Process for synthesizing beta-lactamase inhibitor intermediates

Abstract

There is provided a process for the preparation of bicyclicheteroaryl carboxaldehydes having the structural Formula I where X and Y are defined in the specification The bicyclic heteroaryl carboxaldehydes are useful as intermediates in the preparation of β-lactamase inhibitors.

1 . A process for the preparation of bicyclic heteroaryl carboxaldehydes of Formula I  
     
       
         
         
             
             
         
       
       wherein:  
       Y is (CH 2 ) n ;  
       n is 1 or 2;  
       X is NR, O, or S;  
       R is alkyl of 1 to 6 carbon atoms, or arylalkyl(C 1  to C 6 );  
       provided n is 2 when X is NR or O;  
       which process comprises the steps of:  
       a. nitrosating an amino acid I of the formula  
       
         
           
           
               
               
           
         
       
       wherein X and Y are defined as above with a nitrosating reagent to form a nitroso compound of formula 2 wherein X and Y are defined as above  
       
         
           
           
               
               
           
         
       
       b. reacting the nitroso compound 2 with a dehydrating agent and neutralizing with an inorganic base to form the ylide of formula 3 wherein X and Y are defined as above  
       
         
           
           
               
               
           
         
       
       c. reacting the ylide of formula 3 with a propiolate ester of formula 4  
         HC≡CCO 2 R 1    4  
       where R 1  is alkyl of 1 to 6 carbon atoms, in aprotic solvents to form a mixture of bicyclic-heteroaryl-3-carboxylate ester of formula 5 and bicyclic-heteroaryl-2-carboxylate ester of formula 6 wherein R 1 , X and Y are defined as above  
       
         
           
           
               
               
           
         
       
       d. reacting the mixture of bicyclic-heteroaryl-3-carboxylate ester 5 and bicyclic-heteroaryl-2-carboxylate ester 6 with a hydrolyzing reagent MOR 5  where M is an alkali metal or R 4 N where R 4  is straight or branched alkyl of 1 to 6 carbon atoms when R 5  is H, in an alcohol solvent, or when M is an alkali metal and R 5  is alkyl of 1 to 6 carbon atoms in an aqueous alcohol solvent to preferentially form a salt 7 of the formula wherein X, Y and M are defined as above  
       
         
           
           
               
               
           
         
       
       e. isolating the salt 7;  
       f. reacting the salt 7 with acid to form bicyclic-heteroaryl-2-carboxylic acid 8 of formula wherein X and Y are defined as above  
       
         
           
           
               
               
           
         
       
       g. reacting the bicyclic-heteroaryl-2-carboxylic acid 8 or salts thereof with an acid halide reagent or coupling reagent to form an activated intermediate of formula 9 where Q is a leaving group formed from the coupling reagent or acid halide reagent wherein X and Y are defined as above  
       
         
           
           
               
               
           
         
       
       h. reacting an activated intermediate of formula 9 or the bicyclic-heteroaryl carboxylic acid 8 with a substituted hydroxylamine of the formula R 3 NHOR 2  10 where R 2  and R 3  are independently alkyl of 1 to 6 carbon atoms in the presence of an organic base or inorganic base to provide an amide of formula 11 wherein X, Y, R 2  and R 3  are defined as above  
       
         
           
           
               
               
           
         
         i. reducing the amide of formula 11 with a reducing agent to provide a bicyclic heteroaryl carboxaldehyde of Formula I wherein X and Y are defined as above  
         
           
             
             
                 
                 
             
           
         
       
       and isolating the heteroaryl carboxaldehyde of Formula I.  
     
   
   
       2 . A process according to  claim 1  wherein the nitrosating reagent is sodium nitrite in hydrochloric acid.  
   
   
       3 . A process according to  claim 1  wherein R 1  is methyl or ethyl.  
   
   
       4 . The process according to  claim 1  wherein the dehydrating agent is trifluoroacetic anhydride.  
   
