Process for Producing Fluorocytosine and Fluorocytosine Derivatives

Abstract

The present invention relates to a method of manufacturing a fluorocytosine-based compound of Formula I. The invention also relates to a compound obtained by such a method, a pharmaceutical drug substance and a method for its manufacture, a pharmaceutical composition, and also various uses in therapy of the compounds, pharmaceutical drug substances, and pharmaceutical compositions of the invention.

1 . A method of manufacturing a compound of Formula I, or a salt or solvate thereof: 
       
         
           
           
               
               
           
         
         the method comprising reacting a compound of Formula II (or a salt, solvate, or synthetic equivalent thereof): 
       
       
         
           
           
               
               
           
         
         with an electrophilic fluorinating agent; 
         wherein:
 X is NR x , O, or S; wherein R x  is hydrogen or is independently selected from any R N  group; 
 Y is O, S, or NR y ; wherein R y  is hydrogen or is independently selected from any R N  group; 
 R 1  is hydrogen or is independently selected from any R s  group, though most suitably R 1  is an electron donating group (EDG), most suitably an EDG selected from NR 1a R 1b  or OR 1a , wherein R 1a  and R 1b  are each independently selected from hydrogen or any R N  group; 
 R 2  hydrogen or is independently selected from any R s  group; 
 
         each R N  group is independently selected from (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, aryl, aryl-(1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-6C)alkyl, (3-8C)cycloalkenyl, (3-8C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, formyl, carboxy, (2-6C)alkanoyl, (1-6C)alkoxycarbonyl, carbamoyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl; wherein each R N  group is optionally independently substituted with one or more R s  groups; 
         each R s  group is independently selected from halogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, ureido, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyloxy,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino, (1-6C)alkoxycarbonylamino, N-(1-6C)alkyl-(1-6C)alkoxycarbonylamino, N′-(1-6C)alkylureido, N′,N′-di-[(1-6C)alkyl]ureido, N-(1-6C)alkylureido, N,N′-di-[(1-6C)alkyl]ureido, N,N′,N′-tri-[(1-6C)alkyl]ureido,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of the formula:
   L 1 —Q 1  
 
 
         wherein L 1  is a direct bond or is selected from (CR L1 R L2 ) n , O, S, SO, SO 2 , N(R L1 ), CO, CR L1 (R L2 ), CON(R L1 ), N(R L1 )CO, N(R L1 )C(O)O, N(R L1 )CON(R L2 ), SO 2 N(R L1 ), N(R L1 )SO 2 , OC(R L1 ) 2 , SC(R L1 ) 2  and N(R L1 )C(R L2 ) 2 , wherein n is an integer between 1 and 3, and wherein R L1  and R L2  are each independently hydrogen or (1-8C)alkyl; and Q 1  is (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, aryl, aryl-(1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-6C)alkyl, (3-8C)cycloalkenyl, (3-8C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl; 
         and wherein any R s  group is independently optionally further substituted by one or more R s  groups; 
       
       optionally thereafter transforming a synthetic equivalent of the compound of Formula I (or a salt or solvate thereof) into a compound of Formula I (or a salt or solvate thereof) via one or more chemical transformations; 
       optionally, and if necessary:
 (a) removing any protecting groups present; 
 (b) converting the compound Formula I into another compound of Formula I; and/or 
 (c) forming a pharmaceutically acceptable salt thereof; 
 wherein the reaction between the compound of Formula II and the electrophilic fluorinating agent is performed in a continuous flow reactor. 
 
     
     
         2 . The method as claimed in  claim 1 , wherein the continuous flow reactor is operated to continuously mix a first input load comprising the compound of Formula II (the first input material) with a second input load comprising the electrophilic fluorinating agent (the second input material) to form a reaction mixture. 
     
     
         3 . The method as claimed in  claim 2 , wherein the respective input materials are mixed together in pre-determined relative quantities, at pre-determinated relative rates, and allowed or caused to react together for a pre-determined time period. 
     
     
         4 . The method as claimed in any of  claim 2  or  3 , wherein the continuous flow reactor includes:
 a first input flow line for carrying the first input load; 
 a second input flow line for carrying the second input load, 
 a junction at which the first and second input flow lines converge and at which the first and second input loads mix to form the reaction mixture; 
 an internal reactor, through which the reaction mixture is configured to flow, located at or downstream from the first junction; and 
 a first output flow line for carrying an output load from the internal reactor; 
 
       wherein the continuous flow reactor is operated to feed the reaction mixture through the internal reactor. 
     
