediate... Enantioselective synthesis of azetidinone intermediate...

2002-03-25

2003-09-30

Morris, Patricia L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06627757

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to a process for producing intermediates for hydroxy-alkyl substituted azetidinones. Hydroxy-alkyl substituted azetidinones, for example, 1-(4-fluorophenyl)-3(R)-[3(S)-hydroxy-3-(4-fluorophenyl)propyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone, are described in U.S. Pat. No. 5,767,115. These compounds are useful as hypocholesterolemic agents in the treatment and prevention of atheroschlerosis.
Processes for preparing the corresponding azetidinone without the 3-hydroxy substituent are claimed in U.S. Pat. Nos. 5,728,827 and 5,561,227. Other processes for preparing 1-(4-fluorophenyl)-3(R)-[3(S)-hydroxy-3-(4-fluorophenyl)-propyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone are disclosed in U.S. Pat. Nos. 5,631,365, 5,739,321 and 6,207,822 B1 (the '822 patent).
As per the procedure described in the '822 patent, the intermediate compound of Formula I, is protected with a suitable hydroxy-protecting group, such as a silyl protecting group such as that derived from chlorotrimethylsilane (TMSCI) or t-butyldimethyl-silyl chloride (TBDMSCI). This silylated product is further reacted with a silyl-enol ether silylating agent such as bistrimethylsilyl acetamide (BSA). A cyclizing agent such as a quaternary alkyl-, aryl-alkyl or arylalkyl-alkylammonium fluoride salt is then added to cause an intra-molecular cyclization of the previously silylated compound of Formula I. Finally, the protecting groups are removed from the cyclizied compound using conventional methods, such as treatment with a dilute acid, in order to form the hypocholesterolemic azetidinone having the Formula
SUMMARY OF THE INVENTION
This invention provides an improved, simple, high yielding process for preparing an intermediate compound useful in the production of azetidinones. The intermediate, a compound of Formula I:
is prepared by a process which comprises:
a) mixing a compound of Formula II
in tetrahydrofuran in the presence of an acid, or alternatively in tetrahydrofuran in the absence of an acid, to form a mixture;
b) combining the mixture of step a) with a catalyst selected from either (A) a compound selected from the group of compounds represented by Formula III, or (B) a compound of Formula IV,
wherein R
1
of Formula III is a (C
1
-C
6
)alkyl and wherein R and S indicate stereochemistry at the chiral carbons;
c) reducing the ketone adjacent to the p-fluorophenyl with a borane-tetrahydrofuran complex; and
d) quenching the reaction with MeOH.
DETAILED DESCRIPTION
In one embodiment, there is described herein a process for preparing a compound of Formula I
which comprises the steps (a)-(d) shown above.
In a preferred embodiment, the process comprises:
a) mixing a compound of Formula II in tetrahydrofuran in the presence of an acid to form a mixture;
b) combining the mixture of step a) with a catalyst selected from either (A) a compound selected from the group of compounds represented by Formula III, or (B) a compound of Formula IV
wherein R
1
of Formula III is a (C
1
-C
6
)alkyl and wherein R and S indicate stereochemistry at the chiral carbons;
c) reducing the ketone adjacent to the p-fluorophenyl with a borane-tetrahydrofuran complex; and
d) quenching the reaction with MeOH.
Except where stated otherwise, the following definitions apply throughout the present specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms. Hence the definition of “alkyl” applies to “alkyl” as well as to the “alkyl” portions of “alkoxy”, “alkylamino” etc.
“Alkyl” represents a straight or branched saturated hydrocarbon chain having the designated number of carbon atoms. Where the number of carbon atoms is not specified, 1 to 6 carbons are intended.
The acid in step a) is selected from the group consisting of BF
3
.OEt
2
, BCl
3
, p-toluene sulfonic acid, trifluoroacetic acid, methanesulfonic acid and camphorsulfonic acid.
If the catalyst of Formula IV is employed, it must be used in the presence of a trialkyl borate, preferably a trimethyl borate.
In another embodiment of the present invention, the ratio of the acid to the compound of Formula II is in a mole % of 1-10%, preferably 1-5%, more preferably in a mole % of 2-3%.
In another embodiment of the present invention, the ratio of the catalyst to the compound of Formula II of step b) is in a mole percent of 0.1-10%, preferably 1-5%, more preferably in a mole % of 2-3%.
In further embodiments of the present invention, the temperature of the reduction step c) is generally between −15 and 65° C., preferably between −10 and 55° C., more preferably between 0° and 30° C. and typically between 230 and 28° C.
In another embodiment of the invention, there is described a process for preparing a compound of Formula I
which process has no acid in step (a). The process, thus, comprises:
a) dissolving a compound of Formula II in tetrahydrofuran to form a mixture;
b) combining the mixture of step a) with a catalyst selected from either (A) a compound selected from the group of compounds represented by Formula III, or (B) a compound of Formula IV
wherein R
1
of Formula III is a (C
1
-C
6
)alkyl and wherein R and S indicate stereochemistry at the chiral carbons;
c) reducing the ketone adjacent to the p-fluorophenyl with a borane-tetrahydrofuran complex; and
d) quenching the reaction with MeOH.
In a preferred embodiment of the alternate process (with no acid in step (a)) described immediately above, the temperature of the reduction step c) is between 23 and 28° C.
In another embodiment of the alternate process (with no acid in step (a)) described immediately above, the ratio of the catalyst to the compound of Formula II of step b) is in a mole % of 0.1-10%, preferably 1-5%, more preferably in a mole % of 2-3%.
The present invention discloses a novel chemo selective and stereo selective reduction of the ketone adjacent to the p-fluorophenyl using a BH
3
-THF complex. In a previous process patent, U.S. Pat. No. 6,207,822 B1 (the '822 patent), the disclosure of which is incorporated herein by reference thereto, there is disclosed a reduction of said ketone using BH
3
Me
2
S (BMS) complex as a reducing agent. However, use of said BMS complex may lead to environmental concerns. The replacement of BMS with borane tetrahydrofuran complex eliminates the environmental issues raised by use of the BMS complex.
However, simple replacement of BH
3
Me
2
S with BH
3
-THF in the reduction generated a substantial amount of over-reduction of the amide bond, compared to the reduction of the ketone adjacent to the p-fluororophenyl, thus resulting in poor selectivity. Thus, initial experiments with BH
3
-THF yielded a desirable % of desired enantiomer (SS) to the undesired enantiomer (SR), however, the solution yield was not optimized due to the production of the above-noted over-reduced by-product from the amide. Applicants found, in the present process, that reversing the addition sequence surprisingly overcame the poor chemoselectivity in the reduction. The production of the over-reduced by-product from the amide was significantly reduced while at the same time resulting in high diasteroselectivity in the product.
The new process calls for adding BH
3
-THF to the solution of Formula II and (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborolidine (abbreviated as (R)-MeCBS) catalyst in THF (from Sigma-Aldrich, St. Louis, Mo.). Several experiments yielded results where the over-reduced by-product was minimized to <1% with diastereoselectivity of 97:3. In fact, the molar equivalent (eq) of BH
3
-THF was kept to ~0.6 eq, while % molar yields were generally over 97%. Similar results could be obtained with a “in-situ” prepared catalyst using the compound of Formula IV (R-diphenylprolinol) and trimethylborate. (See reference: M. Masui, T. Shioiri, Synlett, 1997, 273).
The following examples used to prepare the compound of Formula I illustrate the present invention, although such examples should not be construed as

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