Applicant: KRKA

Our file: 80558 WO

PROCESS FOR PREPARATION OF 0-DESMETHYL VENLAF AXINE

AND ITS ANALOGUES

FIELD OF THE INVENTION

The present invention belongs to the field of organic chemistry and refers to a process for the preparation of O-desmethylvenlafaxine (l-[2-Dimethylamino)-l-(4-hydroxyphenyl)ethyl]cyclo- hexanol), its analogues and pharmaceutical acceptable salts thereof. The invention also relates to a catalytic hydrogenation of cyano-group of the substituted acetonitrile.

BACKGROUND OF THE INVENTION

The antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine, are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and O-desmethylvenlafaxine have no significant affinity for muscarinic, histaminergic, or (alpha)- 1 adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and O-desmethylvenlafaxine do not possess monoamine oxidase (M AO) inhibitory activity.

The therapy area of venlafaxine is the treatment and prevention of major depressive disorder, anxiety disorder, pain, attention deficit hyperactivity disorder and premenstrual syndrome. Panic disorder, social phobia, cerebral function disorders, obsessive-compulsive disorder, substance abuse, migraines, obesity, weight gain, incontinence are other, but not limited to, potent activities of venlafaxine for treating or preventing above mentioned disorders.

Beside general benefits of venlafaxine several adverse effects among drug-treated patients are enumerated and are referred to affect body as whole, cardiovascular, dermatological, gastrointestinal, nervous, metabolic, respiration and urogenital systems (PDR, Micromedex, Expert Opinion on Investigational Drugs; 6, 1997, 65-78). O-desmethylvenlafaxine appears to be equipotent referring its overall action on neurotransmitter uptake and receptor binding but has significant advantages described in the prior art.

Method for preparing O-desmethylvenlafaxine as a venlafaxine metabolite is disclosed in EP 112669. Starting precursor was prepared by condensing amide compound in the form of lithium derivative with cyclohexanone in an organic solvent.

The preparation of O-desmethylvenlafaxine as described in EP 112669 follows the steps as shown in Scheme I.

Bn = benzyl

Scheme I

The main drawback of the process is demanding reduction step of amide group.

Another method for the preparation of O-desmethylvenlafaxine comprises the step of O-deme-

thylating of venlafaxine and/or its salts following the reduction and iV-methylation steps (Scheme II).

Scheme II

WO 00/59851 disclosed demethylation by contacting venlafaxine with lithium diphenylphos- phide to form O-desmethylvenlafaxine. Demethylating venlafaxine with a high molecular weight alkane, arylalkyl or arene thiolate anion in a hydroxylic or ethereal solvent is described in WO 03/048104. In general, O-demethylation is difficult to carry out routinely.

Reduction of the cyano-group is the key point in the synthesis route for production of venlafaxine and its derivatives. Reduction could be enhanced by different reagents as known from the prior art: EP 112669, EP 1343750, EP 1238967, EP 1249447, WO 03/080560, WO 2004/080934, US 2004/0106818, WO 2006/035457, US 2005/0033088, IP.com Journal 2005, 5 (2) 34, WO 00/59851, CN 1225356.

As presented in WO 03/080560 catalytic hydrogenation of compound l-[cyano-(p-methoxy- phenyl)methyl]cyclohexanol using Pd/C under neutral as well as acidic conditions the reduced retrogression product was obtained.

Most prior art processes for preparing O-desmethylvenlafaxine suffer from several drawbacks including demanding hydrogenation and demethylation step. In contrast, the present invention provides a process overcoming these problems by omitting demethylation while preparing O- desmethylvenlafaxine. Moreover, reaction conditions are substantially mildly, yields and purity of product are high, and consequently the product is easily recovered. The invention method is economical, safe and scalable to industrial production.

