CA2455954A1

CA2455954A1 - 4-phenylpiperidine compounds

Info

Publication number: CA2455954A1
Application number: CA002455954A
Authority: CA
Inventors: Franciscus Bernardus Gemma Benneker; Frans Van Dalen; Jacobus Maria Lemmens; Theodorus Hendricus Antonium Peters; Frantisek Picha
Original assignee: Individual
Current assignee: Synthon BV
Priority date: 1997-06-10
Filing date: 1997-06-10
Publication date: 1998-12-17

Abstract

The invention relates to a compound, and pharmaceutically acceptable salts, having formula (I), wherein: R represents an alkyl or alkynyl group having 1-4 carbon atoms, or a phenyl group optionally substituted by C 1-4 alkyl, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl or methylenedioxy, or represents tetrahydronaphthyl; R 1 represents hydrogen, trifluoro (C 1-4 ) alkyl, alkyl or alkynyl; X represents hydrogen, alkyl having 1-4 carbon atoms, alkoxy, trifluoroalkyl, hydroxy, halogen, methylthio or aralkoxy; R 2 represents: a C 1 -C 10 alkyl group; a phenyl group optionally substituted by one or more of the following groups: a C 1 -C 10 alkyl group, a halogen group, a nitro group, hydroxy group, and/or an alkoxy group.

Description

This is a divisional application of Canadian application No. 2,293,247. The parent application describes sulfonate salts of paroxetine analogs, a process for their preparation and medical uses thereof. The present divisional application is directed to a process for preparing high purity non-sulfonate salts of paroxetine analogs, free bases thereof and products made therefrom.
The present invention relates to a group of tri-substituted, 4-phenylpiperidines, to a process for preparing such compounds, to a medicament comprising such compounds, and to the use of such compounds for the manufacture of a medicament.
The compound paroxetine, trans-4-(4'-fluorophenyl)-3-(3',4'-methylene dioxyphenoxymethyl)piperidine having the formula below:
F

\ \
o -0 N
H
is known and has been used in medicaments for treating, amongst other ailments, depression.
Paroxetine has been used as a therapeutic agent in the form of a salt with pharmaceutically acceptable acids.
The first clinical trials were conducted with the acetate salt.

la A known useful salt of paroxetine is the hydrochloride. This salt is considered to be the active substance in several marketed pharmaceutical products, e.g.
Paxil or Seroxat. A number of forms of paroxetine hydrochloride have been described:
- the anhydrous form in several crystalline modifications (PCT Appl. WO 96/24595);

- the hydrated form - a hemihydrate (EP 223403) and in the solvated forms.
The comparison of behaviour between anhydrous and hydrated form of paroxetine hydrochloride is descri-bed in the Intl. Journal of Pharmaceutics, 42, 135-143 (1988) .
EP 223403 discloses paroxetine hydrochloride hemihydrate and pharmaceutical compositions based thereon.
Most of these known salts of paroxetine have unsuitable physico-chemical characteristics for ensuring safe and efficient handling during production thereof and formulation into final forms, since they are unstable (acetate, maleate) and possess undesirable hygroscopi-city.
Furthermore their formation by crystallization from both aqueous or non-aqueous solvents is generally low-yielded and troublesome as they usually contain an undefined and unpredicted amount of bound solvent which is difficult to remove.
The crystallir_e paroxetine hydrochloride hemihydrate approaches these problems, but as stated in WO 95/16448, its limited photostability causes undesired colouration during classical wet tabletting procedure.
Moreover, crystalline paroxetine hydrochloride hemihydrate exhibits only limited solubility in water.
It has been generally suggested that where the aqueous solubility is low, f or example less than 3 mg/ml, the dissolution rate at in vivo administration could be rate-limiting in the absorption process. The aqueous solubility of the paroxetine hemihydrate at room temperature exceeds this threshold by a relatively small margin.
An object of the present invention is to provide a compound with improved characteristics.
According to a first aspect, the invention of the parent application comprises a compound, and pharmaceutically acceptable salts, having the formula I:

X

~OR

HO- S-RZ

R represents an alkyl or alkynyl group having 1-4 carbon atoms, or a phenyl group optionally substituted by C1_4 alkyl, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl or methylenedioxy, or represents tetrahydronaphthyl, R1 represents hydrogen, trifluoro (C1_4) alkyl, alkyl or alkynyl, X represents hydrogen, alkyl having 1-4 carbon atoms, alkoxy, trifluoroalkyl, hydroxy, halogen, methylthio, or aralkoxy, R2 represents:
- a C1-Clo alkyl group, - a phenyl group optionally substituted by one or more of the following groups:
- a C1-Clo alkyl group, - a halogen group, - a nitro group, - hydroxy group, - and/or an alkoxy group.

