Abstract:
A process is described which permits the preparation of Ritonavir with only five intermediate stages using the same starting materials as those used in the process described in WO 94/14436; the process described here is also particularly satisfactory from the point of view of environmental impact because nearly all of the carbon atoms used are subsequently incorporated in the final molecule. Finally, the improvement afforded by this novel process is linked with the fact that an inexpensive reagent, such as bis-trichloromethyl carbonate (BTC), is used in two of the five stages.

Description:
This application is a 371 of PCT/IT00/00368 Sep. 18, 2000. 
     BACKGROUND OF THE INVENTION 
     Ritonavir (CAS Number [155213-67-5]), the structural formula of which is given below,                           
     is an inhibitor of human HIV protease which was described for the first time by Abbott in International Patent Application WO 94/14436, together with the process for the preparation thereof. 
     In the synthesis scheme given in WO 94/14436, Ritonavir is manufactured starting from valine and from compounds 1, 4 and 7, the structural formulae of which are also given below.                           
     The synthesis process in question was subsequently optimised in its various parts by Abbot, who then described and claimed the individual improvements in the patent documents listed below: U.S. Pat. No. 5,354,866, U.S. Pat. No. 5,541,206, U.S. Pat. No. 5,491,253, WO 98/54122, WO 98/00393 and WO 99/11636. 
     The process for the synthesis of Ritonavir carried out on the basis of the abovementioned patent documents requires, however, a particularly large number of intermediate stages; it is also unacceptable from the point of view of so-called “low environmental impact chemical synthesis” (B. M. Trost Angew. Chem. Int. Ed. Engl. (1995) 34, 259-281) owing to the increased use of activating groups and protective groups which necessitate not inconsiderable additional work in disposing of the by-products of the process, with a consequent increase in the overall manufacturing costs. 
     SUMMARY OF THE INVENTION 
     The object of the present invention is therefore to find a process for the synthesis of Ritonavir which requires a smaller number of intermediate stages and satisfies the requirements of low environmental impact chemical synthesis, thus limiting “waste of material”. 
     A process has now been found which, by using as starting materials the same compounds as those used in WO 94/14436, leads to the formation of Ritonavir in only five stages and with a minimum use of carbon atoms that are not incorporated in the final molecule. 
    
    
     DESCRIPTION OF THE DRAWING 
     The process, which constitutes the main subject of the present invention, is shown in FIG.  1 . 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The process, which constitutes the main subject of the present invention is made up of the following stages: 
     (a) valine is condensed with bis-trichloromethyl carbonate to give intermediate 2, the structural formula of which is given below;                           
     (b) intermediate 2 so obtained is reacted with compound 1 to give intermediate 3, the structural formula of which is given below;                           
     (c) intermediate 3 so obtained is reacted with compound 4 to give intermediate 5, the structural formula of which is given below;                           
     (d) the primary amine group of intermediate 5 is subjected to deprotection by removing the two benzyl groups to give intermediate 6, the structural formula of which is given below;                           
     (e) intermediate 6 so obtained is reacted with compound 7 to give Ritonavir. 
     As any average person skilled in the art will appreciate, in addition to a reduced number of intermediate stages, the process according to the present invention also has a particular value from the point of view of environmental impact because, with the exception of a carbon atom used as an activator and protector of intermediate 5 and of the p-nitrophenol used as activator in the final reaction, all the carbon atoms used are then incorporated in the final molecule. 
     The improvement afforded by this new approach to synthesis is also linked with the fact that an inexpensive reagent, such as bis-trichloromethyl carbonate (BTC), is used in two of the total of five stages. 
     A second subject of the invention is represented by the compound of formula 3, which is novel per se, and by its use as an intermediate in the synthesis of Ritonavir. Finally, a further subject of the present invention is represented by the process for the preparation of the intermediate of formula 5. 
     From a practical point of view, stages (a) to (e) are carried out under standard reaction conditions which will be evident to any person skilled in the art; the preferred conditions of each individual stage are, however, listed hereinafter purely for purposes of illustration: 
     stage (a) is preferably carried out in an aprotic organic solvent, such as, for example, dioxane, tetrahydrofuran, CH 2 Cl 2  and CHCl 3 , at a temperature of from 20° C. to the reflux temperature of the solvent; dioxane is the preferred solvent. 
     stage (b) is preferably carried out in a non-polar organic solvent, even more preferably CH 2 Cl 2 , CHCl 3 , C 2 H 2 Cl 4 , in the presence of a tertiary amine, generally triethylamine, at a temperature of from −30 to 0° C.; 
     stage (c) is also preferably carried out in a non-polar organic solvent, such as CH 2 Cl 2 , CHCl 3 , C 2 H 2 Cl 4 , in the presence of a tertiary amine, generally triethylamine, at a temperature of from −20 to +10° C.; 
     the deprotection of the primary amine group of intermediate 5 (stage (d)) is preferably carried out by catalytic hydrogenation, generally on palladium; the solvent is preferably acetic acid, the temperature and the pressure are from +70 to +90° C. and from 3.5 to 5 bar, respectively; 
     stage (e) is preferably carried out in an aprotic polar organic solvent, even more preferably ethyl acetate, at a temperature of from +40 to +80° C. 
     Those and other aspects of the invention will become clear from the following Examples which are to be regarded as illustrative and non-limiting with respect to the invention. 
     EXAMPLES 
     
       
         
               
             
               
             
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 Stage 1 
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
             
          
           
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
             
          
           
               
                 Reagent 
                 Molecular weight 
                 Amount 
                 Mmol 
                 Eq. 
               
