FIELD OF THE INVENTION

The present invention relates to a process for the preparation of 4-acetyl-1-naphthoic acid or its derivatives of formula (I) where R is hydrogen or C1-C4 alkyl, using novel compounds. The invention further relates to use of compound (I) for the preparation of Afoxolaner.

BACKGROUND OF THE INVENTION

The 4-acetyl-1-naphthoic acid or its derivatives (I) are key compounds in the field of pharmaceuticals, agrochemicals, and veterinary medicinal productfor example Afoxolaner. Afoxolaner is useful as an insecticide and an acaricide that belongs to class of isooxazoline compound.

The research article Canadian Journal of Chemistry (1981), 59, 2629-41discloses a method for preparation of 1-(4-bromonaphthalen-1-yl) ethan-1-oneby reacting 1-halonaphthalene with acetyl chloride in presence aluminium chloride and dichloromethane at 0°C. The above reaction involves the isolation of compound by distillation under reduced pressure which result into low reaction yield (71%).However, the research article does not disclose the applications of 1-(4-bromonaphthalen-1-yl) ethan-1-one.

Another research articles Justus Liebigs Annalen der Chemie (1932), 496, 99-115 disclose the preparation of 4-acetyl-1-naphthoic acid of formula (I) using p-bromoacetophenone in presence of carcinogenic reagent copper cyanide and potassium cyanide and the resulting compound is obtained by filtration to remove unreacted copper cyanide The resulting filtrate was heated and further treated with hydrochloric acid and recrystallized form hot water. The research article involves carcinogenic reagent such as copper cyanide and potassium cyanide; and tedious operation for isolation of 4-acetyl-1-naphthoic acid of formula (I).

The prior-art process(es) involves one or more tedious operations; expensive and carcinogenic reagents; generate huge hazardous waste; which further involves disposal process, thus increases overall production cost and consequently of Afoxolaner. Also, prior art documents do not disclose novel compounds (IV) and (V), its process and their use for preparation of4-acetyl-1-naphthoic acid or its derivatives of formula (I).

The inventors of present invention have developed a process for the preparation of 4-acetyl-1-naphthoic acid of formula (I)using a novel compound(s)in a cost effective and industrially convenient way in terms of safety, avoids use of cyanide, carbon monoxide and cryogenic conditions.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a process for the preparation of 4-acetyl-1-naphthoic acid or its derivatives of formula (I).

In another aspect, the present invention provides a process for preparation of novel compounds of formula (IV) and (V).

In another aspect, the present invention provides a process for the preparation of 4-acetyl-1-naphthoic acid or its derivatives of formula (I),

Which comprising the steps of:
a) reacting a 1-halonaphthalene of formula (II) with an acylating agent in presence of Lewis acid in solvent to obtain 1-(4-halonaphthalen-1-yl) ethan-1-one of formula (III);

b) reacting a 1-(4-halonaphthalen-1-yl) ethan-1-one of formula (III) with protecting group in presence of a catalyst in solvent to obtain compound of formula (IV);

c) reacting compound of formula (IV) with n-Butyllithium in presence of carbon dioxide; or Grignard reagent in presence of sodium methyl carbonate in a solvent to obtain compound of formula (V);

d) reacting compound of formula (V) with an acid.
In another aspect, the present invention provides a process for the preparation derivatives of formula (I, where R is C1-C4 alkyl)by reacting 4-acetyl-1-naphthoic acid formula (I, where R is hydrogen) with an alcohol in presence of an acid catalyst.

In another aspect, the present invention provides a process for the preparation of Afoxolaner using a4-acetyl-1-naphthoic acid of formula (I) obtained by a process of present invention described herein, where the preparation of Afoxolaner is followed by a process known in the art.

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more detail hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a,” “an,” “the,” include plural referents unless the context clearly indicates otherwise.

The term ‘solvent’ used herein, refers to the single solvent or mixture of solvents.

In one embodiment the present invention provides a process for the preparation of compound4-acetyl-1-naphthoic acid or its derivatives of formula (I) from a 1-halonaphthalene of formula (II) as shown in Scheme.

Scheme:

In one embodiment the present invention provides a process for the preparation of novel compounds of formula (IV) and (V).

In one embodiment the present invention provides a process for the preparation of compound4-acetyl-1-naphthoic acid or its derivative of formula (I) using novel compounds of formula (IV) and (V).

