Synthesis and preparations of duloxetine salts

Abstract

The invention relates to an improved process for the preparation of duloxetine hydrochloride.

1 . A process for preparing duloxetine and duloxetine intermediates comprising reacting (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol (Compound S-II) and 1-fluoronaphthalene (Compound III) and at least one alkaline metal hydroxide or alkoxide in DMSO or DMSO-cosolvent mixtures, where said process does not require the use of a phase transfer catalyst. 
   
   
       2 . The process of  claim 1 , further comprising the use of potassium carbonate or sodium sulphate. 
   
   
       3 . The process of  claim 1 , wherein said at least one alkaline metal hydroxide or alkoxide is at least one of NaOH, KOH, CsOH, sodium tert-butoxide, sodium tertpentoxide and potassium tertpentoxide. 
   
   
       4 . The process of  claim 1 , further comprising at least partially distilling the DMSO solvent or cosolvent such that water is removed and the rate of the reaction increases. 
   
   
       5 . A method for selectively purifying (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-1-propylamine (Compound IV) from (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol (Compound S-II) comprising forming a derivative of (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol (Compound S-II) in a solvent. 
   
   
       6 . The method of  claim 5 , wherein said derivative of (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol (Compound S-II) is an ester derivative. 
   
   
       7 . The method of  claim 5 , wherein said derivative of (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol (Compound S-II) is a mineral acid ester derivative. 
   
   
       8 . The method of  claim 5 , further comprising the use of pyridine sulfur trioxide to form a sulphate derivative of said (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol (Compound S-II). 
   
   
       9 . The method of  claim 5 , wherein said solvent is at least one of a hydrocarbon solvent, an ester solvent, an ether solvent and combinations thereof. 
   
   
       10 . The method of  claim 5 , wherein said solvent is at least one of heptane, toluene, ethyl acetate, isopropyl acetate, isobutyl acetate, tertbutyl methyl ether, tetrahydrofuran and combinations thereof. 
   
   
       11 . The method of  claim 9 , wherein said hydrocarbon solvent is at least one of heptane, toluene and combinations thereof. 
   
   
       12 . The method of  claim 9 , wherein said ester solvent is at least one of ethyl acetate, isopropyl acetate, isobutyl acetate and combinations thereof. 
   
   
       13 . The method of  claim 9 , wherein said ether solvent is at least one of methyl ether, tetrahydrofuran and combinations thereof. 
   
   
       14 . A method of demethylating (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-1-propylamine (Compound IV) comprising reacting Compound IV with 1-chloroethyl chloroformate in the presence of an acid scavenger in a solvent. 
   
   
       15 . (canceled) 
   
   
       16 . The method of  claim 14 , wherein the amount of said acid scavenger is approximately 0.02 to approximately 2 equivalents relative to Compound IV. 
   
   
       17 . The method of  claim 14 , wherein said amount of acid scavenger is approximately 0.05 to approximately 1 equivalents relative to Compound IV. 
   
   
       18 . The method of  claim 14 , wherein said amount of acid scavenger is approximately 0.1 equivalents relative to Compound IV. 
   
   
       19 . The method of  claim 14 , wherein said acid scavenger is a hindered tertiary amine. 
   
   
       20 . The method of  claim 19 , wherein said hindered tertiary amine is diisopropylethylamine. 
   
   
       21 . The method of  claim 14 , wherein said solvent is at least one of an aromatic solvent, an ester solvent, an ether solvent and combinations thereof. 
   
   
       22 . The method of  claim 14 , wherein said solvent is at least one of toluene, xylene, ethyl acetate, isopropyl acetate, isobutyl acetate, tertbutyl methyl ether, tetrahydrofuran and combinations thereof. 
   
   
       23 . The method of  claim 21 , wherein said aromatic solvent is at least on of toluene, xylene and combinations thereof. 
   
