Apparatus and continuous flow process for production of boronic acid derivative

Abstract

A process for a continuous production of a boronic acid derivative and an apparatus of performing the process are disclosed.

What is claimed is: 
     
         1 . An apparatus for production of a compound of Formula (Ia) or (Ib) or salt thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         Q is —(CH 2 ) m —; 
         M is —CH 2 — or —CH═CH—; 
         m is 1 or 2; 
         R 1  is a carboxyl protecting group; 
         R 2  is a hydroxyl protecting group; or 
         R 1  and R 2  together with the atoms to which they are attached form a heterocyclic ring optionally substituted with C 1-4  alkyl; 
         each R 3  is independently selected from hydrogen, —OH, halogen, —CF 3 , C 1 -C 6  alkenyl, C 1 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 3 -C 7  carbocyclyl, 5-10 membered heterocyclyl, C 6-10  aryl, 5-10 membered heteroaryl, cyano, C 1 -C 6  alkoxy(C 1 -C 6 )alkyl, C 6-10  aryloxy, sulfhydryl (mercapto), and —(CH 2 ) m′ —Y′—(CH 2 ) p M′; 
         m′ and p are independently 0 to 3; 
         Y′ is selected from the group consisting of —S—, —S(O)—, —S(O) 2 —, —O—, —CR 4a R 5a —, and 
       
       —NR 1a —;
 M′ is selected from the group consisting of —C(O)NR 1a R 2a ; —C(O)NR 1a OR 3a ; —NR 1a C(O)R 4a ; —NR 1a C(O)NR 2a R 1b ; —NR 1a C(O)OR 3a ; —NR 1a S(O) 2 R 3a ; —NR 1a S(O) 2 NR 2a R 1b ; 
 
       —C(═NR 1a )R 4a ; —C(═NR 1a )NR 2a R 1b ; —NR 1a CR 4a (═NR 2a ); —NR 1a C(═NR 2a )NR 1b R 2b ; C 1-4  alkyl optionally substituted with 0-2 substituents selected from the group consisting, —OR 3a , 
       —NR 1a R 2a , halogen, —C(O)NR 1a R 2a , and —NR 1a C(O)R 4a ; C 3-10  cycloalkyl optionally substituted with 0-2 substituents selected from the group consisting of C 1-4  alkyl, —OR 3a , —NR 1a R 2a , halogen, —C(O)NR 1a R 2a , and —NR 1a C(O)R 4a ; C 6-10  aryl optionally substituted with 0-2 substituents selected from the group consisting of C 1-4  alkyl, —OR 3a , —NR 1a R 2a , halogen, 
       —C(O)NR 1a R 2a , and —NR 1a C(O)R 4a ; 5 to 10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of C 1-4  alkyl, —OR 3a , —NR 1a R 2a , halogen, 
       —C(O)NR 1a R 2a , and —NR 1a C(O)R 4a ; and 4 to 10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C 1-4  alkyl, —OR 3a , —NR 1a R 2a , halogen, —C(O)NR 1a R 2a , and —NR 1a C(O)R 4a ;
 each R 1a , R 2a , R 1b  and R 2b  are independently selected from the group consisting of —H, optionally substituted —C 1-10 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl, optionally substituted C 3-7  cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 6-10 aryl, and optionally substituted 5-10 membered heteroaryl; 
 R 3a  is hydrogen, optionally substituted C 1-10 alkyl, -optionally substituted C 1-10 alkyl-COOH, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl, optionally substituted C 3-7  cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 6-10 aryl, and optionally substituted 5-10 membered heteroaryl; and 
 each R 4a  and R 5a  is independently selected from the group consisting of —H, —OH, optionally substituted alkoxyl, optionally substituted —C 1-10 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl, optionally substituted C 3-7  cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 6-10 aryl, and optionally substituted 5-10 membered heteroaryl; 
 n is 0 to 3; 
 G is selected from the group consisting of —NR 1 R 2 , —N 3 , —C(O)NR 1 R 2 , —S(O) 2 NR 1 R 2 , —SR 3 , —OR 3 , —CH 2 NR 1 C(O)R 5 , —C(═NOR 3 )—X, C(═NOR 3 )—Z, —C(O)OR 3 , —C(O)NR 1 (OR 3 ), 
 
