Process for the preparation of citalopram
The present invention provides, inter alia, a novel process for the preparation of Citalopram, a known antidepressant.
1 . A method for preparing a compound of Formula IV having the following structure:
said method comprising:
(a) contacting a salt of the compound of Formula III having the following structure:
with about 2 to about 10 equivalents of phosphoric acid to form a reaction mixture;
(b) adding an organic solvent to said reaction mixture; and
(c) quenching said reaction mixture with base to form a product mixture comprising said compound of Formula IV.
2 . The method of claim 1 , wherein said salt of the compound of Formula III is a HCl salt.
3 . The method of claim 1 , wherein said phosphoric acid is 20% phosphoric acid.
4 . The method of claim 1 , wherein said compound of Formula III is contacted with about 6 to about 9 equivalents of 20% phosphoric acid.
5 . The method of claim 1 , wherein said compound of Formula III is contacted with about 9 equivalents of 20% phosphoric acid.
6 . The method of claim 1 , wherein said organic solvent in step (b) is a member selected from the group consisting of toluene, benzene, xylene, diethylether, t-butylmethylether, dioxane, and mixtures thereof.
7 . The method of claim 1 , wherein said organic solvent in step (b) is toluene.
8 . The method of claim 1 , wherein said base is a member selected from the group consisting of ammonium hydroxide, sodium hydroxide and potassium hydroxide.
9 . The method of claim 1 , wherein said base is aqueous ammonium hydroxide.
10 . The method of claim 1 , further comprising:
(c) isolating said compound of Formula IV from said product mixture.
11 . The method of claim 10 , wherein step (c) comprises:
(i) separating the organic phase and the aqueous phase;
(ii) re-extracting the aqueous phase with toluene;
(iii) combining the organic phases to form a combined organic phase and washing said combined organic phase with water; and
(iv) distilling said washed organic phase to obtain the compound of Formula IV.
12 . A method for preparing a compound of Formula V having the following structure:
said method comprising:
(a) contacting a compound of Formula IV having the following structure:
with a mixture of cuprous cyanide and sodium cyanide to form a reaction mixture;
(b) heating said reaction mixture until the reaction is complete; and
(c) quenching said reaction mixture to form a product mixture comprising said compound of Formula V.
13 . The method of claim 12 , wherein said compound of Formula IV is in a first organic solvent.
14 . The method of claim 13 , wherein said first organic solvent is a member selected from the group consisting of toluene, benzene, xylene, diethylether, t-butylmethylether, dioxane, and mixtures thereof.
15 . The method of claim 14 , wherein said first organic solvent is toluene.
16 . The method of claim 12 , wherein said mixture of cuprous cyanide and sodium cyanide is in a second organic solvent.
17 . The method of claim 16 , wherein said second organic solvent is a member selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidione, quinoline, collidine, xylene, dimethylsulfone, hexamethylphosphoramide and trifluoromethylchlorobenzene.
18 . The method of claim 16 , wherein said second organic solvent is N,N-dimethylformamide.
19 . The method of claim 12 , wherein the ratio of cuprous cyanide:sodium cyanide in said mixture of cuprous cyanide and sodium cyanide is about 2.5:1.0 to about 1:2.5.
20 . The method of claim 12 , wherein the ratio of cuprous cyanide:sodium cyanide in said mixture of cuprous cyanide and sodium cyanide is about 0.50:1.0 to about 2.5:1.
21 . The method of claim 12 , wherein the ratio of cuprous cyanide:sodium cyanide in said mixture of cuprous cyanide and sodium cyanide is about 0.75:1.0 to about 1.0:1.0.
22 . The method of claim 13 , wherein said first organic solvent is removed from said reaction mixture prior to step (b).
23 . The method of claim 12 , wherein said reaction mixture is quenched with a member selected from the group consisting of aqueous sodium cyanide and aqueous potassium cyanide.
24 . The method of claim 20 , wherein said reaction mixture is quenched with 10% aqueous sodium cyanide.
25 . The method of claim 12 , further comprising:
(d) isolating said compound of Formula V from said product mixture.