SUMMARY OF THE INVENTION

As described herein four steps of preparation of O-desmethylvenlafaxine have been carried out. In particular, the -OH group of the starting p-hydroxybenzylacetonitrile has been protected by the protective groups that are commonly used in organic synthesis (Greene T.W., Wuts P.G.M., Protective groups in organic synthesis, 3 ^rd ed., 1999). Benzyl, substituted benzyl, alkyl, alkenyl, trityl, acetyl, silyl, trialkylsilyl, triarylsilyl, tetrahydropyranyl, tetrahydrofuranyl and carbonates, but not limited to, were particularly selected to temporarily stabilize the -OH group in the p- position of the precursor /?-hydroxybenzylacetonitrile .

Subsequently, the compound of formula 2 was subjected to condensation with cyclohexanone following the procedure known from the prior art (Sauvetre et al., Tetrahedron, 34, 1978, 2135) and that were commonly used in the preparation of venlafaxine intermediates (EP 112669, Yardley et al., J. Med. Chem., 33, 1990, 2899-2905).

Catalytic hydrogenation by H ₂ in the presence of palladium on charcoal and aqueous inorganic acids and organic solvents at ambient temperature has been used for transformation of nitrile

group to primary amine.

Conversion of (^-protected 4 or unprotected N,./V-didesmethylvenlafaxine 6 to 0-desmethylvenla- faxine (7) and its analoges may be quickly proceeded by methylation process as known from the prior art (Yardley et al., J. Med. Chem., 33, 1990, 2899-2905; WO 2005/058796).

The protective group has been selectively removed as known from the prior art for example in Greene T. W., Wuts P.G.M., Protective groups in organic synthesis, 3 ^rd ed., 1999. The protecting group may be removed before or after hydrogenation process, as well as contemporarily during catalytic hydrogenation or after methylation.

The term "(9-desmethylvenlafaxine and its analogues" as used herein is intended to include the pharmaceutically acceptable salts thereof. The term "pharmaceutically acceptable salts" refers in this respect to salts prepared from acetic, benzenesulfonic, benzoic, camphorsulphonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulphonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulphuric, tartaric or/7-toluenesulfonic acid.

FIGURES

Figur 1 discloses a typical X-ray diffraction pattern of O-desmethylvenlafaxine, in which 2-theta degrees (± 0.2 degrees two-theta) are listed together with the corresponding intensities.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides a process for the preparation of pharmaceutically active O-desmethyl- venlafaxine and its analogues characterised by formula (1):

wherein Z is H or any protective group used for the protection of OH group. Protective group used for the protection of OH group is selected from beri2yl, substituted benzyl such as p- methoxybenzyl, 3,4-dimethoxybenzyl and o-nitrobenzyl; alkyl such as methyl, ethyl, propyl, butyl, isopropyl; substituated alkyl such as 1-ethoxyethyl, 2,2,2-trichloroethyl, f-butyl, allyl; alkenyl; trityl; alkanoyl such as formyl, acetyl, benzylformyl, chloroacetyl, trifluoroacetyl, tri- chloroacetyl, benzoyl; silyl such as trimethylsilyl, triethylsilyl, triisopropylsilyl, /-butyldimethyl- silyl, triphenylsilyl; tetrahydropyranyl; tetrahydrofuranyl; methoxymethyl; and carbonates such as methyl carbonate, ethyl carbonate, benzyl carbonate, vinyl carbonate, allyl carbonate, 2,2,2- trichloroethyl carbonate.

That is, the process comprises:

- introducing the protective group on the p-hydroxybenzylcyanide

Scheme III

- condensing the protected nitrile 2 with cyclohexanone to give compound 3

Scheme IV

The compound of formula 3 is further

(A) reduced to obtain compound of formula 4

followed by

(B) methylation of amino group and

(C) optionally deprotection of hydroxyl group before step A or before step B or after step B in case of Z ≠ H.

(Cl) In case deprotection takes place before step A the process proceeds according to Scheme V.

Methylation

Scheme V

(C2) In case deprotection takes place after step B the process proceeds according to Scheme VI.

Methylation

Deprotection

Scheme VI

(C3) In case deprotection takes place before B the process proceeds according to Scheme VII.