       —NR 1 (OR 3 ), —NR 1 C(O)R 5 , —NR 1 C(O)NR 2 R 1a , —NR 1 C(O)OR 3 , —NR'S(O) 2 R 3 , —NR'S(O) 2 NR 2 R 1a , —NR 1 NR 2 R 1a , —C(O)NR 1 NR 2 R 1a , —S(O) 2 NR 1 NR 2 R 1a , —C(═NR 1 )R 5 , —C(═NR 1 )NR 2 R 1a , —NR 1 CR 5 (═NR 2 ), —NR 1 C(═NR 2 )NR 1a R 2a , optionally substituted C 1-10  alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl, optionally substituted C 3-7  carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C 6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C 1-6 alkylene-C 3-7 carbocyclyl, optionally substituted C 1-6 alkylene-5-10 membered heterocyclyl, optionally substituted C 1-6 alkylene-C 6-10 aryl, and optionally substituted C 1-6 alkylene-5-10 membered heteroaryl;
 X is hydrogen or optionally substituted C 1-9 alkyl; 
 Z is selected from optionally substituted C 3-8  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; 
 the apparatus comprising: 
 a first vessel comprising a lithium amide; 
 a second vessel comprising a compound of Formula (IIa) or (IIb) or salt thereof; 
 
       
         
           
           
               
               
           
         
         a third vessel comprising a compound of Formula (III) or salt thereof;
   A-O—C(O)—(CH 2 ) n G   (III)
 
 
         wherein A is a C 6-10 aryl, 5-10 membered heteroaryl, C 3-7 carbocyclyl, or 5-10 membered heterocyclyl; 
         a first continuous flow conduit fluidly coupled to the first vessel and the second vessel; and 
         a second continuous conduit fluidly coupled between the first continuous flow conduit and the third vessel. 
       
     
     
         2 . An apparatus for production of a compound of Formula (Ia) or (Ib) or salt thereof, 
       
         
           
           
               
               
           
         
         Comprising: 
         a first continuous flow conduit; 
         a second continuous flow conduit extending from the first continuous flow conduit to a discharge end, 
         a first vessel comprising a lithium amide and configured to deliver the lithium amide compound to the first continuous flow conduit; 
         a second vessel comprising a compound of Formula (IIa) or (IIb) or salt thereof and configured to deliver the compound of Formula (IIa) or (IIb) or salt thereof to the first continuous flow conduit; and 
       
       
         
           
           
               
               
           
         
         a third vessel comprising a compound of Formula (III) or salt thereof
   A-O—C(O)—(CH 2 ) n G   (III)
 
 
         and fluidly coupled to the discharge end of the second continuous flow conduit. 
       
     
     
         3 . The apparatus of  claim 1 , further comprising a fourth vessel, wherein the fourth vessel comprises tetrahydrofuran and is fluidly coupled with the first vessel to combine the lithium amide and the tetrahydrofuran before the lithium amide flowing into the first continuous flow conduit. 
     
     
         4 . The apparatus of  claim 3 , further comprising a fifth continuous flow conduit, wherein the fifth continuous flow conduit is fluidly coupled the fourth vessel and the first continuous flow conduit to deliver the tetrahydrofuran from the fourth vessel to the first continuous flow conduit. 
     
     
         5 . The apparatus of  claim 3 , wherein the fourth vessel is pressurized. 
     
     
         6 . The apparatus of  claim 1 , further comprising a third continuous flow conduit to fluidly couple the first vessel and the first continuous flow conduit and to deliver the lithium amide from the first vessel to the first continuous flow conduit. 
     
     
         7 . The apparatus of  claim 6 , wherein the first vessel is pressurized. 
     
     
         8 . The apparatus of  claim 4 , further comprising a fourth continuous flow conduit to fluidly couple the second vessel and the first continuous flow conduit and to deliver the compound of Formula (IIa) or (IIb) or salt thereof from the second vessel to the first continuous flow conduit. 
     
     
         9 . The apparatus of  claim 8 , wherein the second vessel is pressurized. 
     
     
         10 . The apparatus of  claim 1 , further comprising one or more cooling elements thermally coupled to the first continuous flow conduit. 
     
     
         11 . The apparatus of  claim 8 , further comprising one or more cooling elements thermally coupled to at least one of the third continuous flow conduit, the fourth continuous flow conduit, and the fifth continuous flow conduit. 
     
     
         12 . The apparatus of  claim 1 , further comprising a heating element thermally coupled to the second continuous flow conduit. 
     
     
         13 . The apparatus of  claim 1 , further comprising one or more cooling elements thermally coupled to at least one of the first and the second continuous flow conduit. 
     