   
       24 . The method of  claim 21 , wherein said ester solvent is at least one of ethyl acetate, isopropyl acetate, isobutyl acetate and combinations thereof. 
   
   
       25 . The method of  claim 21 , wherein said ether solvent is at least one of tertbutyl methyl ether, tetrahydrofuran and combinations thereof. 
   
   
       26 . The method of  claim 14 , further comprising a treatment step with an alcohol, a ketone, an ether, water or mixtures thereof at a temperature of less than or equal to 50° C. 
   
   
       27 . The method of  claim 14 , further comprising a treatment step with an alcohol, a ketone, an ether, water or mixtures thereof at a temperature of less than or equal to 40° C. 
   
   
       28 . A method for synthesizing (S)-N-methyl-[3-(naphthalen-1-yloxy)-3-thiophen-2-yl-propyl]-carbamic acid 1-chloroethyl ester comprising reacting (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-1-propylamine (Compound IV) with 1-chloroethyl chloroformate in the presence of an acid scavenger. 
   
   
       29 . (canceled) 
   
   
       30 . The method of  claim 28 , wherein said acid scavenger is a hindered tertiary amine. 
   
   
       31 . The method of  claim 30 , wherein said hindered tertiary amine is diisopropylethylamine. 
   
   
       32 . A process for preparing (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt comprising:
 (i) reacting sodium hydroxide, potassium carbonate and (S)-3-dimethylamino-1-(2-thienyl)-1-propanol (20 g, 108 mmol) in DMSO;   (ii) adding 1-fluoronaphthalene to the mixture of step (i); and   (iii) reacting the product of step (ii) with oxalic acid dihydrate.   
   
   
       33 . The process of  claim 32 , wherein said (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt is obtained in an enantiomeric ratio of greater than or equal to approximately 94:6. 
   
   
       34 . (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt, Form B. 
   
   
       35 . The (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt, Form B of  claim 34 , wherein said (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt, Form B is characterized by an XRD (2 θ) spectrum having characteristic peaks at approximately 8.7°, 15.7°, 17.3°, 17.9°, 20.4°, 22.8°, 26.0°, 29.4°, 35.1°, 21.1° and 36.0°. 
   
   
       36 . The (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt, Form B of  claim 35 , wherein said (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt, Form B is further characterized by an XRD (2 θ) spectrum having additional peaks at approximately 9.4°, 12.4°, 24.2°, 25.8°, 27.3°, 27.5° and 36.9°. 
   
   
       37 . (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt, Form C. 
   
   
       38 . The (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt, Form C of  claim 37 , wherein said (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt, Form C is characterized by an XRD (2 θ) spectrum having characteristic peaks at approximately 6.3°, 9.3°, 12.5°, 15.6°, 17.2°, 18.7°, 19.8°, 21.4°, 21.9°, 25.0° and 27.9°. 
   
   
       39 . The (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt, Form C of  claim 38 , wherein said (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt, Form B is further characterized by an XRD (2 θ) spectrum having additional peaks at approximately 10.1°, 12.1°, 14.5°, 17.8°, 23.4°, 24.4° and 25.7°. 
   
   
       40 . (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt, Form E. 
   
   
       41 . The (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt, Form E of  claim 40 , wherein said (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt, Form B is characterized by an XRD (2 θ) spectrum having characteristic peaks at approximately 8.2°, 10.0°, 13.1°, 16.5°, 17.6°, 18.6°, 20.0°, 20.5°, 21.1°, 22.6°, 23.1° and 24.6°. 
   
   
       42 . The (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt, Form E of  claim 41 , wherein said (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt, Form B is further characterized by an XRD (2 θ) spectrum having additional peaks at approximately 11.9°, 18.2°, 18.8°, 19.1°, 20.2°, 21.7°, 22.4°, 25.6°, 26.3°, 27.7°, 28.7° and 30.3°. 
   
   
       43 . The method of  claim 5 , wherein said solvent comprises isopropyl acetate.