               
                   
               
             
          
           
               
                 Amine 1 
                 464.65 
                 15 
                 g 
                 32.282 
                 1 
               
               
                 Val-NCA 2 
                 142.13 
                 6.9 
                 g 
                 48.547 
                 1.5 
               
               
                 Triethylamine 
                 101.19 
                 4.5 
                 ml 
                 32.283 
                 1 
               
               
                   
                 (d = 0.726) 
               
               
                 Dichloromethane 
                   
                 108 
                 ml 
                   
                 Sol. 0.3M 
               
               
                   
               
             
          
         
       
     
     Compound Val-NCA 2 was added to a solution of amine 1 (note 1, 2) in dichloromethane (60 ml) at −15° C. under nitrogen followed by a solution of triethylamine in dichloromethane (48 ml) (note 3). The reaction mixture was maintained under agitation at from −15° to −13° C. for two hours (note 4). The solution was used directly for the next stage without further purification. 
     Note 1. Amine 1 was prepared using the procedure described in A. R. Haight et al. Org. Proc. Res. Develop. (1999) 3, 94-100. 
     Note 2. Amine 1 was a mixture of stereoisomers with a ratio of 80:3.3:2.1:1.9. 
     Note 3. This solution was added dropwise over a period of 25 minutes. 
     Note 4. HPLC analysis after 2 hours: Amide 3 70.2%—starting material 4.3% 
     
       
         
               
             
               
             
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
               
                 Stage 2 
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
             
          
           
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
             
          
           
               
                 Reagent 
                 Molecular weight 
                 Amount 
                 Mmol 
                 Eq. 
               
               
                   
               
             
          
           
               
                 Amine 3 
                 563.78 
                   
                   
                 32.282 
                 1 
               
               
                 Solution from stage 1 
               
               
                 Triethylamine 
                 101.19 
                 2.6 
                 ml 
                 18.654 
                 0.6 
               
               
                   
                 (d = 0.726) 
               
               
                 Bis(trichloromethyl)carbonate (BTC) 
                 296.75 
                 3.5 
                 g 
                 11.794 
                 0.36 
               
               
                 Dichloromethane 
                   
                 65 
                 ml 
               
               
                 N-Methyl-4-aminomethyl-2-iso- 
                 170.27 
                 5.5 
                 g 
                 32.282 
                 1 
               
               
                 propylthiazole 4 
               
               
                 Triethylamine 
                 101.19 
                 6.9 
                 ml 
                 49.504 
                 1.5 
               
               
                   
                 (d = 0.726) 
               
               
                 Dichloromethane 
                   
                 52 
                 ml 
               
               
                   
               
             
          
         
       
     
     The triethylamine was added slowly to the solution of amine 3 resulting from stage 1 and this mixture was in turn added slowly to a solution of BTC in dichloromethane (65 ml) at from −15to −13° C. and the reaction mixture was maintained under agitation at that temperature for 1.5 hours (note 1). A solution of amine 4 and triethylamine in dichloromethane (52 ml) was then added slowly to the reaction mixture (note 2) and maintained under agitation at that temperature for one hour (note 3). The reaction was stopped with water (97 ml) and the two phases were separated. The organic phase was 10 washed with a 10% aqueous citric acid solution, filtered over Celite and evaporated with a yield of 25 g of crude urea 5 which was purified by flash chromatography on silica gel (eluant: toluene—ethyl acetate 6:4) to give 9.4 g of pure compound 5 (total yield of the two stages 38%) (note 4). 
     Note 1. HPLC analysis after 1.5 hours of the reaction stopped in tert-butylamine: Amide 3=0.41%—intermediate isocyanate=61.3% 
     Note 2. The solution of amine 4 was added over a period of approximately 20 minutes. 
     Note 3. HPLC analysis after 1 hour: Amide 3=7%—Urea 5=54% 
     Note 4.  1 H-NMR(CDCl 3 , 600 MHz) δ 7.31(m, 4H), 7.28-7.24(m, 4H), 7.21-7.14 (m, 8H), 7.11(d, 2H), 7.05(d, 2H), 6.96(s, 1H), 6.75(bd, 1H), 5.96(bs, 1H), 4.48(d, 1H), 4.39(d, 1H), 4.13(dd, 1H), 4.09(m, 1H), 3.93(bd, 2H), 3.56(bt, 1H), 3.39(d, 2H), 3.28(m, 1H), 3.04(dd, 1H), 2.97(s, 3H), 2.89(m, 1H), 2.74(q, 1H), 2.61(m, 2H), 2.25(m,1H), 1.53(ddd, 1H), 1.38(d, 6H), 1.28(dt, 1H), 0.98(d, 3H), 0.91(d, 3H). 
     