Methylation

Scheme VII

(C4) In case Z is benzyl, trityl, benzyl carbonate or any protective group which is removed by

catalytic hydrogenation) reduction and deprotection are performed in one step (Scheme VIII).

Scheme VIII

It was surprisingly found that the compound O-desmethylvenlafaxine and its analogues characterised by formula (I) can be prepared by a multi step process which comprises the reduction process according to the invention in a very efficient manner and with high yield without formation of substantial amounts of undesired by product or reduced retrogression product. Catalytic hydrogenation by H ₂ in the presence of palladium on charcoal, aqueous inorganic acids and organic solvents at ambient temperature has been used for transformation of nitrile group to primary amine. In details, hydrogenation steps in afore described reaction schemes followed the conditions as presented hereinafter.

Cyano-compound 3 is dissolved in an organic solvent selected from alcohols (methanol, ethanol, isopropanol, propanol, butanol and isobutanol), cyclic ethers (THF, dioxane), carbohydrates, DMF, DMA, xylenes and toluene or mixtures of them. Preferably alcohols are used. To the solution the catalyst palladium on charcoal is added. The amount of Pd on charcoal varies from 1% to 20 %, preferably from 5 % to 10 %. The amount of catalyst in the reaction mixture is from 5 % to 50 %, preferably from 10 % to 30 %. Afterwards inorganic acid chosen between HCl, HBr, HI, H ₂ SO ₄ , H ₃ PO ₄ , HClO ₄ or HNO ₃ is added, preferably HCl or H ₂ SO ₄ . Concentration of the acid is in the range of 20 % to 100%; beneficially aqueous solution of inorganic acid with concentration between 25 % and 50 % was used. At a pressure between 1 and 100 bar, preferably between 2 and 10 bar, and temperature between room temperature and 100 ⁰ C, preferably room temperature, the hydrogenation process is let run between 1 h and 1O h, preferably between 2 h and 6 h. After the reaction is completed, the catalyst is removed by filtration. The filtrate is dried. The drying of filtrate could be performed by evaporation of the filtrate and by addition of a second solvent for drying and its evaporation. The solvents used for drying are: isopropanol,

isobutanol, toluene, cyclohexane, acetates, and ethers. Afterwards, to the concentrate the organic solvent is added. Preferred are alkanes, alcohols, cycloalkanes, halogenated hydrocarbons, hydrocarbons, ethers, esters, xylenes and toluene. The mixture is cooled and the product as corresponding salt (chloride, bromide, iodide, sulphate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogenphosphate, chlorate, nitrate) of compound 4 is separated.

Alternatively, the isolation may be carried out as follows: after the hydrogenation step is completed the reaction mixture is filtered. To the evaporated filtrate water is added and pH is arranged to approximately 10 to 12 by addition of base such as NaOH, KOH, LiOH, NH ₃ ... Then organic solvent selected from the group of alkanes, halogenated alkanes, cycloalkanes, toluene, esters or ethers is added. The phases are separated. The organic phase may be washed and then acidified by addition of appropriate acid to pH approximately 1. This mixture is then dried for example by azeotropic distillation of water. When water is removed from the mixture crystallized product as corresponding salt (chloride, bromide, iodide, sulphate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogenphosphate, chlorate, nitrate) of compound 4 is recovered.

The present invention provides an improved process for preparing O-desmethylvenlafaxine that differs from prior art. The process of the invention presented herein does not encompass the reduction step of amide as described in EP 112669 (Scheme I) or 0-demethylation step of venlafaxine as shown Scheme II. The invention comprising the reduction step of nitriles to amines ( Schemes V, VI, VII and VIII) by catalytic hydrogenation in the presence of palladium on charcoal, aqueous inorganic acids and organic solvents at ambient temperature results in substantially higher yields in comparison to prior art.

O-desmethylvenlafaxine may be obtained by the methods such as extraction and crystallization as known from the art. Process described in prior art such as preparation of O- desmethylvenlafaxine as a free base (WO 00/59851 and WO 03/048104), fumarate salt (EP 0112669), succinate salt (WO 02/064543) and formate salt (WO 03/103603) can be employed.