   
       5 . A process according to  claim 1  wherein the aprotic solvent is N,N-dimethylformamide, chlorobenzene or 1,2-diethoxyethane at a temperature of about 100-165° C.  
   
   
       6 . A process according to  claim 5  wherein the aprotic solvent is 1,2-diethoxyethane or chlorobenzene at a temperature of about 120-125° C. forming a mixture of bicyclic-heteroaryl-3-carboxylate ester 5 and bicyclic-heteroaryl-2-carboxylate ester 6 in a ratio, in the range of about 1:1.5 to about 1:2.5.  
   
   
       7 . A process according to  claim 1  wherein up to 2 moles of hydrolyzing reagent MOR 5  in ethanol is used where M is sodium or potassium and R 5  is H.  
   
   
       8 . A process according to  claim 7  wherein M is potassium.  
   
   
       9 . A process according to  claim 1  wherein the acid is selected from hydrochloric or sulfuric.  
   
   
       10 . A process according to  claim 1  wherein the acid halide reagent is SO 2 Q 2  or QCOCOQ where Q is chloro or bromo.  
   
   
       11 . A process according to  claim 10  wherein the acid halide reagent is selected from thionyl bromide, thionyl choride and oxalyl chloride.  
   
   
       12 . A process according to  claim 11  wherein the acid halide reagent is oxalyl chloride.  
   
   
       13 . A process according to  claim 1  wherein the coupling reagent is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-hydroxybenzotriazole (DEC/HBT), carbonyldiimidazole, carbonyldimidazole/hydroxybenzotriazole dicyclohexylcarbodiimide/HBT, dicyclohexylcarbodiimide/N-hydroxysuccinimide, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), 2-chloro-1-methylpyridinium iodide, diphenylphosphinyl chloride (DPPCl), propanephosphonic anhydride (propanephosphonic acid anhydride, PAA), diethylphosphoryl cyanide, phenyldichlorophosphate plus imidazole, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP-reagent), N,N′bis[2-oxo-3-oxazolidinyl]phosphorodiamidic chloride (BOB Cl), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate, thionyl chloride, thionyl bromide, oxalyl chloride, cyanuric fluoride, isobutyl chloroformate, isopropenyl chloroformate, pentafluorophenyl trifluoroacetate, diphenylphoshoryl azide and diethylphosphoryl cyanide.  
   
   
       14 . The process according to  claim 1  wherein the organic base is selected from triethylamine, N,N-diisopropylethylamine, and pyridine.  
   
   
       15 . The process according to  claim 1  wherein the substituted hydroxylamine is reacted under Schotten-Baumen conditions.  
   
   
       16 . The process according to  claim 1  wherein the reducing agent is a hydride reagent.  
   
   
       17 . The process according to  claim 16  wherein the hydride reagent is selected from lithium aluminum hydride and diisobutyl aluminum hydride [DIBAL(H)].  
   
   
       18 . (canceled)  
   
   
       19 . (canceled)  
   
   
       20 . The process according to  claim 1  wherein the bicyclic heteroaryl carboxaldehyde of Formula I is purified as the water soluble sodium bisulfite complex.  
   
   
       21 . A process for the preparation of bicyclic heteroaryl carboxaldehydes of Formula I  
     
       
         
         
             
             
         
       
       wherein:  
       Y is (CH 2 ) n ;  
       n is 1 or 2;  
       X is NR, O, S, or CH 2 ;  
       R is alkyl of 1 to 6 carbon atoms, or arylalkyl(C 1  to C 6 );  
       provided n is 2 when X is NR or O;  
       which process comprises the steps of:  
       a. reacting a mixture of bicyclic-heteroaryl-3-carboxylate ester of formula 5 and bicyclic-heteroaryl-2-carboxylate ester of formula 6 wherein R 1  is alkyl of 1 to 6 carbon atoms and X and Y are defined as above  
       