3a The invention of the parent application in another aspect further provides a compound of formula I:

X

'OR

H O-RZ

wherein:
- R represents a 3'4'-methylene-dioxyphenyl group, - R1 is hydrogen, - X is halogen, - R2 is - C1-Clo alkyl or - phenyl optionally substituted by one or more of:
- C,,-Clo alkyl ;
- halogen;
- nitro;
- hydroxy; and - alkoxy;
or a pharmaceutically acceptable salt thereof.
The inventors have found that the above compounds exhibit good stability and very high solubility. This yields the advantage that high concentrations of the compound are obtainable in small volumes.

3b compound described above, comprising the steps of (a) mixing together one or more of a compound formula II:
(II) a salt thereof and a base thereof;
wherein:
- R is a 3~4~-methylene-dioxyphenyl group;
- R1 is hydrogen;
- X is halogen;
with a sulfonic acid of formula RZ-S03H, wherein Rz i s :
- C1-Clo alkyl, or - phenyl optionally substituted by one or more of:
- C1-Clo alkyl;
- halogen;
- nitro;
- hydroxy; and - alkoxy;
to form a solution, and (b) precipitating the compound out of the solution.

3c The inventors have found that the above compounds exhibit good stability and very high solubility. This yields the advantage that high concentrations of the compound are obtainable in small volumes.

The R group is preferably the 3,4 methylenedioxyphenyl group of the formula:
~o The X group is preferably a fluorine group attached to position 4 in the phenyl ring.
The R2 group preferably represents a C1-C4 alkyl group, and most preferably represents a C1-C2 alkyl group in order to provide an optimum solubility.
The compounds can have a solubility at about 20°C of at least about. l0 mg/ml water, preferably having a solubility in water of at least 100, for example 500 and most preferably of at least 1000 mg/ml water.
According to another aspect of the invention of the parent application, there is provided a process for preparing a compound as above, comprising the steps of mixing together a 4 phenylpiperidine compound, a salt and/or a base thereof having the formula II:

wherein:
X
OR
R' - R represents an alkyl or alkynyl group having 1-4 carbon atoms, or a phenyl group optionally substituted by C1_5 alkyl, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl or methylenedioxy, or represents tetrahyd~onaphthyl, - R1 represents hydrogen, trifluoro (C1_4) alkyl, alkyl or alkynyl, 5 - X represents hydrogen, alkyl having 1-4 carbon atoms, alkoxy, trifluoroalkyl, hydroxy, halogen, methylthio or aralkoxy, with a sul Tonic acid of the general formula R2-S03H, wherein R' represents - a C1-C10 alkyl group, - a phenyl group optionally substituted by one or more of the following groups - a C1-C10 alkyl group, - a halogen group, - a nitro group, - a.hydroxy groups and/or - an alkoxy group, to form a solution, followed by separating the compound formed frcm this solution.
The compounds of the invention can be prepared from the Free base of the 4 phenylpiperidine, having the formula __, this preferably being paroxetine, by treatment with a sulfonic acid as defined above in a suitable solvent to form a solution of the desired acid additicn salt, whereafter this is precipitated out of the solution.
The equation for paroxetine free base and sulfonic acids is as follows:
F i O
.. O
+ HO-.S -RZ ----.,.
O ."'~n~ ~ _ fi0-6-R~

The forming of a solution may preferably proceed at temperatures from about 0°C to the boiling point of the solvent.
Optionally, the solution may be purified by treatment of activated charcoal, silica gel, kieselguhr or other suitable materials.
Alternatively, the solution of a salt of the invention can be formed by dissolution of a salt of 4 phenyl piperidine having the formula II with an organic sulfonic acid.
For example the compounds of the invention may be prepared from a paroxetine C1-CS carboxylate, such as the acetate, by addition of corresponding organic sulfonic acid to the solution of the said carboxylate, as follows:
F F
\ \

/ / 0 ~~ / / 0 0> + HO-5-Rz~ .~~~ \
::\o \ 0 0 0 N~ - N~ II
HOAc H ~ HOS-Rz According to a further aspect of the invention of the parent application, there is provided a compound obtainable by the above process.
According to another aspect of the invention of the parent application there is provided the above compound for use as a medicament and, according to another aspect, a medicament comprising this compound, and to the use thereof for treating depressions, obsessive compulsive disorders, 6a panic disorders, bulimia, anorexia, pain, obesity, senile dementia, migraine, anorexia, social phobia, depressions arising from pre-menstrual tension.
According to another aspect of the invention of the present divisional application, there is provided the use of a compound of the invention as a reagent in further syntheses. More specifically, the compounds of the present invention can be used as a start reagent f or forming further acid addition salts, for example for providing further paroxetine acid addition salts, by reacting with a suitable reagent, i.e. with a corresponding acid. For example, the formation of paroxetine maleate according to the present invention proceeds by the following equation:
F F
O ON O
.~"~O~O ? OH ~ ~~~O~O
~ HO-S ~ RZ
H O H HO
1 ~ HO
a O
and the formation of paroxetine acetate proceeds as follows:
F F
O O
NOAc ----O ~~O O
2 S H . HO ~-Cti,~ H ~ HOAC
H p H
This is an advantageous route, since by using the substantially pure sulfonic acid salts according to the present invention as a start reagent, the preparation of a further salt, as above, results in this further salt having a high purity. The inventors have shown that such salts have a surprisingly high purity.