In an embodiment of the present invention, compound of formula (IV) is 2-(4-bromonaphthalen-1-yl)-2-methyl-1,3-dioxolane which is characterized by Mass (m/z): 293 (M+H); 1H NMR (400 MHz, CDCl3) d 8.66 (m, 1H), 8.32 (m, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.58 (m, 2H), 4.10 (m, 2H), 3.80 (m, 2H), 1.89 (s, 3H).

In an embodiment of the present invention, compound of formula (V) is 4-(2-methyl-1,3-dioxolan-2-yl)-1-naphthoic acid which is characterized by Mass (m/z): 259 (M+H); 1H NMR (300 MHz, CDCl3) d 13.21 (S, 1H), 8.99 (m, 1H), 8.48 (d, J=8.0 Hz, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.89 (m, 1H), 7.45 (m, 1H), 7.20 (d, 1H) 4.05 (m, 2H), 3.95 (m, 2H), 1.87 (S, 3H).

In an embodiment ofthe present invention, wherein acylatingre agent used in step (a) is selected from acetyl chloride, acetic anhydride and the like.

In an embodiment of the present invention, wherein Lewis’s acid is selected aluminium chloride, boron trifloride, Zinc chloride and the like.

In an embodiment of the present invention, wherein solvent used for in step (a) is selected from chlorinated solvents such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride and the like.

In an embodiment of the present invention, wherein protecting group is selected from ethylene glycol, 2,2-dimethoxy propane, 1,3-propane diol, and trimethyl orthoformate.

In an embodiment of the present invention, wherein catalyst used in step (b) is selected from p-toluene sulfonic acid (PTSA), tertbutyl ammonium bromide (TBAB), benzyl trimethyl ammonium chloride, methyltricapryl ammonium chloride, methyltributyl ammonium chloride, and methyl tributyl ammonium chloride.

In an embodiment of the present invention, wherein solvent used for in step (b) is selected from toluene, n-hexane, cyclohexane, o-xylene and the like.

In an embodiment of the present invention, wherein compound of formula (V) in step (c) is obtained by reacting a compound of formula (IV) with n-Butyllithium in presence of carbon dioxide in a solvent.

In an embodiment of the present invention, wherein compound of formula (V) in step (c) is obtained by reacting a compound of formula (IV) with Grignard reagent in solvent; wherein the Grignard reagent is prepared by using suitable aryl magnesium halide in presence of suitable initiator in a suitable solvent or mixture of solvents.

In another embodiment of the present invention, wherein suitable aryl magnesium halide is prepared by reacting aryl halide with magnesium metal in a suitable solvent at 30°C to 65°C.

In another embodiment of the present invention, wherein suitable initiator is Iodine.

In another embodiment of the present invention, wherein suitable solvents of step (c) and step (d) is ethereal solvent and hydrocarbon solvent.

In another embodiment of the present invention, wherein ethereal solvent is selected from tetrahydrofuran, diethyl ether, methyl tert. butyl ether, dibutyl ether, 2-methyl tetrahydrofuran, tert-butyl methyl ether and the like; preferably tetrahydrofuran.

In another embodiment of the present invention, wherein hydrocarbon solvent is selected from toluene, hexane, heptane, xylene and the like.

In an embodiment of the present invention, wherein the 4-acetyl-1-naphthoic acid (I, where R is hydrogen) is converted into its derivatives (I, where R is C1-C4 alkyl) using an alcohol in presence of an acid.

In an embodiment of the present invention, wherein acid is hydrochloric acid or sulfuric acid.

In an embodiment of the present invention, wherein an alcohol is selected from methyl alcohol, ethyl alcohol, propyl alcohol, n-butanol and the like.

In an embodiment of the present invention, wherein 4-acetyl-1-naphthoic acid of formula (I, where R is hydrogen) obtained by a process of present invention is further converted into Afoxolaner with process(es) known in the art, for example WO2009126668, which is incorporated herein as a reference.

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

EXPERIMENTAL
Example 1.0: Preparation of 1-(4-bromonaphthalen-1-yl) ethan-1-one (III):
In 1-Litre 4-neck RBF, dichloromethane (2-5 Vol)was added and cooled to 0°C to 10°C. An Aluminium trichloride (70.83 g, 2.2 eq) was added and stirred at 0°C to 10°Cfor 10 min. To the reaction solution, acetyl chloride (41.67 g, 2.2 eq.) and a solution of 1-bromonaphthalene (50 g, 1.0 eq.) in dichloromethane (2-5 Vol) was added and reaction mixture was warmed to 25°C, stirred further for1-2 hrs. The reaction mixture was quenched in mixture of ice water and concentrated hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was filtered through celite bed and solvent was evaporated to afford yellow-brown solid (58 g, 96.42 % yield) which is used as such to next step without further purification.