         
           
           
               
               
           
         
       
       with a hydrolyzing reagent MOR 5  where M is an alkali metal or R 4 N where R 4  is straight or branched alkyl of 1 to 6 carbon atoms when R 5  is H, in an alcohol solvent, or when M is an alkali metal and R 5  is alkyl of 1 to 6 carbon atoms in an aqueous alcohol solvent to preferentially form a salt 7 wherein X, Y and M are defined as above  
       
         
           
           
               
               
           
         
       
       b. isolating the salt 7;  
       c. reacting the salt 7 with acid to form bicyclic-heteroaryl-2-carboxylic acid 8 of the formula wherein X and Y are defined as above  
       
         
           
           
               
               
           
         
       
       d. reacting the bicyclic-heteroaryl-2-carboxylic acid 8 or salts thereof with an acid halide reagent or coupling reagent to form a activated intermediate of formula 9 wherein X and Y are defined as above where Q is a leaving group formed from the coupling reagent or acid halide reagent  
       
         
           
           
               
               
           
         
       
       e. reacting an activated intermediate of formula 9 or the carboxylic acid 8 with a substituted hydroxylamine of the formula R 3 NHOR 2  10 where R 2  and R 3  are independently alkyl of 1 to 6 carbon atoms in the presence of an organic base or inorganic base to provide an amide of formula 11 wherein X, Y, R 2 , and R 3  are defined as above  
       
         
           
           
               
               
           
         
         f. reducing the amide of formula 11 with a reducing agent to provide an bicyclic heteroaryl carboxaldehyde of Formula I wherein X and Y are defined as above  
         
           
             
             
                 
                 
             
           
         
       
       and isolating the bicyclic heteroaryl carboxaldehyde of Formula I.  
     
   
   
       22 . A process according to  claim 21  wherein R 1  is methyl or ethyl.  
   
   
       23 . A process according to  claim 22  wherein up to 2 moles of hydrolyzing reagent MOR 5  in ethanol is used where M is sodium or potassium and R 5  is H.  
   
   
       24 . A process according to  claim 23  wherein M is potassium.  
   
   
       25 . A process according to  claim 21  wherein the acid halide reagent is SO 2 Q 2  or QCOCOQ where Q is chloro or bromo.  
   
   
       26 . A process according to  claim 25  wherein the acid halide reagent is selected from thionyl choride, oxalyl chloride and thionyl bromide.  
   
   
       27 . A process according to  claim 26  wherein the acid halide reagent is oxalyl chloride.  
   
   
       28 . A process according to  claim 21  wherein the coupling reagent is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-hydroxybenzotriazole (DEC/HBT), carbonyldiimidazole, carbonyldimidazole/hydroxybenzotriazole dicyclohexylcarbodiimide/HBT, dicyclohexylcarbodiimide/N-hydroxysuccinimide, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), 2-chloro-1-methylpyridinium iodide, diphenylphosphinyl chloride (DPPCl), propanephosphonic anhydride (propanephosphonic acid anhydride, PAA), diethylphosphoryl cyanide, phenyldichlorophosphate plus imidazole, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP-reagent), N,N′bis[2-oxo-3-oxazolidinyl]phosphorodiamidic chloride (BOB Cl), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate, thionyl chloride, thionyl bromide, oxalyl chloride, cyanuric fluoride, isobutyl chloroformate, isopropenyl chloroformate, pentafluorophenyl trifluoroacetate, diphenylphoshoryl azide and diethylphosphoryl cyanide.  
   
   
       29 . The process according to  claim 21  wherein the organic base is selected from triethylamine, N,N-diisopropylethylamine, and pyridine.  
   
   
       30 . The process according to  claim 21  wherein the substituted hydroxylamine is reacted under Schotten-Baumen conditions.  
   
   
       31 . The process according to  claim 21  wherein the reducing agent is a hydride reagent.  
   
