Process for making (2S, 3S, 5S) oxetanone derivatives

Abstract

This invention relates to novel processes for making (2S, 3S, 5S) oxetanone derivative lipase inhibitor compounds and intermediates therefor, which processes for producing such derivatives that are useful as lipase inhibitors are capable of being scaled to commercial quantities. Further the invention relates to processes for producing salts and for producing pharmaceutical compositions compounds comprising at least one such oxetanone derivative or salt, as well as methods for using such compounds and compositions for inhibiting lipases.

What is claimed is:  
     
         1 . A process for making in at least 70% enantiomeric purity a (3S, 4S, 6S) oxetanone compound of the formula (I):  
       
         
           
           
               
               
           
         
       
       or a salt thereof 
 wherein: 
 R 1  and R 3  are each independently a C 1  to C 18  straight or branched alkyl hydrocarbon chain, and  
 R 2  is hydrogen or an alcohol protecting group R 10 , wherein R 10  can be replaced by a hydrogen atom via ester hydrolysis or hydrogenation ether degradation, comprising the steps of:  
 
 (a) selectively hydrogenating a composition comprising a compound which is a member selected from the group consisting of (6R) tetrahydro-2H-pyran-2-one compound of formula (II) and (6R) 5,6-dihydro-2H-pyran-2,4-dione of formula (IIa):  
                     
 wherein 
 R 5  is hydrogen or an alcohol protecting group, which can be replaced by a hydrogen atom via hydrogenation, and R 1  and R 3  are defined as in formula (I), by hydrogenating the compound of formula II with a hydrogenation catalyst selected from the group consisting of PtO 2 , Raney Nichel and the like, and exchanging hydrogen atoms at the 3 and 4 ring positions or oxidizing the 4-oxo group to provide a (3S, 4S, 6R) 4-hydroxy-tetrahydro-2H-pyran-2-one compound of the formula (III):  
                     
 
 wherein R 1  and R 3  are defined as in formula (I);  
 (b) re-protecting the 4-hydroxy group of the compound of formula (II) produced in (a) with an ether protecting group R 6 , which can be replaced by a hydrogen atom via ester hydrolysis or hydrogenation ether degradation, opening the lactone ring and esterifying the resulting free acid group to provide a (2S, 3S, 5R) [R 7 ]2-[R 3 ]-3-[R 6- oxy]-5-[hydroxy, R 1 ]pentanoic acid ester compound of the formula (IV):  
                     
 wherein 
 R 1  and R 3  are defined as in formula (I), R 6  is an alcohol protecting group, which can be replaced by a hydrogen atom via ester hydrolysis or hydrogenation ether degradation, and  
 R 7  is an ester group which can be removed by base or acid hydrolysis, or by hydrogenation;  
 
 (c) inverting the chirality of the 5-hydroxy group of the compound of formula (IV) produced in step (b), wherein the inversion comprises a step which is a member selected from the group consisting of 
 (iv) a Mitsunobu reaction,  
 (v) esterifying the 5-hydroxy group to a carboxylic acid ester such as the trichloroacetic acid ester, and the like, and hydrolyzing the resultant ester in a water ether solvent such as 3:1 H 2 O/dioxane, and  
 (vi) esterifying the 5-hydroxy group to a sulfonic acid ester, such as p-toluene sulfonic acid ester and the like, and reacting the ester with an excess of an organic acid salt selected from the group consising of potassium acetate, sodium acetate, tetraethylammonium acetate, and the like, to provide an ester exchange with the organic acid,  
 
  wherein the free inverted (5S) 5-hydroxy group of (i) and (ii) is esterified with a hydroxy protecting group R 10  which can be which can be replaced by a hydrogen atom via ester hydrolysis or hydrogenation ether degradation, to provide a compound of the formula (V):  
                     
 wherein 
 R 1  and R 3  are defined as in formula (I),  
 R 6  is an alcohol protecting group, which can be replaced by a hydrogen atom via ester hydrolysis or hydrogenation ether degradation,  
 R 9  is an ester group which can be removed by base or acid hydrolysis, or by hydrogenation, and  
 R 10  is an alcohol protecting group, which can be replaced by a hydrogen atom via ester hydrolysis or hydrogenation ether degradation, and wherein R 10  is selectively removable with respect to the R 6  alcohol protecting group; and  
 
 (d) selectively removing the R 6  alcohol protecting group and R 9  ester group of the compound of formula (V) produced in (c), and cyclizing the 3 position alcohol group with the 1 position acid group using a lactone cyclizing catalyst, such as benzene-sulphonyl chloride, in a solvent such as pyridine at a temperature of about −10 to 10° C. and optionally replacing the R 10  alcohol protecting group of formula (V) with a hydrogen atom, to yield a (3S, 4S, 6S) oxetanone compound of the formula (I):  
                     
 or a salt thereof.  
 
     
     
         2 . A process according to  claim 1 , providing a compound of formula (I) wherein R 1  is undecyl, R 3  is hexyl and R 2  is hydrogen, which is (2S, 3S, 5S) tetrahydroesterastin.  
     