26 . The method of claim 21 , wherein step (d) comprises:
(i) adding ethylenediamine and a first organic solvent to said reaction mixture and separating the organic phase and the aqueous phase;
(ii) re-extracting the aqueous phase with said first organic solvent;
(iii) combining the organic phases to form a combined organic phase and back-extracting the combined organic phase with an acid to form an acid extract;
(iv) neutralizing said acid extract with a base to a pH of about 8.5 to about 11 to form a neutralized extract;
(v) extracting said neutralized extract with a second organic solvent to form a second organic solvent extract;
(vi) treating said second organic solvent extract with charcoal and removing said second organic solvent to generate the compound of Formula V.
27 . The method of claim 26 , wherein said first and second organic solvents are independently selected from the group consisting of toluene, benzene, xylene, diethylether, t-butylmethylether, dioxane, and mixtures thereof.
28 . The method of claim 27 , wherein said first and second organic solvents are both toluene.
29 . The method of claim 26 , wherein said acid in step (iii) is a member selected from the group consisting of HCl, HBr, H 2 SO 4 , H 3 PO 4 , trifluoroacetic acid and acetic acid.
30 . The method of claim 29 , wherein said acid in step (iii) is 20% aqueous acetic acid.
31 . The method of claim 26 , wherein said base in step (iv) is a member selected from the group consisting of sodium hydroxide, potassium hydroxide and sodium carbonate.
32 . The method of claim 26 , wherein said base in step (iv) is sodium hydroxide.
33 . The method of claim 26 , wherein in step (iv) said acid extract is neutralized with said base to a pH of about 9 to about 10.
34 . The method of claim 26 , wherein said compound of Formula V is further purified using simulated moving bed chromatography having a stationary phase and a mobile phase.
35 . The method of claim 34 , wherein the stationary phase is a reverse phase silica gel and the mobile phase is an organic solvent/water mixture.
36 . The method of claim 35 , wherein said reverse phase silica gel is a C 18 -derivatized silica gel.
37 . The method of claim 35 , wherein the pH of the mobile phase is about 1.5 to about 4.0.
38 . The method of claim 37 , wherein the pH of the mobile phase is about 2.5.
39 . The method of claim 37 , wherein the pH of the mobile phase is maintained by the addition of 0.1 to 2% trifluoroacetic acid.
40 . The method of claim 35 , wherein said organic solvent in the mobile phase is methanol.
41 . The method of claim 35 , wherein said organic solvent in the mobile phase is ethanol.
42 . The method of claim 35 , wherein said organic solvent in the mobile phase is acetonitrile.
43 . The method of claim 34 , wherein the stationary phase is a normal phase silica gel and the mobile phase is an organic solvent mixture.
44 . The method of claim 42 , wherein said organic solvent mixture is a mixture of an alcohol, a hydrocarbon and an organic base.
45 . The method of claim 43 , wherein said alcohol is a member selected from the group consisting of methanol, ethanol, n-propanol and isopropanol.
46 . The method of claim 43 , wherein said hydrocarbon is a member selected from the group consisting of heptane, n-heptane, hexane, isohexane, toluene, cyclohexane, benzene and combinations thereof.
47 . The method of claim 43 , wherein said organic base is a member selected from the group consisting of triethylamine, diethylamine, trimethylamine, dimethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine and diethylisopropylamine.
48 . The method of claim 43 , wherein said organic base is present in said organic solvent mixture at about 0.05 to about 5%.
49 . The method of claim 48 , wherein said organic base is present in said organic solvent mixture at about 0.1 to about 0.5%.
50 . The method of claim 48 , wherein said organic base is present in said organic solvent mixture at about 0.2 to about 0.4%.
51 . The method of claim 43 , wherein said organic solvent mixture is a mixture of ethanol, heptane and triethylamine.
52 . The method of claim 34 , wherein the stationary phase is a chiral phase silica gel and the mobile phase is an organic solvent mixture.
53 . The method of claim 52 , wherein said organic solvent mixture is a mixture of an alcohol, a hydrocarbon and an organic base.
54 . The method of claim 53 , wherein said alcohol is a member selected from the group consisting of methanol, ethanol, n-propanol and isopropanol.
55 . The method of claim 53 , wherein said hydrocarbon is a member selected from the group consisting of heptane, n-heptane, hexane, isohexane, toluene, cyclohexane, benzene and combinations thereof.