   
       32 . The process according to  claim 31  wherein the hydride reagent is selected from lithium aluminum hydride and disobutyl aluminum hydride [DIBAL(H)].  
   
   
       33 . The process according to  claim 21  wherein X is —CH 2 —.  
   
   
       34 . The compound 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carbaldehyde prepared by the process of  claim 21 .  
   
   
       35 . The process according to  claim 21  wherein the bicyclic heteroaryl carboxaldehyde of Formula I is purified as the water soluble sodium bisulfite complex.  
   
   
       36 . A process for the preparation of bicyclic-heteroaryl 2-carboxylic acid salt of formula 7  
     
       
         
         
             
             
         
       
       wherein:  
       Y is (CH 2 ) n ;  
       n is 1 or 2;  
       X is NR, O, S, or CH 2 ;  
       R is alkyl of 1 to 6 carbon atoms, or arylalkyl(C 1  to C 6 );  
       M is an alkali metal salt or H;  
       provided n is 2 when X is NR or O;  
       which process comprises the steps of:  
       a. reacting a mixture of bicyclic-heteroaryl-3-carboxylate ester of formula 5 and bicyclic-heteroaryl-2-carboxylate ester of formula 6 wherein R 1  is alkyl of 1 to 6 carbon atoms and X and Y are defined as above  
       
         
           
           
               
               
           
         
       
       with a hydrolyzing reagent MOR 5  where M is an alkali metal or R 4 N where R 4  is straight or branched alkyl of 1 to 6 carbon atoms when R 5  is H, in an alcohol solvent, or when M is an alkali metal and R 5  is alkyl of 1 to 6 carbon atoms in an aqueous alcohol solvent to preferentially form a salt 7 wherein X, Y and M are defined as above  
       
         
           
           
               
               
           
         
       
       b. isolating the salt 7.  
       c. optionally reacting the salt 7 with acid to form the bicyclic-heteroaryl-2-carboxylic acid 8 of the formula wherein X and Y are defined as above  
       
         
           
           
               
               
           
         
       
       and isolating the bicyclic-heteroaryl-2-carboxylic acid 8.  
     
   
   
       37 . A process according to  claim 36  wherein up to 2 moles of hydrolyzing reagent MOR 5  in ethanol is used where M is sodium or potassium and R 5  is H.  
   
   
       38 . The process according to  claim 36  wherein potassium salt of 5,6-dihydro-4H-pyrrolo-[1,2-b]pyrazole-2-carboxylic acid is produced.  
   
   
       39 . A compound of the formula  
     
       
         
         
             
             
         
       
       wherein:  
       Y is (CH 2 ) n ;  
       n is 1 or 2;  
       X is NR, O, S, or CH 2 ;  
       R is alkyl of 1 to 6 carbon atoms, or arylalkyl(C 1  to C 6 );  
       provided n is 2 when X is NR or O;  
       R 2  and R 3  are independently alkyl of 1 to 6 carbon atoms.  
     
   
   
       40 . A compound according to  claim 39  wherein X is —CH 2 —.  
   
   
       41 . The compound according to  claim 40  which is N-methoxy-N-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]-pyrazole-2-carboxamide.  
   
   
       42 . A compound of the formula 8  
     
       
         
         
             
             
         
       
       wherein:  
       Y is (CH 2 ) n ;  
       n is 1 or 2;  
       X is NR, O, S, or CH 2 ;  
       R is alkyl of 1 to 6 carbon atoms, or arylalkyl(C 1  to C 6 );  
       provided n is 2 when X is NR or O;  
       or an alkali metal salt thereof.  
     
   
   
       43 . The compound according to  claim 42  where the alkali metal is potassium and X is —CH 2 —.  
   
   
       44 . The compound according to  claim 42  which is 5,6-dihydro-4H-pyrrolo-[1,2-b]pyrazole-2-carboxylic acid or the potassium salt thereof.  
   