     
         5 . The method as claimed in any preceding claim, wherein X is NR x ; wherein R x  is hydrogen or is a 5-membered heterocyclyl group optionally substituted with one or more hydroxyl, (1-3C)alkyl, or (1-3C)alkyl substituted with hydroxyl, wherein where R x  is other than hydrogen, R x  forms a hemiaminal ether (or glycosidic) linkage with the nitrogen atom to which it is attached. 
     
     
         6 . The method as claimed in any preceding claim, wherein R 1  is independently selected from NR 1a R 1b  or (1-6C)alkoxycarbonylamino, wherein R 1a  and R 1b  are each independently selected from hydrogen or (1-6C)alkyl. 
     
     
         7 . The method as claimed in any preceding claim, wherein R 2  hydrogen. 
     
     
         8 . The method as claimed in any preceding claim, wherein each R s  group is independently selected from halogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy, amino, formyl, carboxy, carbamoyl, ureido, (1-8C)alkyl, (1-6C)alkoxy, (1-6C)alkoxycarbonylamino; wherein any R s  group is independently optionally further substituted by one or more R s  groups as defined in this or any preceding claim. 
     
     
         9 . The method as claimed in any preceding claim, wherein where R s  is substituted with one or more further R s  groups, suitably said further R s  groups are selected from hydroxy, (1-8C)alkyl, hydroxy-(1-8C)alkyl, (1-3C)alkoxy-(1-8C)alkyl, or (1-6C)alkoxy. 
     
     
         10 . The method as claimed in any preceding claim, wherein the compounds of Formula II and Formula I, and a potential impurity compound of Formula I-imp are respectively defined by the structural Formulae IIb, Ib, and Ib-imp shown below: 
       
         
           
           
               
               
           
         
         or a salt, solvate, or synthetic equivalent thereof; 
         wherein R 1a , R 1b , R 2 , R x , and any groups associated therewith have any one of the meanings defined in any preceding claim. 
       
     
     
         11 . The method as claimed in any preceding claim, wherein the compounds of Formula II and Formula I, and a potential impurity compound of Formula I-imp are respectively defined by the structural Formulae IIe, Ie, and/or Ie-imp shown below: 
       
         
           
           
               
               
           
         
         or a salt or solvate. 
       
     
     
         12 . The method as claimed in any preceding claim, wherein the compound of Formula I is selected from flucytosine, emtricitabine, or capecitabine, or a pharmaceutically acceptable salt and/or solvate thereof. 
     
     
         13 . The method as claimed in any preceding claim, wherein the electrophilic fluorinating agent is fluorine gas, optionally provided as an electrophilic fluorinating gaseous composition (i.e. corresponding to a second input load) comprising fluorine and optionally one or more carrier gases. 
     
     
         14 . The method as claimed in  claim 13 , wherein the electrophilic fluorinating gaseous composition comprises between 1 and 30% fluorine. 
     
     
         15 . The method as claimed in  claim 14 , wherein the electrophilic fluorinating gaseous composition consists essentially of 5 to 15% fluorine and 85 to 95% nitrogen. 
     
     
         16 . The method as claimed in any of  claims 2  to  15 , wherein the first input load comprises the compound of Formula II and a diluent system, wherein the diluent system suitably comprises an acid having a pK a  greater than or equal to 3.17. 
     
     
         17 . The method as claimed in  claim 16 , wherein the diluents system comprises or consists essentially of formic acid. 
     
     
         18 . The method as claimed in any of  claims 16  to  17 , wherein the first input load comprises the compound of Formula II at a concentration between 0.5M to 1.5M. 
     
     
         19 . The method as claimed in any preceding claim, wherein the molar ratio of electrophilic fluorinating agent to compound II is between 1.2:1 and 1.6:1. 
     
     
         20 . The method as claimed in any of  claims 2  to  19 , wherein the volumetric residence time of the reaction mixture is between 1 second and 10 seconds, where the residence time is calculated as:
 where T r  is the residence time given in units of time, V r  is the internal volume of a region within the continuous flow reactor during which a reaction between the first and second input materials occurs (i.e. internal volume of an internal reactor) given in units of volume, and F 0  is overall volumetric flow rate given in units of volume per unit time. 
 