     
         3 . A process according to  claim 1 , In another aspect the present invention relates to coupling such compound of formula (I) to an acyl compound via an acid or base esterification procedure without inversion of the 5S hydroxy group.  
     
     
         4 . A process according to  claim 1 , wherein the compound of formula (II) or (IIa) in step (a) is present at a ratio of from 90 to 100% with respect to the corresponding (6S) enantiomer.  
     
     
         5 . A process according to  claim 3 , wherein the compound of formula (II) or (IIa) in step (a) is present at a ratio greater than 97% with respect to the corresponding (6S) enantiomer.  
     
     
         6 . A process according to  claim 1 , further comprising isolating a compound which is a member selected from the group consisting of the 6R compound of formula (IV), or its corresponding (6R, 3RS, 4RS) racemate with an alcohol protected 3 hydroxyl group, from a compound which is a member selected from the 6S, 3R, 4R enantiomer with an alcohol protected 3 hydroxyl group corresponding to the compound in formula (IV) and a compound which is the (6S, 3RS, 4RS) racemate corresponding to the compound of formula (IV), comprising a separation step with is a member selected from the group consisting of: 
 (i) selectively esterifying the 6-position hydroxyl group in the presence of a lipase such as PS 30, porcine pancreas lipase, and the like, and separating the ester from the alcohol,    (ii) selectively hydrolyzing an ester an ester of the 6-position hydroxyl group via a lipase such as PS 30, porcine pancreas lipase, and the like, and separating the ester from the alcohol,    (iii) forming a chiral salt with a chiral alcohol resolving agent such as L-alaninol, D-alaninol, L-tartaric acid, D-tartaric acid, S-methylbenzyl-amine, D-methylbenzylamine in an appropriate solvent such as methyl acetate, and the like, and separating the two enantiomers by re-cyrstallization; and    (iv) other known chiral alcohol separating procedures, and removing any ester or protecting groups from the 6R chiral hydroxyl group.    
     
     
         7 . A process according to  claim 1 , further comprising the steps of 
 (a) inverting the 5S hydroxyl group of a (2R, 3R, 5S or 2RS, 3RS, 5S) [R 7 ]2-[R 3 ]-3-[R 6- oxy]-5-[hydroxy, R 1 ] pentanoic acid ester compound of the formula (VII):                          wherein 
 R 1 , R 3 , R 6  and R 7  are defined as in formula IV;  
   wherein the inversion comprises a step which is a member selected from the group consisting of 
 (v) a Mitsunobu reaction, and freeing the hydroxyl group  
 (vi) esterifying the 5-hydroxy group to a carboxylic acid ester such as the trichloroacetic acid ester, and the like, and hydrolyzing the resultant ester in a water ether solvent such as 3:1 H 2 O/dioxane to the inverted hydroxyl group,  
 (vii) esterifying the 5-hydroxy group to a sulfonic acid ester, such as p-toluene sulfonic acid ester and the like, and reacting the ester with an excess of an organic acid salt selected from the group consising of potassium acetate, sodium acetate, tetraethylammonium acetate, and the like, to provide an ester exchange with the organic acid, and hydrolyzing the organic acid ester to the inverted hydroxyl group,  
 (viii) other known chiral alcohol inversion procedures,  
   (b) hydrolyzing the R 7  ester group to provide the free acid compound of the formula (VIII):                          wherein 
 R 1 , R 3  and R 6  and R 7  are defined as in formula (VII), and  
   (c) cyclizing the inverted alcohol group of the compound of formula (VIII) with the 1 position acid group in the presence of a lactone cyclizing catalyst such as tonuene-4-sulfonic acid monohydrate in an alcohol at about 50-60° C. to provide a 6R tetrahydro-2H-pyran-2-one compound of formula (IX):                          wherein 
 R 1 , R 3 , R 6  and R 7  are defined as in formula (VIII); and  
   (d) selectively hydrogenating the (6R) tetrahydro-2H-pyran-2-one compound of formula (IX) with a hydrogenation catalyst selected from the group consisting of PtO 2 , Raney Nichel and the like, and exchanging hydrogen atoms at the 3 and 4 ring positions to provide a (3S, 4S, 6R) 4-hydroxy-tetrahydro-2H-pyran-2-one compound of the formula (IV):                          wherein R 1  and R 3  are defined as in formula (I).    
     
     
         8 . An intermediate compound according to the formula:  
       
         
           
           
               
               
           
         
         wherein: 
 R 1  and R 3  are each independently a C 5  to C 18  straight or branched alkyl chain which can be interrupted by 1 or 2 alkenyl double bonds, and  
 R 2  is hydrogen or an alcohol protecting group R 10 , wherein R 10  can be replaced by a hydrogen atom via ester hydrolysis or hydrogenation ether degradation, and R 10  is selectively removable with respect to the R 6  alcohol protecting group, or, a salt thereof.  
 
       
     
     
         9 . A compound according to  claim 8 , wherein R 1  is undecyl and R 3  is hexyl or, a salt thereof.