Synthesis and preparations of duloxetine salts

Abstract

The invention relates to an improved process for preparing duloxetine hydrochloride. More particularly, the invention relates to the preparation of duloxetine hydrochloride by a process that provides a maximum yield of desired product with a minimum amount of undesired by-products.

1 - 4 . (canceled) 
   
   
       5 . Duloxetine and its pharmaceutically acceptable salts containing less than approximately 0.1% area by HPLC of 4-(3-methylamino-1-thiophen-2-yl-propyl)-naphthalen-1-ol (“Compound II”) having the formula: 
     
       
         
         
             
             
         
       
     
     or a salt thereof. 
   
   
       6 . Duloxetine hydrochloride containing less than approximately 0.1% area by HPLC of Compound II or a salt thereof. 
   
   
       7 . A method for preparing duloxetine hydrochloride comprising converting (S)—N-methyl-[3-(naphthalen-1-yloxy)-3-thiophen-2-yl-propyl]-carbamic acid 1-chloroethyl ester to duloxetine hydrochloride, wherein said duloxetine hydrochloride has less than approximately 0.1% area by HPLC of Compound II or a salt thereof. 
   
   
       8 . A method for preparing duloxetine hydrochloride comprising converting duloxetine base to duloxetine hydrochloride, wherein said duloxetine hydrochloride has less than approximately 0.1% area by HPLC of Compound II or a salt thereof. 
   
   
       9 . The of method  claim 8 , wherein said converting comprises contacting said duloxetine base with ammonium chloride to yield duloxetine hydrochloride. 
   
   
       10 . A formulation comprising duloxetine hydrochloride, wherein said duloxetine hydrochloride has less than approximately 0.1% area by HPLC of Compound II or a salt thereof. 
   
   
       11 . The formulation of  claim 10 , further comprising at least one of a pharmaceutically acceptable diluent and a carrier. 
   
   
       12 . The formulation of  claim 10 , further comprising at least one additional excipient material. 
   
   
       13 . The formulation of  claim 12 , wherein said at least one additional excipient material is at least one of an inert diluent, a granulating and disintegrating agent, a binding agent, a lubricating agent, a preservative agent, an anti-oxidant and combinations thereof. 
   
   
       14 . The formulation of  claim 13 , wherein said inert diluent is at least one of lactose, sodium carbonate, calcium phosphate, calcium carbonate and combinations thereof. 
   
   
       15 . The formulation of  claim 13 , wherein said granulating and disintegrating agent is at least one of corn starch, algenic acid and combinations thereof. 
   
   
       16 . The formulation of  claim 13 , wherein said binding agent is starch. 
   
   
       17 . The formulation of  claim 13 , wherein said lubricating agent is at least one of magnesium stearate, stearic acid, talc and combinations thereof. 
   
   
       18 . The formulation of  claim 13 , wherein said preservative agent is at least one of ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate and combinations thereof. 
   
   
       19 . The formulation of  claim 13 , wherein said anti-oxidant is ascorbic acid. 
   
   
       20 . A process for producing duloxetine hydrochloride having less than approximately 0.1% area by HPLC of Compound II or a salt thereof comprising converting duloxetine base to duloxetine hydrochloride, wherein said process does not require a procedure to separate Compound II or a salt thereof from said duloxetine hydrochloride. 
   
   
       21 . 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol (Compound III) having the formula: 
     
       
         
         
             
             
         
       
     
     and salts thereof, wherein said Compound III and its salts are obtained during the production of duloxetine hydrochloride. 
   
   
       22 . A salt of Compound III according to  claim 21 , wherein said salt is the hydrochloride salt. 
   
   
       23 . The hydrochloride salt of  claim 22  characterized by  1 H NMR (400 MHz, d6-DMSO, 25° C.) having characteristic peaks at approximately 10.25 (1H, s), 8.17 (1H, dd), 8.12 (1H, d), 7.5-7.4 (3H, m), 7.27 (1H, dd), 7.07 (1H, d), 6.93 (1H, d), 6.91 (1H, dd), 5.06 (1H, t), 2.93 (2H, m), 2.7-2.5 (8H, m). 
   
   
       24 . The hydrochloride salt of  claim 22  characterized by  13 C NMR (100.6 MHz, d6-DMSO, 25° C.) having characteristic peaks at approximately 152.6, 149.0, 132.2, 129.2, 126.8, 126.5, 125.2, 124.6, 124.4, 124.4, 123.3, 122.9, 107.8, 55.7, 42.3, 37.9, 31.3. 
   
   
       25 . A method of measuring the purity of duloxetine and its pharmaceutically acceptable salts comprising measuring the quantity of at least one of Compound III and a salt thereof in at least one of a sample of duloxetine, its pharmaceutically acceptable salts and combinations thereof. 
   
   
       26 . A process for preparing Compound II and salts thereof comprising converting Compound III and salts thereof into Compound II and salts thereof. 
   
   
       27 . A process for preparing Compound II and salts thereof comprising converting Compound III and salts thereof into Compound II and salts thereof.