56 . The method of claim 53 , wherein said organic base is a member selected from the group consisting of triethylamine, diethylamine, trimethylamine, dimethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine and diethylisopropylamine.
57 . The method of claim 53 , wherein said organic base is present in said organic solvent mixture at about 0.05 to about 5%.
58 . The method of claim 57 , wherein said organic base is present in said organic solvent mixture at about 0.1 to about 0.5%.
59 . The method of claim 57 , wherein said organic base is present in said organic solvent mixture at about 0.2 to about 0.4%.
60 . The method of claim 26 , wherein said compound of Formula V is further purified using single column chromatography having a stationary phase and a mobile phase.
61 . A method for preparing a compound of Formula VI having the following structure:
said method comprising:
(a) dissolving a compound of Formula V having the following structure:
in an organic solvent to form a reaction mixture; and
(b) contacting said reaction mixture with HBr to form a product mixture comprising said compound of Formula VI.
62 . The method of claim 50 , wherein said organic solvent in step (a) is a member selected from the group consisting of acetone, methylethylketone, ethylacetate, toluene, benzene, xylene, diethylether, t-butylmethylether, dioxane, and mixtures thereof.
63 . The method of claim 51 , wherein said organic solvent in step (a) is diethylether.
64 . The method of claim 51 , wherein said organic solvent in step (a) is acetone.
65 . The method of claim 51 , wherein said HBr is gaseous HBr.
66 . The method of claim 51 , wherein said HBr is aqueous HBr.
67 . The method of claim 50 , further comprising:
(c) isolating said compound of Formula VI from said product mixture.
68 . The method of claim 50 , wherein step (c) comprises:
(i) cooling the product mixture and filtering said product mixture to obtain the compound of Formula VI as a precipitated solid;
(ii) washing said precipitated solid with an organic solvent; and
(iii) drying said precipitated solid to obtain the compound of Formula VI.
69 . The method of claim 55 , further comprising (iv) recrystallizing the compound of Formula VI.
70 . The method of claim 56 , wherein said compound of Formula VI is recrystallized from a solvent mixture of toluene and methanol.
71 . The method of claim 56 , wherein step (iv) comprises:
(i′) combining said precipitated solid with toluene and methanol to form a mixture and heating said mixture;
(ii′) filtering said mixture through Celite and slowly cooling said mixture;
(iii′) filtering said mixture to obtain the crystallized solid, washing the crystallized solid with toluene, and drying said crystallized solid to obtain the compound of Formula VI.
72 . The method of claim 58 , wherein in step (ii′) said mixture is cooled to about ambient temperature.
73 . The method of claim 58 , wherein in step (ii′) said mixture is cooled to about 0° C. to about 5° C.
74 . The method of claim 56 , wherein step (iv) comprises:
(i′) combining said precipitated solid with methanol and isopropylalcohol to form a mixture and heating said mixture;
(ii′) filtering said mixture through Celite and slowly cooling said mixture;
(iii′) filtering said mixture to obtain the crystallized solid, washing the crystallized solid with isopropylalcohol, and drying said crystallized solid to obtain the compound of Formula VI.
75 . A method for removing demethyl- and/or didemethyl-impurities from a mixture of Citalopram containing demethyl- and/or didemethyl impurities in a solvent, said method comprising:
(a) contacting said mixture of Citalopram with a scavenger resin having a functional group that is reactive with a primary or secondary amine to form resin-bound demethyl- and/or didemethyl impurities, wherein said scavenger resin is insoluble in said solvent; and
(b) filtering said resin-bound demethyl- and/or didemethyl-impurities, thereby removing said demethyl and/or didemethyl-impurities from said mixture of Citalopram.
76 . The method of claim 75 , wherein said functional group is a member selected from the group consisting of isocyanates, isothiocyanates, acid chlorides, esters and anhydrides.
77 . The method of claim 75 , wherein said scavenger resin is a polystene-based resin.
78 . The method of claim 75 , wherein said scavenger resin is a silica gel-based resin.
79 . The method of claim 77 , wherein said polystene-based resin has the following structure:
wherein R is a member selected from the group consisting of isocyanates, isothiocyanates, acid chlorides, esters and anhydrides.