   
       45 . A process for the preparation of bicyclic heteroaryl penem-2-carboxylic acid 16 protected acid, pharmaceutically acceptable salt or preferably an alkali metal salt of the formula  
     
       
         
         
             
             
         
       
       wherein:  
       one of A and B denotes hydrogen and the other a moiety  
       
         
           
           
               
               
           
         
       
       Y is (CH 2 ) n ;  
       n is 1 or 2;  
       X is NR, O, S, or CH 2 ;  
       R is alkyl of 1 to 6 carbon atoms, or arylalkyl(C 1  to C 6 );  
       provided n is 2 when X is NR or O;  
       R 3  is alkyl of 1 to 6 carbon atoms;  
       R 6  is H, an in vivo hydrolyzable ester selected from the group C 1 -C 6  alkyl, C 5 -C 6  cycloalkyl, —CHR 3 OCOC 1 -C 6 , benzyl or p-nitrobenzyl protecting groups or a pharmaceutically acceptable salt, preferably an alkali metal salt;  
       which process comprises the steps of:  
       a. nitrosating an amino acid 1 of the formula  
       
         
           
           
               
               
           
         
       
       wherein X and Y are defined as above with a nitrosating reagent to form a nitroso compound of formula 2 wherein X and Y are defined as above  
       
         
           
           
               
               
           
         
       
       b. reacting the nitroso compound 2 with a dehydrating agent and neutralizing with inorganic base to form the ylide of formula 3 wherein X and Y are defined as above  
       
         
           
           
               
               
           
         
       
       c. reacting the ylide of formula 3 with a propiolate ester of formula 4  
         HC≡CCO 2 R 1    4  
       where R 1  is alkyl of 1 to 6 carbon atoms, in aprotic solvents to form a mixture of bicyclic-heteroaryl-3-carboxylic acid ester 5 and bicyclic-heteroaryl-2-carboxylic acid ester 6 wherein R 1 , X and Y are defined as above  
       
         
           
           
               
               
           
         
       
       d. reacting the mixture of bicyclic-heteroaryl-3-carboxylic ester 5 and bicyclic-heteroaryl-2-carboxylic ester 6 with a hydrolyzing reagent MOR 5  where M is an alkali metal or R 4 N where R 4  is straight or branched alkyl of 1 to 6 carbon atoms when R 5  is H, in an alcohol solvent, or when M is an alkali metal and R 5  is alkyl of 1 to 6 carbon atoms in an aqueous alcohol solvent to preferentially form a salt 7 wherein X, Y and M are defined as above  
       
         
           
           
               
               
           
         
       
       e. isolating the salt 7;  
       f. reacting the salt 7 with mineral acid to form bicyclic-heteroaryl 2-carboxylic acid 8 of formula  
       
         
           
           
               
               
           
         
       
       g. reacting the bicyclic-heteroaryl-2-carboxylic acid 8 or salts thereof with an acid halide reagent or coupling reagent to form an activated intermediate of formula 9 where Q is a leaving group formed from the coupling reagent or acid halide reagent wherein X and Y are defined as above  
       
         
           
           
               
               
           
         
       
       reacting an activated intermediate of formula 9 or the bicyclic-heteroaryl-2-carboxylic acid 8 with a substituted hydroxylamine of the formula R 3 NHOR 2  10 where R 2  and R 3  are independently alkyl of 1 to 6 carbon atoms in the presence of an organic base to provide an amide of formula 11 wherein X, Y, R 2 , and R 3  are defined as above  
       
         
           
           
               
               
           
         
       
       h. reducing the amide of formula 11 with a reducing agent to provide a bicyclic heteroaryl carboxaldehyde of Formula I wherein X, Y, R 2  and R 3  are defined as above  
       
         
           
           
               
               
           
         
       
       i. condensing the bicyclic heteroaryl carboxaldehyde of Formula I with bromo-penem 13 of the formula  
       
