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(11) | EP 1 451 143 B9 |
| (12) | CORRECTED EUROPEAN PATENT SPECIFICATION |
| Note: Bibliography reflects the latest situation |
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METHODS FOR PREPARING O-DESMETHYLVENLAFAXINE VERFAHREN ZUR HERSTELLUNG VON O-DESMETHYLVENLAFAXIN PROCEDES DE PREPARATION DE O-DESMETHYLE VENLAFAXINE |
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| Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). |
BACKGROUND OF THE INVENTION
[0002] O-desmethylvenlafaxine is a major metabolite of venlafaxine. Methods to make O-desmethylvenlafaxine are described in U.S. Patent No. 4,535,186. This method uses benzyl blocking groups leading to relatively low throughput.
[0003] A process of making O-desmethylvenlafaxine is also described in WO 00/59851 in which venlafaxine is allowed to react with diphenyl phosphide in THF (generated by adding n-butyl lithium in THF to diphenylphosphine in THF below 0°C) at reflux for an overnight period. The yield was reported to be 73.8%. Furthermore, the method involved extraction steps involving large volumes of solvent.
[0004] The present invention provides a process of making O-desmethylvenlafaxine which is both time and material efficient.
DESCRIPTION OF THE INVENTION
[0005] In accordance with the present invention is provided a method of making O-desmethylvenlafaxine comprising the steps of demethylating a compound of Formula I to provide a compound of Formula II as described in Scheme I.
[0006] As described in Scheme I the starting material, venlafaxine (Formula I), is demethylated. Venlafaxine may be prepared in accordance with procedures known in the art such as described in U.S. Patent No. 4,535,186.
[0007] In accordance with the present invention, demethylation is performed using a high molecular weight alkane, arene, or arylalkyl thiolate anion, such as straight or branched chain alkane thiolate anions having 8 to 20 carbon atoms, mono or bicyclic arene thiolate anions having 6 to 10 carbon atoms, or mono or bicyclic arylalkyl thiolate anions having 7 to 12 carbon atoms in the presence of a protic or aprotic solvent. Optionally, a base such as an alkoxide comprised of a straight or branched chain alkyl group of from 1 to 6 carbon atoms may be present to generate the thiolate anion.
[0008] Preferably the aliphatic thiol has from 10 to 20 carbon atoms and most preferably the aliphatic thiol is dodecanethiol. The aromatic thiol is preferably benzenethiol. The arylalkyl thiolate anion is preferably ∝-toluenethiol or naphthylmethanethiol.
[0009] When present, the alkoxide is preferably a lower alkoxide, e.g., of 1 to 6 carbon atoms (e.g., methoxide, ethoxide and the like) such as sodium methoxide (sodium methylate, sodium methanolate).
[0010] The solvent is preferably a hydroxylic or ethereal solvent or mixtures thereof, and more preferably an alcohol, ethylene glycol or ether of ethylene glycol. Ethers of ethylene glycol include, but are not limited to, ethylene glycol monoethyl ether, triethylene glycol dimethyl ether and polyethylene glycol. Preferably, the solvent is an inert, polar, high boiling point ether of ethylene glycol such as polyethylene glycol and most preferably PEG 400 (polyethylene glycol having a molecular weight range of from about 380-420).
[0011] The reaction is performed at a temperature of from about 150°C to about 220°C, more preferably from about 170°C to about 220°C, and most preferably from about 180°C to about 200°C. The reaction is generally allowed to progress until, ideally, not more than 1% venlafaxine remains. In some aspects of the invention the reaction is complete in from about 2 hours to about 5 hours and more preferably in from about 2 to about 3.5 hours.
[0012] The thiolate anion can be prepared separately or in situ. In some preferred embodiments of the present invention, venlafaxine base is dissolved in polyethylene glycol 400 containing dodecanethiol and sodium methylate as a solution in methanol as the temperature is increased to from about 180°C to about 200°C, with stirring for about 2 to about 3.5 hours. In other preferred embodiments of the present invention, venlafaxine base is dissolved in polyethylene glycol containing dodecanethiolate and stirred for about 2 to about 3.5 hours at from about 180°C to about 200°C with stirring.
[0013] Conveniently the process may be carried out in a molar excess of thiolate, preferably the molar ratio of thiolate to venlafaxine is up to about 3.0:1, e.g., in the range from about 1.05:1 to about 2.8:1, preferably about 1.15:1 to about 2.5:1.
[0014] Thereafter the reaction mixture may be cooled to between about 65°C and about 75°C and an alcohol may be added as a diluent before neutralization to the isoelectric point (about pH9.5 to about pH10.0) with an appropriate neutralization agent such as hydrochloric acid. The alcoholic medium may also aid in the crystallization of the product as neutralization is initiated.
[0015] Preferably the alcohol comprises a straight or branched chain alkyl group of 1 to 6 carbon atoms, such as methanol, ethanol, isopropanol, butanol, and the like, and mixtures thereof. In some preferred embodiments of the invention, the alcohol is isopropanol.
[0016] Yields of the present invention are greater than about 75% and generally from about 85% to greater than 90%.
[0017] The following Examples are illustrative but are not meant to be limiting of the present invention.
Example 1
[0018] Dodecanethiol (122 g), venlafaxine (111 g), and a methanolic solution of sodium methanolate (30%, 90 g) and PEG 400 are heated to 190°C. The methanol is distilled off and the solution is stirred 2 h at 190°C. Then the temperature is lowered, 2-propanol (450 g) is added and the pH is adjusted to 9.5 with aqueous HCl. The precipitate is collected by suction filtration, and the cake is washed with 2-propanol, toluene, 2-propanol and water. The wet O-desmethylvenlafaxine is dried in vacuo.
Yield: 87g.
[0019] 1H-NMR: (Gemini 200, Varian, 200 MHz) (DMSO-d6) δ = 9.11 (s, br, 1 H; OH), 6.98 (d, br, J = 8.4, 2H; arom.), 6.65 (d, br, J = 8.4, 2H; arom.), 5.32 (s, br, 1 H; OH), 3.00 (dd, J = 12.3 and 8.5, 1 H), 2.73 (dd, J = 8.5 and 6.3, 1 H), 2.36 (dd, J = 12.3 and 6.3, 1 H), 2.15 (s, 6H, 2 x Me), 1.7-0.8 (m, 10H, c-hex).
Example 2
[0020] Venlafaxine (5.6 g) and benzenethiol sodium salt(6.9 g) are charged to PEG 400 (25 g). The reaction mixture is heated to 160°C for 5 h. Then the temperature is lowered and water is added (60 g). The pH is adjusted to 3.5 with H3PO4. The organic by-products are removed by extraction with heptanes (25 g). The pH of the aqueous layer is then adjusted to 9.5 with aqueous ammonia. The precipitate is collected by suction filtration, re-slurried in water (100 g), isolated by suction filtration and dried in vacuo.
Yield 1 g.
[0021] 1H-NMR: (Gemini 200, Varian, 200 MHz) (DMSO-d6) δ = 9.11 (s, br, 1H; OH), 6.98 (d, br, J = 8.4, 2H; arom.), 6.65 (d, br, J = 8.4, 2H; arom.), 5.32 (s, br, 1 H; OH), 3.00 (dd, J = 12.3 and 8.5, 1 H), 2.73 (dd, J = 8.5 and 6.3, 1 H), 2.36 (dd, J = 12.3 and 6.3, 1 H), 2.15 (s, 6H, 2 x Me), 1.7-0.8 (m, 10H, c-hex).
Example 3
[0022] Dodecanethiol (69 g) venlafaxine (55 g) and an ethanolic solution of sodium ethanolate (21%, 82 g) are charged to a pressure vessel. The temperature is raised to 150°C and the reaction mixture is stirred for 2 days. Then the temperature is lowered and the solution is filtered. The pH of the filtrate is adjusted to 9.5 with aqueous hydrogen chloride. The crystals are collected by suction filtration. The cake is washed with ethanol and dried in vacuo.
Yield: 42g
[0023] 1H-NMR: (Gemini 200, Varian, 200 MHz) (DMSO-d6) δ = 9.11 (s, br, 1 H; OH), 6.98 (d, br, J = 8.4, 2H; arom.), 6.65 (d, br, J = 8.4, 2H; arom.), 5.32 (s, br, 1H; OH), 3.00 (dd, J = 12.3 and 8.5, 1 H), 2.73 (dd, J = 8.5 and 6.3, 1 H), 2.36 (dd, J = 12.3 and 6.3, 1 H), 2.15 (s, 6H, 2 x Me), 1.7-0.8 (m, 10H, c-hex).
Example 4
Step a - Formation of the reagent sodium dodecanethiolate.
[0024] Dodecanethiol (246 g) and sodium methylate in methanol 30% (216 g) are charged to a rotary evaporator. Vacuum is applied and the solvent is abstracted completely using a bath temperature up to 90°C. The remaining sodium dodecanethiolate (272 g) is used without further purification in the subsequent step.
Step b - Demethylation
[0025] A mixture of sodium dodecanethiolate (272 g) venlafaxine (256 g) and PEG 400 (185 g) is stirred 3 h at 190°C. Then the temperature is lowered and 2-propanol (915 g) is added and the pH is adjusted to 9.5 with aqueous HCl. The precipitate is collected by suction filtration, and the cake is washed with 2-propanol and water. The wet O-desmethylvenlafaxine is dried in vacuo. Yield: 200 g.
[0026] 1H-NMR: (Gemini 200, Varian, 200 MHz) (DMSO-d6) δ = 9.11 (s, br, 1 H; OH), 6.98 (d, br, J = 8.4, 2H; arom.), 6.65 (d, br, J = 8.4, 2H; arom.), 5.32 (s, br, 1 H; OH), 3.00 (dd, J = 12.3 and 8.5, 1 H), 2.73 (dd, J = 8.5 and 6.3, 1 H), 2.36 (dd, J = 12.3 and 6.3, 1 H), 2.15 (s, 6H, 2 x Me), 1.7-0.8 (m, 10H, c-hex).
1. A method of preparing O-desmethylvenlafaxine which comprises demethylating venlafaxine
with a straight or branched chain alkane thiolate anion having 8 to 20 carbon atoms;
a mono or bicyclic arene thiolate anion having 6 to 10 carbon atoms; or a mono or
bicyclic arylalkyl thiolate anion having 7 to 12 carbon atoms in a hydroxylic or ethereal
solvent, or mixture thereof.
2. A method according to Claim 1 which is carried out in alcohol, ethylene glycol, ether
of ethylene glycol, or mixture thereof.
3. A method according to Claim 1 in which the solvent is ethylene glycol monoethyl ether,
tri-ethylene glycol, dimethyl ether or polyethylene glycol.
4. A method according to Claim 1 in which the solvent is polyethylene glycol 400.
5. A method according to any one of Claims 1 to 4 wherein the reaction is performed at
150°C to 220°C.
6. A method according to any one of Claims 1 to 4 wherein the reaction is performed at
from 170°C to 220° C.
7. A method according to any one of Claims 1 to 4 wherein the reaction is performed at
from 180°C to 200° C.
8. A method according to any one of Claims 1 to 8 wherein the reaction is carried out
for 2 to 5 hours.
9. A method according to any one of Claims 1 to 8 wherein the straight or branched chain
alkane thiolate anion having 8 to 20 carbon atoms is dodecane-thiolate.
10. A method according to any one of Claims 1 to 8 wherein the arene thiolate anion having
from 6 to 10 carbon atoms is benzene-thiolate.
11. A method according to any one of Claims 1 to 10 wherein the thiolate anion is generated
in the presence of an alkoxide.
12. A method according to Claim 11 wherein the alkoxide is methoxide.
13. A method according to any one of Claims 1 to 12 which is carried out in a stoichiometric
excess of thiolate:venlafaxine up to 3.0:1.
14. A method according to any one of Claims 1 to 12 in which the molar ratio of thiolate:venlafaxine
is from 1.15:1 to 2.5:1.
15. A method according to any one of Claims 1 to 14 further comprising neutralizing the
product to the isoelectric point in the presence of an alcohol comprising a straight
or branched chain alkyl group of from 1 to 6 carbon atoms.
16. A method according to Claim 15 wherein the alcohol is isopropanol.
17. A method according to Claim 15 or Claim 16 in which the reaction mixture is cooled
to between 65°C and 75°C before the an alcohol is added
18. A method according to any one of Claims 15 to 17 wherein the isoelectric point is
from pH9.5 to pH10.
19. A method of preparing O-desmethylvenlafaxine which comprises the steps of demethylating
venlafaxine with dodecyl thiolate and polyethylene glycol 400 in the presence of sodium
methylate in methanol at 180°C to 200°C for 2 to 5 hours; and neutralizing the product
to pH 9.5 in the presence of isopropanol.
1. Verfahren zur Herstellung von O-Desmethylvenlafaxin, das die Entmethylierung von Venlafaxin
mit einem gerad- oder verzweigtkettigen Alkanthiolat-Anion mit 8 bis 20 Kohlenstoffatomen;
einem mono- oder bicyclischen Arenthiolat-Anion mit 6 bis 10 Kohlenstoffatomen; oder
einem mono- oder bicyclischen Arylalkylthiolat-Anion mit 7 bis 12 Kohlenstoffatomen
in einem hydroxylischen oder etherischen Lösemittel oder einem Gemisch davon umfasst.
2. Verfahren nach Anspruch 1, das in Alkohol, Ethylenglykol, Ether von Ethylenglykol
oder einem Gemisch davon durchgeführt wird.
3. Verfahren nach Anspruch 1, bei dem das Lösemittel Ethylenglykolmonoethylether, Triethylenglykol,
Dimethylether oder Polyethylenglykol ist.
4. Verfahren nach Anspruch 1, bei dem das Lösemittel Polyethylenglykol 400 ist.
5. Verfahren nach irgendeinem der Ansprüche 1 bis 4, wobei die Reaktion bei ungefähr
150°C bis ungefähr 220°C durchgeführt wird.
6. Verfahren nach irgendeinem der Ansprüche 1 bis 4, wobei die Reaktion bei ungefähr
170°C bis ungefähr 220°C durchgeführt wird
7. Verfahren nach irgendeinem der Ansprüche 1 bis 4, wobei die Reaktion bei ungefähr
180°C bis ungefähr 200°C durchgeführt wird
8. Verfahren nach irgendeinem der Ansprüche 1 bis 8, wobei die Reaktion für ungefähr
2 bis ungefähr 5 Stunden durchgeführt wird.
9. Verfahren nach irgendeinem der Ansprüche 1 bis 8, wobei das gerad- oder verzweigtkettige
Alkanthiolat-Anion mit 8 bis 20 Kohlenstoffatomen Dodecanthiolat ist.
10. Verfahren nach irgendeinem der Ansprüche 1 bis 8, wobei das Arenthiolat-Anion mit
6 bis 10 Kohlenstoffatomen Benzolthiolat ist.
11. Verfahren nach irgendeinem der Ansprüche 1 bis 10, wobei das Thiolat-Anion in Gegenwart
eines Alkoxids gebildet wird.
12. Verfahren nach Anspruch 11, wobei das Alkoxid Methoxid ist.
13. Verfahren nach irgendeinem der Ansprüche 1 bis 12, das in einem stöchiometrischen
Überschuss von Thiolat:Venlafaxin bis ungefähr 3,0:1 durchgeführt wird.
14. Verfahren nach irgendeinem der Ansprüche 1 bis 12, bei dem das Molverhältnis von Thiolat:Venlafaxin
ungefähr 1,15:1 bis ungefähr 2,5:1 beträgt.
15. Verfahren nach irgendeinem der Ansprüche 1 bis 14, ferner umfassend die Neutralisierung
des Produkts bis zum isoelektrischen Punkt in Gegenwart eines Alkohols, der eine gerad-
oder verzweigtkettige Alkylgruppe mit 1 bis 6 Kohlenstoffatomen umfasst.
16. Verfahren nach Anspruch 15, wobei der Alkohol Isopropanol ist.
17. Verfahren nach Anspruch 15 oder Anspruch 16, bei dem das Reaktionsgemisch auf zwischen
ungefähr 65°C und ungefähr 75°C gekühlt wird, bevor ein Alkohol zugesetzt wird.
18. Verfahren nach irgendeinem der Ansprüche 15 bis 17, wobei der isoelektrische Punkt
ungefähr pH 9,5 bis ungefähr pH 10 beträgt.
19. Verfahren zur Herstellung von O-Desmethylvenlafaxin, das folgende Schritte umfasst:
Entmethylierung von Venlafaxin mit Dodecylthiolat und Polyethylenglykol 400 in Gegenwart
von Natriummethylat in Methanol bei ungefähr 180°C bis ungefähr 200°C für ungefähr
2 bis ungefähr 5 Stunden; und Neutralisierung des Produkts auf pH 9,5 in Gegenwart
von Isopropanol.
1. Procédé de préparation d'O-desméthylvenlafaxine qui comprend la déméthylation de la
venlafaxine avec un anion thiolate d'alcane à chaîne linéaire ou ramifiée ayant 8
à 20 atomes de carbone ; un anion thiolate d'arène mono ou bicyclique ayant 6 à 10
atomes de carbone; ou un anion thiolate d'arylalkyle mono ou bicyclique ayant 7 à
12 atomes de carbone dans un solvant hydroxylique ou éthéré, ou un mélange de ceux-ci.
2. Procédé selon la revendication 1, qui est conduit dans de l'alcool, de l'éthylène
glycol, de l'éther d'éthylène glycol, ou un mélange de ceux-ci.
3. Procédé selon la revendication 1, dans lequel le solvant est le monoéthyl éther d'éthylène
glycol, le triéthylène glycol, l'éther de diméthyle ou le polyéthylène glycol.
4. Procédé selon la revendication 1, dans lequel le solvant est le polyéthylène glycol
400.
5. Procédé selon l'une quelconque des revendications 1 à 4, dans lequel la réaction est
effectuée à d'environ 150°C jusqu'à environ 220°C.
6. Procédé selon l'une quelconque des revendications 1 à 4, dans lequel la réaction est
effectuée à d'environ 170°C jusqu'à environ 220°C.
7. Procédé selon l'une quelconque des revendications 1 à 4, dans lequel la réaction est
effectuée à d'environ 180°C jusqu'à environ 220°C.
8. Procédé selon l'une quelconque des revendications 1 à 8, dans lequel la réaction est
conduite sur environ 2 à environ 5 heures.
9. Procédé selon l'une quelconque des revendications 1 à 8, dans lequel, l'anion thiolate
d'alcane à chaîne linéaire ou ramifiée ayant 8 à 20 atomes de carbone est le dodécane-thiolate.
10. Procédé selon l'une quelconque des revendications 1 à 8, dans lequel l'anion thiolate
d'arène ayant de 6 à 10 atomes de carbone est le benzène-thiolate.
11. Procédé selon l'une quelconque des revendications 1 à 10, dans lequel l'anion thiolate
est généré en présence d'un alcoxyde.
12. Procédé selon la revendication 11, dans lequel l'alcoxyde est le méthoxyde.
13. Procédé selon l'une quelconque des revendications 1 à 12, qui est conduit en un excès
stoechiométrique de thiolate : venlafaxine jusqu'à environ 3,0 : 1.
14. Procédé selon l'une quelconque des revendications 1 à 12, dans lequel le rapport molaire
de thiolate : venlafaxine est d'environ 1,15 : 1 jusqu'à environ 2,5 : 1.
15. Procédé selon l'une quelconque des revendications 1 à 14 comprenant en outre la neutralisation
du produit au point isoélectrique en présence d'un alcool comprenant un groupe alkyle
à chaîne linéaire ou ramifiée de 1 à 6 atome(s) de carbone.
16. Procédé selon la revendication 15, dans lequel l'alcool est l'isopropanol.
17. Procédé selon la revendication 15 ou la revendication 16, dans lequel le mélange réactionnel
est refroidi à entre environ 65°C et environ 75°C avant qu'un alcool soit ajouté.
18. Procédé selon l'une quelconque des revendications 15 à 17, dans lequel le point isoélectrique
est d'environ pH 9,5 jusqu'à environ pH 10.
19. Procédé de préparation d'O-desméthylvenlafaxine qui comprend les étapes de déméthylation
de la venlafaxine avec du thiolate de dodécyle et du polyéthylène glycol 400 en présence
de méthylate de sodium dans du méthanol à environ 180°C jusqu'à environ 200°C durant
environ 2 à environ 5 heures ; et la neutralisation du produit à environ pH 9,5 en
présence d'isopropanol.
REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.
Patent documents cited in the description