Moreover, reactions conditions are substantially mildly, yields and purity of products are high, and consequently the final product and/or analogues are easily recovered. The invention method is economical, safe and scalable to industrial production.

The compound of formula 4 prepared according to present process defined may be also used for the preparation of pharmaceutically acceptable salts of compound of formula 1. Examples for suitable pharmaceutically acceptable salts comprise an acetic, benzenesulfonic, benzoic, camphorsulphonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulphonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulphuric, tartaric or p-toluenesulfonic acid salts. Preferably, the salt is a succinate salt or a formate salt.

The present invention pertains also to the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof, which is prepared according to the present process, and wherein an active ingredient can be combined with a pharmaceutical carrier in preparing the compositions for an oral dosage form. Examples of suitable pharmaceutical carriers as well as appropriate oral dosage forms are known in the art.

The process of the present invention is in the following illustrated by examples that should not be construed to limit the scope of the invention in any manner.

EXAMPLES

Melting points were taken on a Koffler melting point apparatus and IR spectra were taken on a Paragon 100 Perkin-Elmer FT-IR spectrometer.

X-ray powder diffraction patterns were obtained by a Phillips PW3040/60 X'Pert PRO diffractometer using CUKQ radiation of 1 ,541874 A.

FT-IR analysis was performed on FT-IR System SPECTRUM GX Perkin Elmer [4000-400] cm ^' '. Resolution 4 cm ^"1 , KBr tbl.]

Example 1

0.98 g of (4 mmol) l-(l-cyano-l-(4-methoxyphenyl)methyl)cyclohexanol was dissolved in 15 ml

of methanol. Then 0.6 ml of HCl cone, and 300 mg of 10 % Pd/C were added and hydrogenation at ambient temperature for 6 h at 3.5 bar was performed. After the reaction was completed (HPLC area %: Product 97.32%, Starting compound 1.06%), the mixture was filtered and evaporated to give the title oily residue. Addition of 20 ml isopropanol and evaporation to approximate volume of 2 ml were followed. The mixture was stirred for 3 h at room temperature and 10 h at temperature below 0 °C. The precipitated product was filtered off and yielded 0.95 g of product that corresponded to 83%. HPLC area %: Product 99.7 %.

Example 2

0.98 g of (4 mmol) l-(l-cyano-l-(4-methoxyphenyl)methyl)cyclohexanol was dissolved in 15 ml of methanol. Then 2 ml of 2.5 M HCl in ethanol and 300 mg of 10% Pd/C were added and hydrogenation at ambient temperature for 6 h at 3.5 bar was performed. After the reaction was completed (HPLC area %: Product 98.3%, Starting compound 1.0%), the mixture was filtered and evaporated to give the title oily residue. 25 ml of diisopropyl ether was added followed by evaporation to approximately 3 ml. Additionaly, 4ml diisopropyl ether were admixed and stirred for 2 h on ice. After filtration 1.04 g of product (91%) was obtained. HPLC area %: Product 99.5 %.

Example 3

0.98 g of (4 mmol) l-(l-cyano-l-(4-methoxyphenyl)methyl)cyclohexanol was dissolved in 15 ml of methanol. After admixing of 0.8 ml of 37 % H ₂ SO ₄ and 200 mg of 5 % Pd/C the mixture was hydrogenated at ambient temperature for 6 h at 3.5 bar. After the reaction was completed (HPLC area %: Product 97.8%), the mixture was filtered and evaporated. To the resulting oily residue 15 ml of water and 3 M NaOH (pH was adjusted to 12) were added. By adding 15 ml of isopropyl acetate, two phases system was obtained, and after thorough mixing separated. Repeatedly, the aqueous layer was extracted with 10 ml of isopropyl acetate. Combined organic phases were evaporated to ¹ A volume and acidified to pH below 1. The mixture was then dried by adding and evaporating the isopropyl acetate. Finally, the mixture was evaporated to the approximate volume 3-5 ml and 5 ml of hexane were added. Then stirring for 1 h at room temperature and 1 h in an ice bath were carried out. The precipitated product was filtered off and yielded 1 g of

product (88 %).