         
           
           
               
               
           
         
       
       R 6  having a protected acid where R 6  is an in vivo hydrolyzable ester selected from the group C 1 -C 6  alkyl, C 5 -C 6  cycloalkyl, and —CHR 3 OCOC 1 -C 6  or additionally benzyl or p-nitrobenzyl protecting groups;  
       in the presence of a Lewis acid, and a mild base to form an aldol 14 of the formula wherein X, Y and R 6  are defined as above  
       
         
           
           
               
               
           
         
       
       j. reacting aldol 14 with an acid chloride or anhydride, (R 4 )Cl or (R 4 ) 2 O, or with tetrahalomethane, C(X 1 ) 4 , and triphenyl phosphine, to form intermediate compound 15 wherein R 4  is alkylSO 2 , arylSO 2 , alkylCO, or arylCO; X 1  is Br, I, or Cl; X, Y and R 6  are as defined above; and R 5  is X 1  or OR 4 ; and  
       
         
           
           
               
               
           
         
       
       k. converting the intermediate compound 15 by a reductive elimination process to the bicyclic-heteroaryl-penem-2-carboxylic acid 16 where R 6  is H and A and B are defined as above and if desired converting to an ester wherein R 6  is C 1 -C 6  alkyl, C 5 -C 6  cycloalkyl, or —CHR 3 OCOC 1 -C 6 , a pharmaceutically acceptable salt preferably an alkali metal salt of the formula  
       
         
           
           
               
               
           
         
       
       and isolating the bicyclic-heteroaryl-penem-2-carboxylic acid, preferably as an alkali salt.  
     
   
   
       46 . A process according to  claim 45  wherein the Lewis acid is anhydrous magnesium halide.  
   
   
       47 . A process according to  claim 46  wherein the Lewis acid is anhydrous MgBr 2 .  
   
   
       48 . A process according to  claim 45  wherein the mild base is triethylamine, dimethylaminopyridine or diisopropyl ethyl amine.  
   
   
       49 . A process according to  claim 45  wherein the low temperature is from about −20° C. to about −40° C.  
   
   
       50 . A process according to  claim 45  wherein intermediate compound 15 is an acetate, triflate or a tosylate.  
   
   
       51 . A process according to  claim 45  wherein the intermediate compound 15 is not isolated.  
   
   
       52 . A process according to  claim 45  wherein the reductive elimination process is carried out using activated zinc and a phosphate buffer at a pH of about 6.5 to 8.0 or hydrogenating over a catalyst.  
   
   
       53 . A process according to  claim 52  wherein the catalyst is palladium on charcoal.  
   
   
       54 . A process according to  claim 52  wherein the reductive elimination process is at a temperature of about 20° C. to 35° C.  
   
   
       55 . The process according to  claim 45  wherein the bicyclic heteroaryl carboxaldehyde of Formula I is purified as the water soluble sodium bisulfite complex.  
   
   
       56 . A process for the preparation of a bicyclic heteroaryl carboxaldehyde of Formula I  
     
       
         
         
             
             
         
       
       wherein:  
       Y is (CH 2 ) n ;  
       n is 1 or 2;  
       X is NR, O, S, or CH 2 ;  
       R is alkyl of 1 to 6 carbon atoms, or arylalkyl(C 1  to C 6 );  
       provided n is 2 when X is NR or O;  
       which process comprises reducing a compound as claimed in  claim 39  with a reducing agent to provide a bicyclic heteroaryl carboxaldehyde having Formula I.  
     