     
     
         21 . The method as claimed in any preceding claim, wherein the output load comprises:
 100 parts by moles compound of Formula I   1-20 parts by moles compound of Formula I-imp   0.1-5 parts by moles compound of Formula II.   
     
     
         22 . The method as claimed in any preceding claim, wherein the output load comprises:
 100 parts by moles compound of Formula I   2-10 parts by moles compound of Formula I-imp   
     
     
         23 . The method as claimed in any preceding claim, wherein the output load is collected as the “collected output load”, which is then isolated and/or purified, either partially or fully, to yield a purified product comprising:
 100 parts by moles compound of Formula I 
 0-2 parts by moles compound of Formula I-imp 
 0-2 parts by moles compound of Formula II. 
 
     
     
         24 . The method as claimed in any preceding claim, wherein the molar yield of the purified product (by reference to the quantity of input material compound of Formula II) is greater than or equal to 60%. 
     
     
         25 . A method of manufacturing a pharmaceutical drug substance, or a pharmaceutically acceptable salt or solvate thereof, the method comprising:
 manufacturing a compound of Formula I, or a salt or solvate thereof, by the method as claimed in any of  claims 1  to  24 ;   optionally thereafter performing one or more further step or steps to produce the pharmaceutical drug substance (or a pharmaceutically acceptable salt, solvate, or synthetic equivalent thereof);   optionally transforming a synthetic equivalent of the pharmaceutical drug substance (or a salt or solvate thereof) into another pharmaceutical drug substance (or a salt or solvate thereof) via one or more suitable chemical transformations (e.g. deprotections);   optionally, and if necessary:   (a) removing any protecting groups present;   (b) converting the pharmaceutical drug substance into a different pharmaceutical drug substance; and/or   (c) forming a pharmaceutically acceptable salt thereof.   
     
     
         26 . The method as claimed in  claim 25 , wherein the pharmaceutical drug substance is selected from flucytosine, emtricitabine, capecitabine, or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         27 . The method as claimed in  claim 26 , wherein the method comprises:
 manufacturing flucytosine, or a salt or solvate thereof, by the method as claimed in any of  claims 1  to  24 ;   N-coupling flucytosine, via an internal ring nitrogen (NH) thereof, with 2-(hydroxymethyl)-1,3-oxathiolan-5-ol to form a corresponding N-cyclic hemiaminal ether, by reacting flucytosine or a derivative thereof with 2-(hydroxymethyl)-1,3-oxathiolan-5-ol or a derivative thereof;   and optionally, and if necessary:   
       (a) removing any protecting groups present; 
       (b) forming a pharmaceutically acceptable salt thereof. 
     
     
         28 . The method as claimed in  claim 26 , wherein the method comprises:
 manufacturing flucytosine, or a salt or solvate thereof, by the method as claimed in any of  claims 1  to  24 ;   N-coupling flucytosine, via an internal ring nitrogen (NH) thereof, with 5-methyltetrahydrofuran-2,3,4-triol to form a corresponding N-cyclic hemiaminal ether, by reacting flucytosine or a derivative thereof with 5-methyltetrahydrofuran-2,3,4-triol or a derivative thereof;   N-coupling the N-cyclic hemiaminal ether, via an external nitrogen (NH 2 ) thereof, to a n-pentoxycarbonyl group to form a corresponding carbamate, by reacting the N-cyclic hemiaminal ether with n-pentoxycarbonic acid or a synthetic derivative or activated derivative thereof;   and optionally, and if necessary:   
       (a) removing any protecting groups present; 
       (b) forming a pharmaceutically acceptable salt thereof. 
     
     
         29 . A pharmaceutical composition comprising a pharmaceutical drug substance (or a pharmaceutically acceptable salt or solvate thereof) obtained by the method of any of  claims 25  to  28 , and a pharmaceutically acceptable diluent or carrier. 
     
     
         30 . A pharmaceutical drug substance (or a pharmaceutically acceptable salt, solvate, or synthetic equivalent thereof) obtained by the method of any of  claims 25  to  28 , or the pharmaceutical composition of  claim 29  for use in therapy. 
     
     
         31 . A method, compound, pharmaceutical drug substance, pharmaceutical composition, or any of the aforementioned for use in therapy, substantially as hereinbefore described with reference to the accompanying Examples.