HPLC area %: Product 98.6%

Example 4

4-benzyloxyphenylacetonitrile

The mixture of 2.0 g (15 mmol) of 4-hydroxyphenylacetonitrile, 2.08 g Of K ₂ CO ₃ , 2.15 g (18 mmol) of benzyl bromide, 20 ml of CH ₂ Cl ₂ and 20 ml of methanol is heated under reflux temperature for 3.5 h. The mixture is cooled and then 50 ml of CH ₂ Cl ₂ and 50 ml of water were added and stirred for 10 min. The phases were separated and organic phase is washed twice with 50 ml of water. Organic phase is dried over Na ₂ SO ₄ , filtered and evaporated to the solid residue which is title product. The product is collected and dried (2.82 g, 85 %).

M.p.: 59-65 °C

¹ HNMR (DMSO-d ₆ ); δH, ppm: 3.93 (s, 2H, -CH ₂ -CN), 5.10 (s, 2H, -CH ₂ -Ph), 7.0-7.5 (m, 9H, Ph)

IR: 2247, 1615, 1514, 1454, 1248, 1015, 806

Example 5

l-(l-cyano-l-(4-benzyloxyphenyl)methyl)cyclohexanol

The mixture of 3.35 g (15 mmol) of 4-benzyloxyphenylacetonitrile and 15 ml of THF is cooled to -70 ⁰ C under inert atmosphere. Then 9.6 ml of 1.6 M (in hexane) butyllithium is added very slowly. After the addition, the mixture is stirred for 0.5 h and then 1.75 ml (16.9 mmol) of cyclohexanone is added and the mixture is stirred at -70 °C for 2.5 h. The reaction mixture is poured into 80 ml of aqueous solution of NH ₄ Cl and after one hour the precipitated product is separated. The product is dried and 4.50 g (93 %) of l-(l-cyano-l-(4- benzyloxyphenyl)methyl)cyclohexanol is isolated.

Mp.: 136-140 ⁰ C

¹ HNMR (DMSO-Cl ₆ ); δH, ppm: 1.0- 1.8 (m, 1OH, cyclohexane), 4.04 (s, IH, CHCN), 4.90 (s, IH, -OH), 5.08 (s, 2H, -CH ₂ -Ph), 6.95-7.5 (m, 9H, Ph)

IR: 2238, 1612, 1514, 1454, 1238, 1155, 1040, 982, 788, 731

Example 6

4-(2-amino-l-(l-hydroxycyclohexyl)ethyl)phenol

0.53 g (1.7 mmol) of l-(l-cyano-l-(4-benzyloxyphenyl)methyl)cyclohexanol is dissolved in 14 ml of methanol and then 0.4 ml of concentrated HCl and 0.2 g of 10 % Pd/C are added and the mixture is hydrogenated for 23 h at 3.5 bar. After the reaction is completed, the catalyst is filtered and the filtrate is evaporated under reduced pressure. To the residue 20 ml of toluene is added and evaporated again. Residue is suspended in 10 ml of isopropyl acetate and the product is isolated as hydrochloride salt (0.35 g, 76 %).

M.p.: 230-238 °C

¹ HNMR (DMSO-d ₆ ); δH, ppm: 0.9-1.6 (m, 1OH, cyclohexyl),2.73 (m, IH, -CH), 3.09 (m, 2H, - CH ₂ -NH ₂ ), 4.44 (s, IH, -OH), 6.72 (d, 2H, Ph), 7.05 (d, 2H, Ph), 7.57 (bs, 2H, -NH ₂ ), 9.36 (s, IH, Ar-OH)

IR: 1616, 1514, 1473, 1446, 1228, 840, 668, 542

Example 7

4-(2-(dimethylamino)-l-(l-hydroxycyclohexyl)ethyl)phenol

0.34 g (1.2 mmol) of 4-(2-amino-l-(l-hydroxycyclohexyl)ethyl)phenol hydrochloride is

dissolved in 1 ml of 3 M NaOH and then 0.2 ml (5 mmol) of formic acid and 0.2 ml (2.8 mmol) of 37 % formaldehyde are added. The mixture is heated at 100 °C for 5 h. Then the reaction mixture is cooled and neutralized to pH = 9-10. The precipitated product is filtered and dried (0.26 g, 84 %).