     
         14 . The apparatus of  claim 3 , further comprising a cooling element thermally coupled to the fourth vessel. 
     
     
         15 . The apparatus of  claim 14 , wherein the cooling element comprises a cooling bath. 
     
     
         16 . The apparatus of  claim 1 , further comprising one or more flow control members fluidly coupled to at least one of the first, the second, and the third vessels. 
     
     
         17 . The apparatus of  claim 1 , further comprising a gas purging member configured to purge the apparatus with nitrogen or argon atmosphere. 
     
     
         18 . The apparatus of  claim 1 , wherein the first and second continuous flow conduits are made of stainless steel. 
     
     
         19 . The apparatus of  claim 1 , wherein the first and the second vessels are made of stainless steel. 
     
     
         20 . The apparatus of  claim 3 , wherein the fourth vessel is not a continuous flow conduit and does not comprise a continuous outflow. 
     
     
         21 . The apparatus of  claim 3 , wherein the fourth vessel comprises the compound of Formula (IIa) or salt thereof. 
     
     
         22 . The apparatus of  claim 1 , wherein the compound of Formula (Ia) is 
       
         
           
           
               
               
           
         
       
       or salt thereof. 
     
     
         23 . The apparatus of  claim 2 , further comprising a fourth vessel, wherein the fourth vessel comprises tetrahydrofuran and is fluidly coupled with the first vessel to combine the lithium amide and the tetrahydrofuran before the lithium amide flowing into the first continuous flow conduit. 
     
     
         24 . The apparatus of  claim 23 , further comprising a fifth continuous flow conduit, wherein the fifth continuous flow conduit is fluidly coupled the fourth vessel and the first continuous flow conduit to deliver the tetrahydrofuran from the fourth vessel to the first continuous flow conduit. 
     
     
         25 . The apparatus of  claim 3 , wherein the fourth vessel is pressurized. 
     
     
         26 . The apparatus of  claim 2 , further comprising a third continuous flow conduit to fluidly couple the first vessel and the first continuous flow conduit and to deliver the lithium amide from the first vessel to the first continuous flow conduit. 
     
     
         27 . The apparatus of  claim 6 , wherein the first vessel is pressurized. 
     
     
         28 . The apparatus of  claim 24 , further comprising a fourth continuous flow conduit to fluidly couple the second vessel and the first continuous flow conduit and to deliver the compound of Formula (IIa) or (IIb) or salt thereof from the second vessel to the first continuous flow conduit. 
     
     
         29 . The apparatus of  claim 8 , wherein the second vessel is pressurized. 
     
     
         30 . The apparatus of  claim 2 , further comprising one or more cooling elements thermally coupled to the first continuous flow conduit. 
     
     
         31 . The apparatus of  claim 28 , further comprising one or more cooling elements thermally coupled to at least one of the third continuous flow conduit, the fourth continuous flow conduit, and the fifth continuous flow conduit. 
     
     
         32 . The apparatus of  claim 2 , further comprising a heating element thermally coupled to the second continuous flow conduit. 
     
     
         33 . The apparatus of  claim 2 , further comprising one or more cooling elements thermally coupled to at least one of the first and the second continuous flow conduit. 
     
     
         34 . The apparatus of  claim 23 , further comprising a cooling element thermally coupled to the fourth vessel. 
     
     
         35 . The apparatus of  claim 14 , wherein the cooling element comprises a cooling bath. 
     
     
         36 . The apparatus of  claim 2 , further comprising one or more flow control members fluidly coupled to at least one of the first, the second, and the third vessels. 
     
     
         37 . The apparatus of  claim 2 , further comprising a gas purging member configured to purge the apparatus with nitrogen or argon atmosphere. 
     
     
         38 . The apparatus of  claim 2 , wherein the first and second continuous flow conduits are made of stainless steel. 
     
     
         39 . The apparatus of  claim 2 , wherein the first and the second vessels are made of stainless steel. 
     
     
         40 . The apparatus of  claim 23 , wherein the fourth vessel is not a continuous flow conduit and does not comprise a continuous outflow. 
     
     
         41 . The apparatus of  claim 23 , wherein the fourth vessel comprises the compound of Formula (IIa) or salt thereof. 
     
     
         42 . The apparatus of  claim 2 , wherein the compound of Formula (Ia) is 
       
         
           
           
               
               
           
         
       
       or salt thereof.