       
         
               
             
               
             
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 Stage 3 
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
             
          
           
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
             
          
           
               
                 Reagent 
                 Molecular weight 
                 Amount 
                 Mmol 
                 Eq. 
               
               
                   
               
             
          
           
               
                 Urea 5 
                 760.05 
                 3.5 
                 g 
                 4.605 
                 1 
               
               
                 Pd(OH)2/C 20% 
                   
                 5.25 
                 g 
                   
                 30% w/w 
               
               
                 Acetic acid 
                   
                 31 
                 ml 
                   
                 Sol. 0.15M 
               
               
                   
               
             
          
         
       
     
     The Pearlman catalyst (note 1) was added to a solution of urea 5 in acetic acid and the mixture was hydrogenated for 5 hours at from 4 to 4.5 bar and from 78 to 82° C. (note 2). The catalyst was filtered and the solvent was removed under reduced pressure. The crude product was dissolved in water (35 ml), the pH was adjusted to a value of 8 with NaOH, and extracted with CH 2 Cl 2 (2×15 ml). The organic phase was washed with water (10 ml) and the solvent was evaporated under reduced pressure with a yield of 1.8 g of amine 6 as a free base which was used for the next stage without further purification (note 3, 4). 
     Note 1. Of the various reaction conditions tested, such as HCOONH 4 Pd—C in MeOH, H 2 /Pd—C in methanol, H 2 /Pd—C/CH 3 SO 3 H in methanol, H 2 /Pd(OH) 2 /C in methanol, etc., the best conditions we have found hitherto are those described in this Example. 
     Note 2. HPLC analysis after 5 hours: amine 6=52%—monobenzyl derivative=9.3%. 
     Note 3. HPLC analysis on the free base: amine 6=54%—monobenzyl derivative=6%. 
     Note 4.  1 H-NMR (CDCl 3 , 600 MHz) δ 7.29(m, 4H), 7.22-7.14(m, 6H), 7.00(s, 1H) 6.83(bd, 1H), 6.15(bs, 1H), 4.49(d, 1H), 4.41(d, 1H), 4.25(m, 1H), 4.08(m, 1H), 3.38(m, 1H), 3.29(m, 1H), 2.99(s, 3H), 2.92(dd 1H), 2.84(m, 2H), 2.76(m, 1H), 2.47(m, 1H), 2.28(m, 1H), 1.76(dt, 1H), 1.61(dt, 1H), 1.38(d, 6H), 0.95(d, 3H), 0.89(d, 3H). 
     
       
         
               
             
               
             
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 Stage 4 
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
             
          
           
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
             
          
           
               
                 Reagent 
                 Molecular weight 
                 Amount 
                 Mmol 
                 Eq. 
               
               
                   
               
             
          
           
               
                 Amine 6 
                 579.80 
                 1.8 
                 g 
                 3.10 
                 1 
               
               
                 Compound 7.HCl 
                 316.70 
                 1.28 
                 g 
                 4.03 
                 1.3 
               
               
                 NaHCO 3   
                 84.00 
                 370 
                 mg 
                 4.40 
                 1.4 
               
               
                 Ethyl acetate 
                   
                 31 
                 ml 
                   
                 Sol. 0.1M 
               
               
                   
               
             
          
         
       
     
     A solution of the chloride of compound 7 in ethyl acetate was treated with an aqueous sodium bicarbonate solution. The phases were separated and the organic phase was added to a solution of amine 6 in ethyl acetate. The reaction mixture was heated at 60° C. for 12 hours, then concentrated; ammonia was added and the solution was maintained under agitation for 1 hour. The organic phase was washed with a 10% aqueous potassium carbonate solution (3×5ml) and with a saturated sodium chloride solution (5 ml); the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluant ethyl acetate) to give 900 mg of pure Ritonavir (total yield of the two stages 27%) (note 1). 
     Note 1.  1 H-NMR (DMSO, 600 MHz) δ 9.05(s, 1H), 7.86(s, 1H), 7.69(d, 1H), 7.22-7.10(m, 11H), 6.88(d, 1H), 6.02(d, 1H), 5.16(d, 1H), 5.12(d, 1H), 4.60(bs, 1H), 4.48(d, 1H), 4.42(d, 1H), 4.15(m, 1H), 3.94(dd, 1H), 3.83(m, 1H), 3.59(bt, 1H), 3.23(m, 1H), 2.87(s, 3H), 2.69-2.63(m, 3H), 2.60(m, 1H), 1.88(m, 1H), 1.45(m, 2H), 1.30(d, 6H), 0.74(d, 6H).