Mp.: 228-231 °C

¹ HNMR (DMSO-d ₆ ); δH, ppm: 0.8-1.6 (m, 1OH, cyclohexyl), 2.13 (s, 6H, 2 ^χ CH ₃ ), 2.33 (dd, IH, -CH), 2.71 (dd, IH, -CH ₂ -NMe ₂ ), 2.98 (dd, IH, -CH ₂ -NMe ₂ ), 5.37 (bs, IH, -OH), 6.62 (d, 2H, Ph), 6.95 (d, 2H, Ph), 9.21 (s, IH, Ar-OH)

IR: 2936, 1620, 1518, 1277, 1038, 1009, 841, 570, 553

Example 8

4-cyanomethylphenyl acetate

The mixture of 1.33 (10 mmol) of 4-hydroxyphenylacetonitrile, 2.0 ml of acetic acid anhydride and 30 ml of pyridine is stirred at room temperature for 3.5 h. To the mixture 150 ml of isopropyl acetate and 100 ml of water were added and stirred for 10 min. The phases were separated and organic phase is washed twice with 100 ml of 1 % HCl. Organic phase is dried over Na ₂ SO ₄ , filtered and evaporated to the oily residue which is title product (1.90 g).

¹ HNMR (DMSO-d ₆ ); δH, ppm: 1.96 (s, 3H, -CH ₃ -COO-), 4.04 (s, 2H, -CH ₂ -CN), 7.15 (d, 2H, Ph), 7.39 (d, 2H, Ph)

Example 9

4-(2-(dimethylamino)-l-(l -hydroxy cyclohexyl)ethyl)phenol

The mixture of 2.1g (12 mmol) of 4-cyanomethylphenyl acetate and 14 ml of THF is cooled to - 70 ⁰ C under inert atmosphere. Then 7.7 ml of 1.6 M (in hexane) butyllithium is added very

slowly. After the addition, the mixture is stirred for 0.5 h and then 1.40 ml (13.5 mmol) of cyclohexanone is added and the mixture is stirred at -70 °C for 2.5h. The reaction mixture is poured into 45 ml of aqueous solution OfNH ₄ Cl and then 60 ml of isopropyl acetate is added and stirred. The phases were separated and organic phase is washed twice with 50 ml of water, dried over Na ₂ SO ₄ , filtered and evaporated to the oily residue. This residue was dissolved in 50 ml of methanol and then 2.4 ml of concentrated HCl and 1.2 g of 10 % Pd/C is added. The mixture is hydrogenated for 6 h at 3.5 bar and after the reaction is completed the mixture is filtered and evaporated. The residue is dissolved in 6ml of 3 M NaOH and heated to 50 °C and stirred at this temperature for Ih. The solution is cooled and then 1.2 ml (32 mmol) of formic acid and 1.2 ml (16 mmol) of 37 % formaldehyde are added. The mixture is heated at 100 °C for 5 h. Then the reaction mixture is cooled and neutralized to pH = 9-10. The precipitated product is filtered and dried (2.4 g, 78 %).

Mp.: 228-232 °C

¹ HNMR (DMSO-d ₆ ); δH, ppm: 0.8-1.7 (m, 1OH: cyclohexyl), 2.13 (s, 6H, 2><CH ₃ ), 2.33 (dd, IH, -CH), 2.71 (dd, IH, -CH ₂ -NMe ₂ ), 2.98 (dd, IH, -CH ₂ -NMe ₂ ), 5.37 (bs, IH, -OH), 6.62 (d, 2H, Ph), 6.94 (d, 2H, Ph), 9.21 (s, IH, Ar-OH)

IR: 2936, 1620, 1518, 1277, 1039, 1009, 841, 570, 554