BACKGROUND OF THE INVENTION

Field of the Invention

The present disclosure relates to a process for the preparation of an imidazole derivative, 4-[l-(2, 3-Dimethylphenyl) ethyl]- IH-imidazole and related intermediates. The synthesis is made from affordable commercially available starting materials. Many of the previous synthesis use expensive 4-substituted imidazole derivatives as starting material. In this invention the imidazole ring is instead built up during the synthesis.

Description of the Related Art

4-[l-(2, 3-Dimethylphenyl) ethyl] -IH-imidazole is commonly known as medetomidine (I).

Medetomidine, first described in EP-A-72615, is a racemic mixture of equal proportions of two optical enantiomers, the levo- and dextro-rotatory optical isomers (MacDonald et al., 1991 ; Savola and Virtanen, 1991) with generic names levomedetomidine (LEV) and dexmedetomidine (DEX) respectively. This compound belongs to a new class of alpha2 -receptor agonists containing a 4- substituted imidazole ring with high selectivity towards 2-adrenoreceptors (Savola et al, 1986).

Receptors affected by catecholamine neurotransmitters, such as

norepinephrine and epinephrine, are termed adrenergic receptors (or

adrenoceptors) and can be divided into alpha- and beta-subclasses. The alpha2- adrenoreceptors are involved in the auto-inhibitory mechanism of neurotransmitter release and play a significant role in the regulation of hypertension, bradycardia (reduced heartbeat rate) and even regulation of alertness and analgesia (reduced sensitivity to pain).

Medetomidine has been studied in human clinical trials and has also been used as an anesthetic for animals with the (S)-enantiomer, dexmedetomidine, being the active component.

Recently, it has been reported that certain pharmacological compounds that act upon serotonin and dopamine neurotransmitters have the ability to either impede or promote the attachment of certain marine organisms e.g. barnacles. U.S. patent 7,531 ,581 taught for the first time the use of medeotmidine as antifouling agent. Later on, U.S. patent 7,31 1 ,766 and U.S. patent 7,531 ,581 disclosed coating compositions comprising medetomidine for inhibiting or preventing marine biofouling on a solid surface.

The potential uses of medetomidine necessitate the availability of the same affordable, economically viable process for its preparation.

There are few methods known for the preparation of medetomidine.

A multistep process for the preparation of medetomidine has been described by Kudzma et al. This process is disadvantageous as it involves usage of a highly inflammable and corrosive compound like butyl lithium, and further, the reaction is carried out at low temperature of about -78°C.

European patent EP1918282 describes a method of preparation of medetomidine and its salts. The method utilizes halogenated imidazoles towards transmetalation with Grignard reagents and the subsequent reaction with 2, 3- dimethyl benzaldehyde. The method involves protection of the imidazole nitrogen and deprotection using trityl chloride.

Cordi et al, discloses a method of preparation of medetomidine in the form of its tartarate salt. The drawback with this method is that the synthesis starts from rather expensive starting materials.

GB2453982 describes a method of preparation of medetomidine that comprises reacting 2, 3-dimethyl-methylbenzylalcohol with N- trimethylsilylimidazole. The method suffers from the disadvantage of requiring the use of strong Lewis acids and excess of reagents. The present disclosure provides a simple yet non-obvious process, which can overcome the disadvantages of the methods already known in the prior art. The multi-step process starting from 2, 3-dimethylbenzoic acid is scalable and safe for commercial production. The synthetic route is also an economically viable route for the preparation of medetomidine.

SUMMARY OF THE INVENTION

The present disclosure provides a process for the preparation of medetomidine (formula I),

Formula I

comprising the steps of:

esterifying 2, 3-dimethylbenzoic acid to (2-nitrophenyl)-2,3- dimethylbenzoate;

converting (2-nitrophenyl)-2,3-dimethylbenzoate to l-(2,3-dimethylphenyl)- 2-nitroethanone;

preparing 3-(benzylamino)-l -(2,3-dimethylphenyl)-2-nitro-prop-2-en-l-one from 1 -(2,3-dimethylphenyl)-2-nitroethanone;

reducing 3-(benzylamino)-l-(2,3-dimethylphenyl)-2-nitro-prop-2-en-l-o ne to 2-amino-3-(benzylamino)-l-(2, 3-dimethylphenyl)prop-2-en-l-one;

cyclizing 2-amino-3-(benzylamino)-l-(2,3-dimethylphenyl)prop-2-en-l-on e to (l -benzylimidazol-4-yl)-(2,3-dimethylphenyl) methanone; converting (l-benzylimidazol-4-yl)-(2,3-dimethylphenyl)methanone to 1- benzyl-4- [l -(2,3-dimethylphenyl)vinyl]imidazole; and

hydrogenating l-benzyl-4- [l-(2,3-dimethylphenyl)vinyl]imidazole to obtain compound of Formula I.

Instead of using expensive 4-substituted imidazole derivatives as a starting material, the present method relies on building up the imidazole ring during the synthesis. Furthermore, none of the reaction steps require temperatures below 0°C which is an advantage since cooling large volumes below 0°C is quite expensive and time consuming.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 : Illustrates reaction schemes according to the present invention for the preparation of the compounds having the structural formula I

DETAILED DESCRIPTION OF THE INVENTION AND

PREFERRED EMBODIMENTS THEREOF

The present disclosure relates to a process for the preparation of an imidazole derivative, 4-[l-(2, 3-Dimethylphenyl) ethyl]- lH-imidazole and related intermediates.

In the preferred embodiment the present invention disclosures a process for the preparation of a compound of Formula I,

Formula I

comprising steps of: esterifying 2,3-dimethylbenzoic acid to (2-nitrophenyl)-2,3- dimethylbenzo ate ;

converting (2-nitrophenyl)-2,3-dimethylbenzoate to l-(2,3-dimethylphenyl)- 2-nitroethanone;

preparing 3-(benzylamino)-l -(2,3-dimethylphenyl)-2-nitro-prop-2-en-l-one from 1 -(2,3-dimethylphenyl)-2-nitroethanone;

reducing 3-(benzylamino)-l-(2,3-dimethylphenyl)-2-nitro-prop-2-en-l-o ne to 2-amino-3-(benzylamino)-l -(2, 3-dimethylphenyl)prop-2-en-l -one;

cyclizing 2-amino-3-(benzylamino)-l -(2,3-dimethylphenyl)prop-2-en-l -one to (l-benzylimidazol-4-yl)- (2, 3-dimethylphenyl)methanone;

converting (l -benzylimidazol-4-yl)-(2,3-dimethylphenyl)methanone to 1-benzyl- 4- [l-(2,3-dimethylphenyl)vinyl]imidazole; and

hydrogenating l-benzyl-4- [l-(2,3-dimethylphenyl)vinyl]imidazole to obtain compound of Formula I.

In another embodiment of the present disclosure, the 2, 3-dimethylbenzoic acid is esterified using oxalyl chloride and 2-nitrophenol.

In yet another embodiment of the present disclosure, the l-(2, 3- dimethylphenyl)-2-nitroethanone is prepared using nitro methane and a base.

In still another embodiment of the present disclosure, the base is selected but not limiting to a group comprising potassium carbonate, potassium t-butoxide, sodium methoxide, 4-dimethylaminopyridine, potassium fluoride and sodium carbonate; preferably potassium carbonate.

In still another embodiment of the present disclosure, the 3-(benzylamino)- 1 -(2,3-dimethylphenyl)-2-nitro-prop-2-en- 1 -one is prepared using benzylamine and triethylorthoformate.

In still another embodiment of the present disclosure, the reduction is carried out using a reducing agent selected from the group consisting of zinc- ammonium salt, Raney nickel-hydrogen, and palladium on carbon-hydrogen preferably Raney nickel-hydrogen.

In still another embodiment of the present disclosure, the ammonium salt is selected from a group consisting of ammonium formate, ammonium acetate, ammonium oxalate, ammonium chloride and hydrazine hydrate; preferably ammonium formate.

In still another embodiment of the present disclosure, the (1- benzylimidazol-4-yl)- (2, 3-dimethylphenyl)methanone is prepared using triethylortho formate .

In still another embodiment of the present disclosure, the l -benzyl-4-[l- (2,3-dimethylphenyl)vinyl]imidazole is prepared using methylmagnesium halide followed by dehydration using acid.

In still another embodiment of the present disclosure, the acid is selected but not limiting to a group comprising hydrochloric acid, hydrobromic acid, acetic acid and p-toluene sulphonic acid; preferably hydrochloric acid.

In still another embodiment of the present disclosure, the

methylmagnesium halide is selected from a group consisting of methylmagnesium chloride, methylmagnesium iodide and methylmagnesium bromide, preferably methylmagnesium bromide.

In still another embodiment of the present disclosure, the l -benzyl-4-[l- (2,3-dimethylphenyl)vinyl]imidazole is hydrogenated using a hydrogenating agent selected from a group consisting of hydrogen-palladium on carbon and palladium hydroxide on carbon, preferably hydrogen-palladium on carbon.

In still another embodiment of the present disclosure, 1 -(2,3- dimethylphenyl)-2-nitroethanone is prepared by a process comprising steps of; preparing (2,3-dimethylphenyl)-imidazol-l -yl-methanone from 2,3- dimethylbenzoic acid; and

treating (2,3-dimethylphenyl)-imidazol-l -yl-methanone with nitromethane in presence of a base to obtain l-(2,3-dimethylphenyl)-2-nitroethanone.

The present disclosure is also in relation to a compound of formula II:

Formula II

The present disclosure is also in relation to a compound of formula III,

Formula III

The present disclosure is also in relation to a compound of formula IV,

Formula IV

The present disclosure is also in relation to a compound of formula V,

Formula V In the last step of the synthesis, reduction of an alkene and removal of a protected group is made in one single step. This is often done in two steps in previous synthesis pathways; first reducing the double bond and then removing the protective group. During the synthesis process the temperature can be kept at 0°C or above. Meaning that there is no need for further cooling. This together with the different steps hereby disclosed makes the process suitable for large- scale synthesis.

Finally, medetomidine can be converted to its salts by addition of either an organic or an inorganic acid using standard methods. If there are problems while handling the medetomidine due to dust-formation a suitable high concentration product can be made by dissolving medetomidine into l-methoxy-2-propanol.

In summary this disclosure provides an industrially feasible process for the preparation of medetomidine. The process involves the use of simple and cost- effective reagents to arrive at medetomidine as a free base.

Any formula given herein is intended to represent compounds having structures depicted by the structural formula. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and their mixtures, including the racemic mixtures, are part of the present disclosure.

The present disclosure is not to be limited in terms of the particular embodiments described in this application, which are intended as illustrations of various aspects. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods within the scope of the disclosure, in addition to those enumerated herein will be apparent to those skilled in the art from the foregoing descriptions.

It is to be understood that this disclosure is not limited to particular methods, reagents, compounds and compositions, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

The invention is described in detail below. The examples and experimental details are disclosed to provide an improved understanding and guidance for those skilled in the art. EXAMPLE 1

The present disclosure, which is exemplified as given below, should not be construed to limit the scope of the disclosure. One of ordinary skill in the art will understand how to vary the exemplified preparation to obtain the desired result.

Step-la: Preparation of (2-nitrophenyl) 2,3-dimethylbenzoate

Et ₃ N, CH ₂ CI ₂

To the compound 1 (50 g, 0.32 mol) in dry dichloromethane (1 .8 L) was added N- dimethylformamide (0.2 ml) and oxalyl chloride (84.5 g, 0.66 mol) at about 15 °C for about 1 h and continued stirring until a clear solution appeared (~1 h). The reaction mixture was concentrated to get acid chloride derivative. To a mixture of 2-nitrophenol (46.5 g, 0.33 mol), triethylamine (68 g, 0.66 mol) in dichloromethane (500 ml) was added a solution of acid chloride in

dichloromethane (250 ml) and stirred for about 2 h. The reaction mixture was quenched with ice-cold water (500 ml) and extracted with dichloromethane. The organic layer was washed with sat. NaHC0 ₃ solution (500 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure to get a beige solid. The crude material was crystallized using 20 % ethyl acetate- n- hexane (600 ml) to furnish 2a as a pale yellow solid. Yield 81 g (90).

The ^! H NMR spectrum (CDC1, 300 MHz) of the compounds obtained after each step below was measured using standard methodology. It was recorded at 300 MHz and referenced to an internal standard (TMS). Signals are reported in ppm (δ). ^! H NMR (300 MHz, CDC1 ₃ ): 5 8.18 (d, J =8.3 Hz, 1H), 7.83 (d, J = 7.5 Hz, 1H), 7.75 - 7.69 (m, 1H), 7.48- 7.36 (m, 3H), 7.25 - 7.17 (m, 1H), 2.57 (s, 3H), 2.40 (s, 3H)

Step-2a: Preparation of l-(2,3-dimethylphenyl)-2-nitroethanone.

To a suspension of pulverized dry K ₂ CO ₃ (76.3 g, 0.55 mol) in N,N- dimethylformamide (300 ml) was added nitromethane (47 g ,0.735 mol) at about 0 °C for about 30 min under nitrogen atmosphere and stirred at 0 °C for 20 min. A solution of 2a (50 g, 1.5 mol) was added and stirred at about 0 °C for about 20 min. The reaction mixture was then heated at about 80 °C for about 3 h. The reaction mixture was poured into ice-cold water (500 ml), pH adjusted to 1 with Cone. HC1 and extracted with ethyl acetate (2 x 500 ml). The organic layer was dried over anhydrous sodium sulphate and concentrated. The crude residue was purified by flash column chromatography using ethyl acetate - petroleum ether to afford 3 pale yellow color solid. Yield: 21 g (60 %).

1H NMR (300 MHz, CDC1 ₃ ): δ 7.4 -7.2 (m, 3H), 5.76 (s, 2H), 2.44 (s, 3H), 2.32 (s, H) LCMS (mix): 192.6 (M-l )

Compound 3 or l -(2, 3-dimethylphenyl)-2-nitroethanone can be obtained as specified above (steps l a to 2a), by esterifying 2,3-dimethylbenzoic acid to (2- nitrophenyl)-2,3-dimethylbenzoate using oxalyl chloride and 2-nitrophenol followed by a conversion of (2-nitrophenyl)-2,3-dimethylbenzoate to 1 -(2,3- dimethylphenyl)-2-nitroethanone using nitromethane and a base. Alternatively, one can use 2,3-dimethylbenzoic acid (compound 1 ) to prepare (2,3- dimethylphenyl)-imidazol- 1 -yl-methanone which is subsequent treated with nitromethane in presence of a base to obtain l -(2,3-dimethylphenyl)-2- nitroethanone (see steps lb-2b below). The start material is the same but reagent b varies.

Step-lb: Preparation of (2,3-dimethylphenyl)-imidazol-l-yl-methanone.

To the compound 1 (250 g, 1.66 mol) in dry dichloromethane (1.8 L) was added N- dimethylformamide (15 ml) and oxalyl chloride (222 g, 1.75 mol) at about 15 °C for about 1 h and continued stirring for about 1 h at about 25 °C. A solution of imidazole (225.7 g, 3.32 mol) in dichloromethane (1.8 L) was added dropwise at about 0 °C and stirred for about 1 h. The reaction mixture was quenched with ice-cold water (1.5 L) and extracted with dichloromethane. The organic layer was washed with sat. NaHC0 ₃ solution (1.25 L), dried over anhydrous sodium sulphate and concentrated under reduced pressure to get 2b as a yellowish syrupy mass. Yield 291 g (87 %).

^! H NMR (300 MHz, CDC1 ₃ ): δ 7.84 (s, 1H), 7.46- 7.35 (m, 2H), 7.23 (d, J = 4.8 Hz, 2H), 7.1 1 (m, 1H), 2.36 (s, 3H), 2.22 (s, 3H)

LCMS (m z): 200.6 (M+l)

To a suspension of pulverized dry K ₂ C0 ₃ (622 g, 4.5 mol) in N,N- dimethylformamide (900 ml) was added nitromethane (325 ml, 6 mol ) at about 0 °C for about 30 min under nitrogen atmosphere and stirred at about 0 °C for about 1 h. A solution of 2b (300 g, 1.5 mol) in N, N- dimethylformamide (300 ml) was added dropwise at about 0- 5 °C and stirred for about 30 min. The reaction mixture was slowly warmed to 45 °C and stirred for 12 h. The reaction mixture was poured into ice-cold water (6 L) and pH adjusted to 7.5 with Cone. HC1. The resultant solid was filtered, suspended in 2.5 N HC1 (1.5 L) and extracted with ethyl acetate (3 L). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 3 as a beige color solid. Yield: 173 g (60 %).

^! H NMR (300 MHz, CDC1 ₃ ): δ 7.4 -7.2 (m, 3H), 5.76 (s, 2H), 2.44 (s, 3H), 2.32

(s, 3H), LCMS (m z): 192.6 (M-l)

Step-3: Preparation of 3-(benzylamino)-l-(2, 3-dimethylphenyl)-2-nitro-prop-2- en-l-one (compound of formula II).

The compound 3 (120 g, 0.62 mol) in glacial acetic acid (600 ml) was added with tri ethyl orthoformate (321.7 g, 2.17 mol) and stirred at about 100 °C for about 1 h. To this refiuxing solution was added benzylamine (99.5 g, 0.93 mol) slowly and stirred for about 2 h. The reaction mixture was poured into ice-cold water (750 ml), basified with 20% NaOH solution and extracted with ethyl acetate (2 x 600 ml). The organic layer washed with 1 N HC1 solution (300 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude residue was crystallized with 20 % isopropyl alcohol and n-hexane (1.5 L) to afford 4 (compound of formula II) as a pale yellow solid. Yield: 153 g (80 %). ^! H NMR (300 MHz, CDCI3): δ 10.97 (bs, 1H), 8.72 (d, J = 14.4 Hz , 1H), 7.48 - 7.3 (m, 5H), 7.20- 6.94 (m, 3H), 4.68 (d, J = 6 Hz, 2H), 2.36 (s, 3H), 2.24 (s, 3H) LCMS (m z): 31 1.2 (M). Step -4: Preparation of 2-amino-3-(benzylamino)-l-(2, 3-dimethylphenyl)prop- 2-en-l-one (compound of formula III).

The compound 4 (150 g, 0.48 mol) in methanol (1.5 L) was hydrogenated over 50 % Raney Ni (75 g) at about 50 °C and about 3 Kg pressure for about 6 h. The reaction mixture was filtered through celite and the celite washed with methanol (100 ml). The combined organic filtrates were concentrated to furnish 5 (compound of formula III) as a thick brown semi solid. Yield 1 15 g (85 %).

LCMS (mix): 281.3 (M+l)

Step-5: Preparation of l-benzylimidazol-4-yl)-(2, 3-dimethylphenyl) methanone (compound of formula IV).

To a solution of 5 (1 15 g, 0.41 mol) in ethanol (1 L) was added triethyl orthoformate (304.8 g, 2.05 mol) and acetic acid (2 ml) and refluxed for 4 h. The reaction mixture was concentrated and crystallized using methylbutyl ether (360 ml) to result in 6 (compound of formula IV) as an off- white solid. Yield 80 g (67 %)

^! H NMR (300 MHz, CDC1 ₃ ): δ 7.59(s, 1H), 7.55 (s, 1H), 7.43- 7.31 (m, 3H), 7.29- 7.13 (m, 5H), 5.16 (s, 2H), 2.33 (s, 3H), 2.26(s, 3H)

LCMS (m z): 291.3 (M+l) Step-6: Preparation of l-benzyl-4-[l-(2,3-dimethylphenylvinyl]imidazole (compound of formula V).

To a suspension of 6 (78.6 g, 0.27 mol) in tetrahydrofuran (780 ml) was added methyl magnesium bromide in ether (3M solution, 270 ml, 0.812 mol) over a period of about 30 min at about 25 °C. The resultant brown color reaction mixture was stirred for about 2 h at about 25 °C. 6N HCI (780 ml) was added to the reaction mixture and refiuxed for about 3 h. The reaction mixture was cooled and extracted with ethyl acetate (2 x 400 ml). The organic layer was washed with sat. NaHC0 ₃ solution (400 ml), brine solution (400 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure to get a tan color crude material. The crude was crystallized with 20 % isopropyl alcohol - n- hexane (930 ml) to give rise to 7 (compound of formula V) as an off- white solid. Yield 48 g (62 %)

^! H NMR (300 MHz, CDC1 ₃ ):5 7.61 (s, 1H), 7.36- 7.3 l(m, 3H), 7.12- 7.06(m, 5H), 6.33 (s, 1 H), 6.15(d, J = 2.1Hz, 1H), 5.05 (s, 2H), 5.01 (d, J = 2.1 Hz, 1H), 2.3 (s, 3H), 2.12 (s, 3H) LCMS (m/z): 289.1 (M+l)

Step -7: Preparation of 4-[l-(2, 3-Dimethylphenyl) ethyl] -lH-imidazole (compound of formula I)

The compound 7 (47 g, 0.162 mol) in methanol (470 ml) was hydrogenated over 10 % Pd on carbon (20 g, 50 % wet) at about 70 °C and 5 Kg pressure for about 5 h. The reaction mixture was cooled, filtered through celite and the celite washed with methanol (100 ml). The combined organic filtrates were concentrated to furnish thick pale yellow syrupy mass. The crude material was crystallized with 10 % toluene - cyclohexane (470 ml) to afford 8 (compound of formula I), 4-[l - (2, 3-Dimethylphenyl) ethyl] -l H-imidazole or medetomidine as a white solid. Yield 28.5 g (87 %)

!H NMR (300 MHz, CDC1 ₃ ): δ 7.38 (s, 1H), 7.07- 6.94(m, 3H), 6.70 (s, 1H), 4.38 (q, J = 7.2 Hz, 1H), 2.29 (s, 3H), 2.22 (s, 3H), 1.58 (d, J = 7.2 Hz, 3H)

LCMS (m z): 200.7 (M+l ).

While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting.

REFERENCES

1. Kudzma, Linas V.; Turnbull, Stanhope P., Jr. Synthesis, pp 1021-22, 1991

2. Cordi, Alex A.; Persigand, Thierry; Lecouve, Jean-Pierre. Synthetic Communications, 26(8), 1585-93, 1996