7a According to one aspect of the invention of the present divisional application, there is provided a process for preparing a non-sulfonate salt of a paroxetine analog, the process comprising mixing (a) one or more of a compound of formula I:

X

'OR

H S-R
O- z wherein:
R represents a 3'4'-methylene-dioxyphenyl group R1 is hydrogen X is halogen R2 is: i) C1-Clo alkyl or ii) phenyl optionally substituted by one or more of:
- C1-Clo alkyl ;
halogen;
- nitro;
- hydroxy; and - alkoxy;
or a pharmaceutically acceptable salt thereof, with (b) a reagent selected from the group consisting of hydrochloric acid, oxalic acid, hydrobromic acid, succinic acid, hydriodic acid, tartaric acid, acetic acid, citric 7b acid, propionic acid, embonic acid, pamoic acid, malefic acid, sulfuric acid, and fumaric acid.
According to another aspect of the invention of the present divisional application a process for providing a free base paroxetine analog, the process comprising mixing (a) one or more of a compound of formula I:

X

~OR

H S-R
O- z wherein:
R represents a 3'4'-methylene-dioxyphenyl group R1 is hydrogen X is halogen RZ is : i ) CI-Clo alkyl or ii) phenyl optionally substituted by one or more of:
- C1-Clo alkyl;
- halogen;
- vitro;
- hydroxy; and - alkoxy;
or a pharmaceutically acceptable salt thereof, with (b) one or more of a base selected from an organic base and an inorganic base.

7c Similarly, the compounds of the present invention can react with a base, such as an inorganic and/or an organic base, to form (liberate) free bases of the corresponding compounds. As exemplified on S
paroxetine, the reaction proceeds according to the equation:
F F -i ~ p NaOH ~ ~ e ~ ~ + CH SO Na .,ate \ I p O~O
OO
HO-S-CHI
H O H
The free bases liberated from the compounds of the present invention have surprisingly higher purity than if prepared by known methods which is especially important in case of their use for production of pharmaceuticals.
Accordingly, the new compounds of the first aspect o. the invention can also form hydrates and/or solvates by a contact with a corresponding reaction partner, i~.e. with water and/or with a solvent. Examples of such Further salts, hydrates and solvates, for example these of paroxetine, are the:
hydrochloride oxalate .. dehydrate hydrobromide succinate trihydrate hydroiodide tartrate hexahydrate -acetate citrate methanolate propionate embonate ethanolate maleate hemihydrate fumarate hydrate The inventors have shown that such salts have a surprisingly high purity.
Examples of bases which can be employed in the preparation of the free bases are: sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, sodium carbonate, methylamine, dimethylamine, triethylamine, pyridine and such like.
Since the compounds according to the present invention exhibit high solubility, they can be dosed, for example injected, in a high concentration, low volume solution, this method of dosing being particularly advantageous with certain patients, such as manic ,_ depressives and such like, i.e. patients who are unable or unwilling to swallow medicine.
The compounds of the present invention can be formulated into various types of pharmaceutical compositions for treatmer~t of humans and animals.
Pharmaceutical compositions according to the present invention comprise a compound of the invention alone or together with a pharmaceutically acceptable carrier or diluent. The preferred formulations are those for oral administration (tablet s capsules) but formulations for parenteral or topical administration are also within the scope of the invention. The high water solubility of the compounds of the invention enables high dissolution rates in solid dosage forms based on the compounds of the invention to be obtained, during the in vitro release as well as good bioavailability after peroral application in vivo.
The tablets containing compounds of the present invention can be prepared both by tabletting procedure in which water is present (e. g, aqueous granulation) as well as by tabletting processing it which water is absent (direct compression, dry granulation) and may be coated by any suitable means of coating.
The present invention will now be further elucidated by way of the following examples and results.
EXPERIMENTAL
A seeding crystal of paroxetine methane sulfonate was made as follows:
2.? g (8.2 mmol) of paroxetine was dissolved in 15 ml of hot ethanol.
1.0 g (10.4 mmol) of methanesulfonic acid in 15 ml of ethanol was added and the mixture was cooled to room temperature. When the mixture had reached room temperature the mixture was~put in the freezer at -20°C overnight. No crystal line compound was obtained.
The mixture was evaporated to dryness leaving 5 an oil. .
After 1 month at room temperature a waxy solid was obtained. Part of this solid was taken apart and the rest was dissolved in 10 m1 of EtOAc. The waxy crystals were added and the 10 mixture was put in the freezer at -20°~
overnight. A white crystalline product was precipitated. After filtration and drying in a vacuumoven .
2.5 g (~.9 mmol) of paroxetine methane sulfonate was obtained.
Yield 72%
This seeding crystal was subsequently used in following examples 1 and 3.
Examples Example 1 s.
Paroxetine methane sulfor~ate from paroxetine To a solution of 43.5 g (132 mmol) of paroxetine, prepared by the procedure disclosed in US
4007196, 12.7 g (132 mmol) of methane sulfonic acid was added to 150 ml of boiling ethyl acetate. The mixture was left at room temperature for 2 hours. Subsequently the mixture was placed overnight at -20°C, with a seeding crystal. The obtained solid was -filtered off and washed with 50 ml of ether. The obtained white solid was dried overnight in a vacuumoven.
47.1 g (111 mmol) of product Yield 99.5%