   
   
       57 . A process according to  claim 56 , wherein the compound as claimed in  claim 39  is prepared by reacting a mixture of bicyclic-heteroaryl-3-carboxylic acid ester 5 and bicyclic-heteroaryl-2-carboxylic acid ester 6  
     
       
         
         
             
             
         
       
       wherein where R 1  is alkyl of 1 to 6 carbon atoms and X and Y are as defined in  claim 55 , with a hydrolyzing reagent MOR 5  where M is an alkali metal or R 4 N where R 4  is straight or branched alkyl of 1 to 6 carbon atoms when R 5  is H, in an alcohol solvent, or when M is an alkali metal and R 5  is alkyl of 1 to 6 carbon atoms in an aqueous alcohol solvent to form a bicyclic-heteroaryl 2-carboxylic acid 8 of formula  
       
         
           
           
               
               
           
         
       
       (wherein X and Y are defined as above) in free or salt form and reacting the bicyclic-heteroaryl 2-carboxylic acid 8 or a reactive derivative thereof with an amine having the formula R 3 NHOR 2  10 (where R 2  and R 3  are independently alkyl of 1 to 6 carbon atoms) or a reactive derivative thereof to form an amide.  
     
   
   
       58 . A process according to  claim 56  wherein X is —CH 2 —.  
   
   
       59 . A process according to  claim 57  wherein X is —CH 2 —.  
   
   
       60 . A process according to  claim 58  wherein the compound having the formula 11 is N-methoxy-N-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]-pyrazole-2-carboxamide.  
   
   
       61 . A process according to  claim 59  wherein the compound having the formula 11 is N-methoxy-N-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]-pyrazole-2-carboxamide.  
   
   
       62 . A process for the preparation of bicyclic heteroaryl penem-2-carboxylic acid 16 protected acid, pharmaceutically acceptable salt or preferably an alkali metal salt of the formula  
     
       
         
         
             
             
         
       
       wherein:  
       one of A and B denotes hydrogen and the other a moiety  
       
         
           
           
               
               
           
         
       
       (wherein X and Y are as defined in  claim 55)  and R 6  is H, an in vivo hydrolyzable ester selected from the group C 1 -C 6  alkyl, C 5 -C 6  cycloalkyl, —CHR 3 OCOC 1 -C 6 , benzyl or p-nitrobenzyl protecting groups or a pharmaceutically acceptable salt, preferably an alkali metal salt;  
       which process comprises  
       (1) reducing a compound as claimed in  claim 39  with a reducing agent to provide a bicyclic heteroaryl carboxaldehyde having Formula I  
       
         
           
           
               
               
           
         
       
       wherein Y and X are as defined above and  
       (2) converting the bicyclic heteroaryl carboxaldehyde having Formula I into the compound having formula 16.  
     
   
   
       63 . A process according to  claim 62 , wherein the compound as claimed in  claim 39  is prepared in the manner defined in  claim 57 .  
   
   
       64 . A process according to  claim 62  wherein X is —CH 2 —.  
   
   
       65 . A process according to  claim 63  wherein X is —CH 2 —.  
   
   
       66 . A process according to  claim 64  wherein the compound having the formula 11 is N-methoxy-N-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]-pyrazole-2-carboxamide.  
   
   
       67 . A process according to  claim 65  wherein the compound having the formula 11 is N-methoxy-N-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]-pyrazole-2-carboxamide.  
   
   
       68 . A process according to  claim 62  to prepare (5R, 6Z)-6-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl-methylene)-7-oxo-4-thiazabicyclo-[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt.  
   
   
       69 . A process according to  claim 63  to prepare (5R, 6Z)-6-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl-methylene)-7-oxo-4-thiazabicyclo-[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt.  
   
   
       70 . A process according to  claim 64  to prepare (5R, 6Z)-6-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl-methylene)-7-oxo-4-thiazabicyclo-[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt.  
   
   
       71 . A process according to  claim 65  to prepare (5R, 6Z)-6-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl-methylene)-7-oxo-4-thiazabicyclo-[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt.  
   
   
       72 . A process according to  claim 66  to prepare (5R, 6Z)-6-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl-methylene)-7-oxo-4-thiazabicyclo-[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt.