Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-10
2004-06-29
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S512000, C549S332000, C564S336000, C564S355000, C564S358000
Reexamination Certificate
active
06756502
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to European Patent Application No. 01303347.7-2117, filed Apr. 10, 2001, the contents being incorporated by reference herein.
BACKGROUND OF THE INVENTION
This invention relates to a novel intermediate which is valuable in the synthesis of a known medicament by a more advantageous route. The invention further relates to processes by which such an intermediate may first be itself prepared and thereafter may be converted into the known anti-depressant (±)-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol of structural formula (IX):
and pharmacologically-acceptable salts thereof, e.g. Venlafaxine hydrochloride, supplied by American Home Products, Inc., under the trade name Effexor®.
Venlafaxine selectively inhibits the neuronal uptake of serotonin-norepinephrine and to a lesser extent dopamine. Studies indicate that it has comparable or possibly slightly greater efficacy to other selective serotonin reuptake inhibitors (SSRI's). It appears to be as effective as standard antidepressants such as imipramine. Venlafaxine's unique chemical structure and neuro-pharmacological activity give it a broader spectrum of activity than other antidepressants.
Previously known methods for the preparation of Venlafaxine include e.g. that taught in EP 0,112,669, which discloses the preparation of various 2-aryl-2-(1-hydroxycyclohexyl)ethylamine derivatives via &agr;-aryl-&agr;-(1-hydroxy-cyclohexyl) acetonitriles or &agr;-aryl-N,N-dimethyl-&agr;-(1-hydroxycyclohexyl) acetamide as chemical intermediates. These chemical intermediates are prepared by condensing &agr;-arylacetonitriles or -aryl-N,N-dimethyl acetamides with cyclohexanone.
GB 2,227,743 discloses the preparation of 2-(1-hydroxycyclohexylethyl-thioacetamide) derivatives for the synthesis of Venlafaxine. The thioacetamido derivative is prepared from 4-methoxyacetophenone via Kindler modification of the Willgerodt reaction.
Zhou Jinpei et al. (Zhongguo Yaoke Daxue Xuebao (Journal of China) 1999, 30(4), 249-250) have reported the synthesis of Venlafaxine using methoxy-benzene as a starting material. The route involves 5 steps and gives 11% overall yield. In this route anisole is treated with chloroacetyl chloride under Friedel-Crafts acylation conditions followed by substitutions of &agr;-halo-p-methoxyacetophenone by dimethylamine which is reduced by potassium borohydride to give a &bgr;-hydroxydimethylamine derivative. This intermediate, on treatment with PBr
3
followed by magnesium in tetrahydrofuran (THF), and subsequent treatment with cyclohexanone, yields Venlafaxine.
These known synthetic routes tend to involve the use of hazardous, costly and moisture sensitive reagents. For example, the synthesis described in EP 0,112,669 requires a very low reaction temperature (−50° C. to −70° C.), and a hydrogenation step which uses expensive rhodium catalyst. Materials in this route are not easily available, and the reaction conditions are harsh, with high demands on equipment, and high production costs.
The process taught in GB 2,227,743 uses a ratio of 50:1 Raney nickel to thioamide in its hydrogenation step, and also requires the use of toxic solvents such as dioxane for the reduction of thioamide. These reagents and conditions make this process commercially unattractive.
Zhou Jinpei's process requires the use of costly chemicals such as potassium borohydride and PBr
3
, as well as the purification of an important intermediate via distillation under high vacuum, which further adds to the cost.
We have now evolved a synthetic route for the preparation of Venlafaxine which starts from easily available materials, and employs mild reaction conditions and simple after-treatment procedures, thus making it suitable for large-scale production. In this new route, hazardous, moisture-sensitive, and highly inflammable reagents are completely avoided, as are costly chemicals such as rhodium catalyst and potassium borohydride.
Certain alternatives are available in the early stages of this route, which is indeed advantageous since it opens the way to the use of different reaction strategies, from a range of starting materials, which may be selected according to cost and availability. All of these alternative routes however pass through the same novel epoxy nitrile intermediate.
According to the present invention, there is provided the epoxy-nitrile compound of structural formula (I):
namely 2-(4-methoxy-phenyl)-1-oxa-spiro[2.5]octane-2-carbonitrile.
The present invention also provides a process for the preparation of the compound of formula (I), in which (1-bromo-cyclohexyl)-(4-methoxy-phenyl)-methanone of structural formula (II):
is subjected to treatment with a cyanation agent, so as to yield the epoxy nitrile intermediate of formula (I).
The cyanation agent employed is preferably sodium cyanide or potassium cyanide, although other cyanation agents may be used, such as trimethyl silyl cyanide, cuprous cyanide, other alkali and alkaline earth metal cyanides, or other cyanating agents known from the literature.
The reaction can be readily performed in solution in methanol at room temperature. Alternatively, solvents such as ethanol, isopropyl alcohol, acetonitrile, dimethyl formamide, dimethyl sulphoxide, dimethyl acetamide, hexamethylene phosphoric triamide (HMPT), ethyl acetate, or sulfolane, may be used, as may benzene, toluene, cyclohexane, dichloromethane, or chloroform, in the presence of a phase transfer catalyst. The phase transfer catalyst is required when using these non-polar solvents, as the solubility of inorganic cyanides therein is practically nil. The catalyst therefore acts so as to carry the cyanide ion to the organic phase for reaction.
The reaction may be carried out at a temperature in the range of from −10° C. to 60° C. Preferably the reaction temperature is in the range of from 20° C. to 25° C.
The reaction time may be in the range of from 2 to 48 hours, or more preferably is in the range of from 6 to 8 hours.
The ratio of solvent to (1-bromo-cyclohexyl)-(4-methoxyphenyl)-methanone (II) may be in the range of from 1:1 to 100:1. Preferably the ratio used is substantially 25:1.
Preferably, the process additionally comprises a further step of previously preparing the compound of formula (II), by subjecting cyclohexyl-(4-methoxy-phenyl)-methanone of structural formula (III):
to treatment with an &agr;-keto-halogenating agent, so as to give the compound of formula (II). A reaction for the preparation of the bromo-ketone (II) is reported in Bull. Soc. Chim. France (1962) 90-6.
The &agr;-keto-halogenation is preferably effected using phenyltrimethyl ammonium perbromide. Alternatively, a brominating agent may be selected from liquid bromine, N-bromo succinimide, 1,3-dibromo-5,5-dimethyl-hydantoin, quaternary ammonium and phosphonium perbromides, N-chlorosuccinimide, and other halogenating agents known in the literature.
The solvent used may be selected from methanol, acetic acid, benzene, toluene, chloroform, carbon tetrachloride, tetrahydrofuran (THF), acetonitrile, ethanol, dichloromethane, dioxane, t-butanol, and substituted benzenes.
The reaction is preferably carried out at a temperature of substantially 68° C., for a time of about 6 hours.
The ratio of solvent to ketone may be in the range of from 1:1 to 100:1, but preferably is substantially 20:1.
At this point it should be noted that the starting point for the above-described stage in the overall syntheses, namely cyclohexyl-(4-methoxy-phenyl)-methanone of formula (III), is itself a known compound, disclosed in Izv.Akad.Nauk Turkm.SSR.Ser.Fiz-Tekhn.,Khim.iGeol.Nauk 1963, No. 1,115-6. The overall process of the present invention therefore may include an additional step of subjecting methoxy-benzene of structural formula (IV):
to Friedel-Crafts acylation treatment so as to yield the compound of formula (III).
Thus, the cyclohexyl-(4-methoxy-phenyl)-methanone (III) may for instance be synthesized by Friedel-Crafts reaction between cyclohexan
Deoahar Mandar Manohar
Gharpure Milind Moreshwar
Patel Nishant Mahendra
Rathod Dhiraj Mohansinh
Rengaraju Srinivasan
Alembic Limited
Trinh Ba K.
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