Analytical characterization of the compound ..
obtained is shown in Table 1. The purity of the compound obtained was 98~ (HPLC).
Example 2 Paroxetine benzene sulfonate from paroxetine 3.8 g (11.5 mmol) of paroxetine was dissolved in ml of hot ethylacetate.

10 1.82 g (11.5 mmol) of anhydrous benzenesulfonic acid was added. The mixture was left at room temperature for 2 h. The mixture was evaporated to dryness and dissolved in dichloromethane, and evaporated again to dryness leaving an oil.

This oil was solidified through high vacuum (0.1 mmHg) evaporation leaving 5.0 g (1.3 mmol) of an off white solid. To this solid was added 5 ml of acetone and the suspension was stirred for 5 minutes during which a white suspension was obtained. The solid was filtered off and dried under vacuum.

4.8 g (9.9 mmol) of product~was obtained.

Yield 85%

Analytical characterization of the compound obtained is shown in Table 1. The purity of the compound obtained was 99.4% (HPLC).

Example 3 Faroxetine p-toluene sulf ovate from oaroxetine 5.0 g (15 mmol) of paroxetine was dissolved in 25 ml of hot ethylacetate. _ 2.9 g (15 mmol) of p-toluenesulfonic acid was added.
The mixture was left at room temperature for 2 h and subsequently put in the freezer, with a seeding crystal, f or 14 h. The solid was filtered off and washed once with ml of n-Hexane. The obtained white solid was~dried overnight in a vacuumoven.
4.8 g (10 mmol) of a white solid was obtained.
Yield 670 5 Analytical characterization of the compound obtained i's shown in Table 1. The purity of the compound obtained was 99.40 (HPLC).
10 Example 4 y Paroxetine t~-chlorobenzene sulfonate from paroxetine 1.1 g (3.3 mmol) of paroxetine was dissolved in 3 ml of hot ethylacetate.
0.7& g (3.3 mmol) of 90% p-chlorobenzenesulfonic acid was added. The mixture was left at room temperature fcr 1 h and washed with 5 ml of water. The organic layer was dried with Na2S09, filtered and evaporated to dryness leaving 1.5 g (2.9 mmol) of an off white solid.
Yield 88%
Analytical characterization of the compound obtained is shown in Table 1. The purity of the compound obtained was 99.40 (HPLC).
Example 5 Paroxetine maleate from paroxeti_nemethanesulfonate 1.0 g (2.4 mmol) of paroxetine methane sulfonate in 5 ml of hot water. To this solution was added 0.32 g (2.8 mmol) of malefic acid. The mixture was placed at 4°C overnight after which a solid with a yellow oil was precipitated on the _ bottom of the flask. The solid/oil was filtered off and washed 3 times with 10 ml of ether and dried in a vacuumoven.
0.8 g (2.0 mmol) off white crystals were obtained Yield 85 0 ' 13 The purity of the compound obtained was 99.5%
t~:fLC) .
~:xam~l a Y~z~Qxet~ne acer.nte from paroxetine methane sulfonate 1.0 g t2.4 mmol) of paroxetine methane sulfonate in 5 ml of hit iso-propanol. To this solution was added 0.2 g (3.2 mmol) of acetic acid. The mixture was l0 placed at 4°C overnight after which a so3.id was precipitated. The solid was filtered off and washed 3 times with ml of ether and dried in a vacuumoven.
0.5 g (1.3 mrnol) off white crystals were obtained Yield 54%
The purity of the compound obtained was 99.5%
( HPLC ) .
Example 7 Paroxetine free base from paroxetine methane sulfonate 10.0 g (24.0 mmol) of paroxetine methane sulfonate in 150 ml of water and 200 ml of ethyl acetate. To this Was added 12.4 g (31 mmol) of an aqueous 10 wt% NaOH solution .

and the suspension was stirred for 15 minutes.

The layers were separated and the aqueous layer was extracted once with 50 m1 of ethyl acetate. The combined organic layers are washed once with 100 ml of water and dried over Na2S04. The Na2S04 was filtered off and washed once with 50 ml of ethyl acetate. The ethyl acetate was evaporated off, leaving 7.5 g (22.8 mmol) of an oily product.

Yield 95%

The purity of the compound obtained was 99.5%

(HPLC) .

A number of the compounds obtained were ~ ,_ analysed. the results being shown in tables 1-5 below:
't"ablc 1 Characterization c~E salts of paroxetine with ccrtiin c~rgavic aul!onic acids R-Sn~ti R = CH j - (parc~zetine methane sulfurtateJ:

m.p.: 1,2'-14-4'C.

DSC curve (closed pan, 10'Clmin): onset I45.H'C, 79.0 J/g.

IR spercrum ( KBr, in cm 1): 531, 54b. 777, X38. 931.
962. 1038, 1100, 1169, 1208. 1469, 1500. 1515. 1615. 257?, 2869, 290(), 3c?23.
--t H-N~'~iR (ppm): 1.99 (br d, HS , 1H): 2.27 (ddd, HS~, l i~i); 2.48-2.65 (m, H3, 1 H); 2.82-?.92 (m, H4 , CHI, 4~; 2.95-3.2U (ttt, H23~, 1 i~~x, ZH); 3.4? (dd , H~. 1H); 3.58-3.74 (m, H2~q, Hue, H~. 3H); 5.88 (x, I~l~-, 2H); 6.10 (dd, H6~, 1H); fi.33 (d. H2.., 1H); 6.61 (d, HS", lI~; 7.U9 (dd.
H-t., HS., 21~p; 7.22 (dd , H2., 11t,., ?H); 8.85 (br d, NHeq, 1F~; 9.I 1 (br d, NH~x, II.i).

13C-N;VIR (ppm): 3U.0 (s, CS); 39.3 (s, C~): 39.5 (~.
C:~); 41.7 (s, SC): 44.6 (s, C~); 45.3 (s, C2); 67.4 (s, C.~): 97.8 (s, CZ..); I O1.2 {x. C'.~.,); 105.4 (s. C~"): 107.8 (s. CS-J: 115.8 (d, C3., CS.): 128.4 {s. C6., C.~,); I37.1 (c, C4..); 142.0 (s, C~,);

148.2 (s, G..); 153.7 (s, Ci..); if 1.9 {d, C4.).

R = C6f~5- (purvxetine benzene sulfonatr):

2 0 m-P-: SS'-50'C.

' IR spectrum t KBr, in czzi ): 530, 564, 6 i4, 689, 728, 764, 828, 92S
; 993, 1007, 1029, 1121, 1179, 1229, 14.43, 1471, 1486. 1 S 14, 1600. 162X, =557, 2842, 3029.

1 H-NMR (ppm): 1.9() (br d, HS . 1H); 2.10-2.28 (m , FL$~, 1 H); 2.38-2.52 (m, H~, 1 H); 2.82 (ddd, Ha, IH); 3.
1-3.18 tai, Hex, H~~x. 2:-1): 3.37 (dd, H~. 1 H):

3.48 (d, H~, 1H): 3.6(1-3.82 (m, H2 . H~ , 2H); S.R7 (;;, H~.., 2H); 6.U6 (dd, I H
dd b d H
~i H

I~

2 5 );
( .2 , 2., );
.60 (d.
5.,, l ); 6.
~,,, ( , r 13., H~, 2H); 7.U4 (dd.

H2., HS., 2H); ?.40 (d, ArH, 3H); 7.94 {d, SArH, 2H):
x.81 (br d, NHS, 1H~;

9.U4 (br d. NH$x l Ii).

13C-NMR (ppm): 29.9 (s, C$): 39.2 (s, C~); 4I.5 (s. C4):
44.~t (s, C6); 47.0 {s, C2); 67.3 (s, C;): 9?.9 (s, C.2.,): 101.1 (s, C~,.): I05.5 (s, C~-) 107.8 y, CS.,);

115.7 (d, C3., CS.); 125.9 (s, C~; 128.6 (s, Cd); l2R.x (s. CG., C2.); I:~0.6 (s, 30 Cc~); I 57.1 (s, C4..); 141.9 (s. C~.): 144.I (s, C.d ); 148.2 (s, C3..): 153.7 (s. C1..);

161.8 (c, Cd,).

R = p-C1~3C6H4 (paroxrtine p-tnlurnr. suljarrate):

m.p.: 148'-1 SU'C.

DSC curve (cloned pan, 10'C/min): onset J51.5"C, 71.6 J/g.

35 IR spectrum ( KBr, in cm-Il: 529, 557, b7I, 771, 80(!, x14, 921, 93f~, 1U00, IU29, 1100, 1157, 1186, 1229. 1471, 148b, 15c)7, i6Utl, ?557, 2829, 3029.

1H-NMR (pptn): 1.89 (br d, Lis~, 1H): 2.10-2.50 (m. fI5'x.
H_i. GH3. 5H): 2.82 (ddd, H4, I H): 2.97-3.1$ (m. H2"x. H6"x. 2H): 3.3fi (dd.
11~. I N): :x.48 (dd, H~.

1H); 3.52-3.77 (m, Hue, Hue. 2H): 5.87 (s, H~.., 2H):
b:06 (dd. H~..,1H); ti.28 ?5 Tablc 1 (conuctucd) Charac:arization of salts of paroxttine with ccc~ain organic sulfonic acids R-SOzH
(d, H,.., 1H); 6.59 (d, HS.., 1H); 6.90 (dd. H~., HS,, 2H): 7.U5 (dd. H2., H~., 2H);
7.24 (d. CHpArH, 2H); 7.83 (d, SArH, 2H); 8.91 {br d, Nf~l~, IH); 9.17 (bt d, NHS. J H).
13C-NMR (ppm): 21.3 (s, Cc); 29.9 (s. CS); 39.2 (,. C~): 4I.5 (s, C4): 44.7 (s, C6): 4b.9 (s, CZ); 67.3 (s. C~); 97.8 (s. C2..); lUl.l (s. C;..); 1Q5.5 (s, C~"): 107.8 (s. CS.,); 115.6 (d. C3., C5.): 125.8 (s, Cb): I2y.U (s, C~,.. C~,.); 129.1 (s. Cc);
137.? (s, C~.,); 140.8 (s, Ca): 141.5 (s, C$): 141.9 (s. C~.); 14A.2 (s, C3..); 153.8 (s, Ci..); 1b1.8 (d, C~,). ..
R = p-CIC6F14 (paroxetinc p-chlQrobert~,ene sulJvnu~c~J;
m.p.:75'-iR spectrum ( KBr, in cm-1 ): 486. 557, 643. 73b, 821, 10(K1, 1029, 1086, I
114, 1186,1229,1471. 1.486, 1514, 1600. 1 fi5?, 2857. 3029_ lf1-NMR (apm): 1.9I (br d, Fis~. 1H); 2.15 (ddd. I15'x. !H); 2.37-2.52 (m, H~, 1H): 2.81 (ddd, H4, IH): 2.93-31I (t21, H~nx~ HGax~ 2I"1)~ :1.37 (dd. H~, 1H):
3.49 (d. H~, 1H); 3.61-3.81 (m, H . H~q~ 21i); 5.88 (s. H?.., 2Ii); 6.05 (dd. H6.., 1H); 6.27 (d, H2.,. 1H); 6.59 (d.., 1H); b.91 (dd. H~.. HS., 2H); ?.03 (dd, H2., H6., 2H): 7.39 (d, flArH, 2H); 7.86 (d, SArf'I, 2Ii); 8.78 (br d, NHS. 1H):
9.02 (flr d, NHaY, 1H).
13C-1\MR (pprrt): 30.0 (s, CS); 39.3 (s, C3); 41..5 (s, C,~); 44.9 (s, C6);
47.1 (s.
CZ): 6i.3 (s, C7); 97.9 (s, C-,..): 101.2 (S, C~..): 1(15.5 (s, C~,..); IQ7.9 (s, CS..);
2 0 115.8 (d, C~,. C5.): 127.6 (s, C~); :28,8 (s. C~,, Cz.): 132.0 (s, C~);
137.0 (s, Cc);
137.2 (s, C~.,); 141.8 (s, C~.): I42.0 (s, C~ ); 148.2 (s, Ci.,): 153.6 (s, C1..); 161.8 (d, C~. ).
The compounds o~ the invention are crystalline, with de=ir_ed melting points, DSC curves and IR spectra.
It cannot b~ excluded that, under different conditions of their Termation and under specific conditions, they could exist also in other crystalline or polymorph modificG:ions which may differ from those as described herein. ~he compounds of the invention are also generally very stab's and non-hygroscopic.
_.. should be understood that the present invention. comprising acid addition salts with organic sulfonic acids are substantially free of the bound organic solvent. Preferably, the amount of bound organic solvent shc~.:ld be less than 2.0% (w/w) as calculated on the anhydrous basis. They nevertheless may contain crystallization water and also unbound water, that is to say water which is other than water of crystallization.

Tn the following tables 2 and 3 , examples of results o~_hygroscopicity tests and stability tests fin compa_ison with known salts or paroxetine? are presented.
Tablc 2 Hygroscopicity of certain salts of paroxctine (40'C. -75 ~% rel.hum).

watcr content (in go) at t = 0 t = 4 wcckc methane sulfonate 0.35 + 0.04 p-toluene culfonate 0.70 < 0.02 hydrochloride - + 2.5 _"

'rahle 3 Solubility of paroxctine salts in water (in mgltut) ' 20'C , 50'C

methane suifonatc > 1000 i ~~ r""' 1300 p-toluene sulfonate > 1400 > 1000 hvdrochlorida hemihydrate 4.9 12.6 hycirochloridc ,=.ahydratc 8.2 24.2 Table 4 2 Stability of paroxetine salts by HPLC (total amount of 0 de8radation is ~Yo).

dc~rad,ation ' C

mcthana suIfoaate not observed ~ < 0.2 ok, 3 months p-toluene sulfonate net observed < 0.2 ~o. 3 months 2 malc:tie 0.2 ~k, 12 months > 5() ~~, 5 days Table 5 Solubility of salte of psroxetine iu nonaquaous solvents ( in mR/ml) methane suifonate p-tctluene xulfonate 3 Ethanol 20'C 36 50 ?R'C 250 > 500 2-Prapanol 20'C ? 14 82'C 330 > 500 Acetone - 20'C 5 I6 56'C 37 125 Ethyl acctau 20'C 2 22 77'C 25 > 500 3 n-Hcxanc 20'C < 0.05 < 0.05 69' C 0.05 < 0.05 examples of analytical data of the paroxetine salts and the free base prepared in Examples 5 to 7 are given in Table 6.
Table 6 Characterization of salts / free base of paroxetine paroxetine maleate:

m.p.: 128-130'C.

1H-NMR (ppm): 1.65-2.00 (m, H~e~, Hsax, 2H); 2.00-2.50 (m, H3, xH); 2.SS-3.1~ (m. Hy3x. H6ax H4, 3H); 3.1~-x.75 (m, H2eq,~ ~H6e , H7 3H); 5.67 (s, H~.., ..
9? (s 2H); 5 1H); 6 12 (dd H
H
1H); 6 42 (d H
~); 6 67 (d H

, .
.
, a, , .
, 2.., .
, S.., );

6.9~-7.3~ (m, H.,., H3., HS,, H6., 4H).

paroxetine acetate:

a m.p.: 123-125 C.

1~ IH_NMR (ppm): 1.70-2.00 (m, HSeq, Hoax, 2H): 1.97 (s.
Ha, 3H); 2.05-2.50 (m, H3, 1H): ?.50-3.00 (m, H~, H.,aX, H6ax, 3H); 3.05-3.75 (m, H,,tq, H~ , H', 3H);

OS (s H
2H); 6 28 (dd H
1H) 58 (d H

d H
~

.
-.., .
6.., , , 2.., ;
.
, );
.
( , ~.,, H); 7.10-7.~0 (m, H.,.. H3., HS., H6., 4H). , paroxetine:

20 1H-NMR (ppm): 1.60-2.00 (m. H~aX, H~eg, 2H); 2.04-2.35 (m, H3, 1H); 2.40-2.95 (m, Hs, H-,ax, H6ax~ 3H); 3.15-3.70 (m, H2e , H~q, H~, 2H); 5.67 (s, H?.., 2H); 6.11 (dd. Hs...IH); 6.43 (d, H.,.., 1H); 6.62 (~, H~", 1H); 6.80-7.35 (m, Hz., H3., HS., H6., 4H).

25 It will be clear that the invention is not limited to the above description, but is rather determined by the following claims.

Reference Psychopharmacology, 57, 151-153 (1978)]; ibid. 68, 229-233 (1980), European Journal of Pharmacology, 47, 351-358 (1978)]; in USP 400719&, the preparation of paroxetine maleate is reported.
t

Claims

1. A process for preparing a non-sulfonate salt of a paroxetine analog, the process comprising mixing (a) one or more of a compound of formula I:
wherein:
R represents a 3'4'-methylene-dioxyphenyl group R1 is hydrogen X is halogen R2 is: i) C1-C10 alkyl or ii) phenyl optionally substituted by one or more of:
- C1-C10 alkyl;
- halogen;
- nitro;
- hydroxy; and - alkoxy;
or a pharmaceutically acceptable salt thereof, with (b) a reagent selected from the group consisting of hydrochloric acid, oxalic acid, hydrobromic acid, succinic acid, hydriodic acid, tartaric acid, acetic acid, citric acid, propionic acid, embonic acid, pamoic acid, maleic acid, sulfuric acid, and fumaric acid.

2. A process according to claim 1, wherein R is a

3,4-methylene-dioxyphenyl group of the formula:
3. A process according to claim 1 or 2, wherein X is fluorine attached to position 4 in the phenyl ring.

4. A process according to claim 1, 2 or 3, wherein R2 is C1-C4 alkyl.

5. A process according to any one of claims 1 to 4, wherein R2 is C1-C2 alkyl group.

6. A process according to any one of claims 1 to 5, wherein the compound of formula I has a solubility at about 20°C of at least about 10 mg per ml water.

7. A process according to claim 6, wherein the solubility is at least 100 mg per ml.

8. A process according to claim 6, wherein the solubility is at least 500 mg per ml.

9. A process according to claim 6, wherein the solubility is at least 1000 mg per ml.

10. A process according to claim 1, wherein the compound of formula I is selected from the group consisting of:
- paroxetine methane sulfonate (formula I) wherein X is fluorine in the p-position, R is 3'4'-methylene-dioxyphenyl, R1 is hydrogen and R2 is methyl;

- paroxetine benzene sulfonate (formula I), wherein X is fluorine in the p-position, R is 3'4'-methylene-dioxyphenyl, R1 is hydrogen, and R2 is phenyl;
- paroxetine p-toluene sulfonate (formula I), wherein X is fluorine in the p-position, R is 3'4'-methylene-dioxyphenyl, R1 is hydrogen and R2 is methyl phenyl; and - paroxetine p-chlorobenzene sulfonate (formula I) wherein X is fluorine in the p-position, R is 3'4'-methylene-dioxyphenyl, R1 is hydrogen and R2 is chlorophenyl.

11. A process according to any one of claims 1 to 10, wherein the compound of formula I is obtained by a process comprising the steps of (a) mixing together one or more of a compound formula II:
a salt thereof and a base thereof;
wherein:
- R is a 3'4'-methylene-dioxyphenyl group;
- R1 is hydrogen;
- X is halogen;
with a sulfonic acid of formula R2-SO3H, wherein R2 is:

- C1-C10 alkyl, or - phenyl optionally substituted by one or more of:
- C1-C10 alkyl;
- halogen;
- nitro;
- hydroxy; and - alkoxy;
to form a solution, and (b) precipitating the compound out of the solution.

12. A process according to any one of claims 1 to 10, wherein the compound of formula I is in the form of a solvate, obtained by mixing together a compound of formula I
with a reagent selected from water, methanol and ethanol.

13. A non-sulfonate salt obtained by the process according to any one of claims 1 to 12.

14. A non-sulfonate salt according to claim 13, having a purity of at least 90 wt%.

15. A non-sulfonate salt according to claim 13, having a purity of at least 95 wt%.

16. A non-sulfonate salt according to claim 13, having a purity of at least 98 wt%.

17. Paroxetine maleate having a purity of at least 98 wt%.

18. Paroxetine acetate having a purity of at least 98 wt%.

19. A process for providing a free base paroxetine analog, the process comprising mixing (a) one or more of a compound of formula I:
wherein:
R represents a 3'4'-methylene-dioxyphenyl group R1 is hydrogen X is halogen R2 is: i) C1-C10 alkyl or ii) phenyl optionally substituted by one or more of:
- C1-C10 alkyl;
- halogen;
- nitro;
- hydroxy; and - alkoxy;
or a pharmaceutically acceptable salt thereof, with (b) one or more of a base selected from an organic base and an inorganic base.

20. A process according to claim 19, wherein R is a 3,4-methylene-dioxyphenyl group of the formula:

21. A process according to claim 19 or 20, wherein X
is fluorine attached to position 4 in the phenyl ring.

22. A process according to claim 19, 20 or 21, wherein R2 is C1-C4 alkyl.

23. A process according to any one of claims 19 to 22, wherein R2 is C1-C2 alkyl group.

24. A process according to any one of claims 19 to 23, wherein the compound of formula I has a solubility at about 20°C of at least about 10 mg per ml water.

25. A process according to claim 24, wherein the solubility is at least 100 mg per ml.

26. A process according to claim 24, wherein the solubility is at least 500 mg per ml.

27. A process according to claim 24, wherein the solubility is at least 1000 mg per ml.

28. A process according to claim 19, wherein the compound of formula I is selected from the group consisting of:
- paroxetine methane sulfonate (formula I) wherein X is fluorine in the p-position, R is 3'4'-methylene-dioxyphenyl, R1 is hydrogen and R2 is methyl;
- paroxetine benzene sulfonate (formula I), wherein X is fluorine in the p-position, R is 3'4'-methylene-dioxyphenyl, R1 is hydrogen, and R2 is phenyl;

- paroxetine p-toluene sulfonate (formula I), wherein X is fluorine in the p-position, R is 3'4'-methylene-dioxyphenyl, R1 is hydrogen and R2 is methyl phenyl; and - paroxetine p-chlorobenzene sulfonate (formula I) wherein X is fluorine in the p-position, R is 3'4'-methylene-dioxyphenyl, R1 is hydrogen and R2 is chlorophenyl.

29. A process according to any one of claims 19 to 28, wherein the compound of formula I is obtained by a process comprising the steps of (a) mixing together one or more of a compound formula II:
a salt thereof and a base thereof;
wherein:
- R is a 3'4'-methylene-dioxyphenyl group;
- R1 is hydrogen;
- X is halogen;
with a sulfonic acid of formula R2-SO3H, wherein R2 is:
- C1-C10 alkyl, or - phenyl optionally substituted by one or more of:
- C1-C10 alkyl;

- halogen;
- nitro;
- hydroxy; and - alkoxy;
to form a solution, and (b) precipitating the compound out of the solution.

30. A process according to any one of claims 19 to 28, wherein the compound of formula I is in the form of a solvate, obtained by mixing together a compound of formula I
with a reagent selected from water, methanol and ethanol.

31. A process according to any one of claims 19 to 30, wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, sodium carbonate, methylamine, dimethylamine, triethylamine, and pyridine.

32. A free base paroxetine analog obtained by the process according to any one of claims 19 to 31, having a purity of at least 95 wt%.

33. A free base paroxetine analog according to claim 32, having a purity of at least 98 wt%.

34. Free base paroxetine obtained by the process according to any one of claims 19 to 31, having a purity of at least 95%.

35. Free base paroxetine obtained by the process according to any one of claims 19 to 31, having a purity of at least 98%.