Mass (m/z) 249 (M+H); 1H NMR (400 MHz, CDCl3) d 8.7 (m, 1H), 8.3 (m, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.63 (m, 2H), 2.71 (s, 3H).

Example 1.1: Preparation of 1-(4-bromonaphthalen-1-yl) ethan-1-one (III)

In 4-neck RBF, dichloromethane (2 to 5Vol) was added and cooled to -20°C to 10°C. An Aluminium trichloride (1.0 to 3.0 eq) was added and the solution was stirred at -20°C to 10°C for 10 to 15 min. The acetyl chloride (1.0 to 3.0 eq.) was added dropwise and a solution of 1-bromonaphthalene (1.0 eq.) in dichloromethane (2 to 5Vol) was added in 1 to 2 hrs. The reaction mixture was stirred further for 1 to 2 hrs. The reaction mixture was quenched into ice water and concentrated hydrochloric acid (5 to 20Vol). The organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was filtered through celite bed. The filtrate was evaporated to afford yellow-brown solid. The solid was purified using aliphatic hydrocarbon solvent(s) to obtain brown solid (73-80 % yield, HPLC purity>99%). Mass (m/z) 249 (M+H); 1H NMR (400 MHz, CDCl3) d 8.7 (m, 1H), 8.3 (m, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.63 (m, 2H), 2.71 (s, 3H).

Example 2.0: 2-(4-bromonaphthalen-1-yl)-2-methyl-1, 3-dioxolane (IV)

In 2-Litre 4-neck RBF equipped with dean-stark apparatus, 1-(4-bromonaphthalen-1-yl)-ethan-1-one (58 g, 1.0 eq) in toluene (5-10 Vol), ethylene glycol (2 to 10 eq) and p-toluene sulfonic acid (5 to 15 mol%) was added at room temperature. The reaction mixture was heated to remove water by azeotropic distillation. The reaction mixture was cooled to room temperature and washed with water. The organic layer was evaporated to obtain brown oil (90-95%). The crude product was used as such in next step without further purification. Mass (m/z): 293 (M+H); 1H NMR (400 MHz, CDCl3) d 8.66 (m, 1H), 8.32 (m, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.58 (m, 2H), 4.10 (m, 2H), 3.80 (m, 2H), 1.89 (s, 3H).

Example 2.1: 2-(4-bromonaphthalen-1-yl)-2-methyl-1, 3-dioxolane (IV)

In 5-Litre 4-neck RBF equipped with dean-stark apparatus, 1-(4-bromonaphthalen-1-yl)-ethan-1-one (1.0 eq) in toluene (5 to 15Vol), ethylene glycol (2 to 10 eq.) and p-toluene sulfonic acid (5 to 15 mol%) was added at room temperature. The reaction mixture was heated to remove water by azeotropic distillation. The reaction mixture was cooled to room temperature. The organic layers were separated and washed with sodium bicarbonate solution. The organic layer was evaporated to obtain crude product as brown oil 95-99%,HPLC Purity 91-95%). The crude product was used as such in next step without further purification. Mass (m/z) 293 (M+H); 1H NMR (400 MHz, CDCl3) d 8.66 (m, 1H), 8.32 (m, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.58 (m, 2H), 4.10 (m, 2H), 3.80 (m, 2H), 1.89 (s, 3H).

Example 3.0: Preparation of 4-acetyl-1-naphthoic acid (I) where R is hydrogen using n-Butyllithium.

In 1-lit 4-neck RBF, 2-(4-bromonaphthalen-1-yl)-2-methyl-1, 3-dioxolane (61 g, 1.0 eq) and THF (360 mL) was added. The solution was cooled to -78°C. An n-Butyllithiumin hexane (1 to 1.5 eq) was added dropwise and reaction mixture was maintained at -78°C for 1hr. The carbon dioxide gas was purged into the reaction mixture. The completion of reaction was monitored by TLC. After completion, the reaction was warmed to 0 to 10°C and then quenched with 1N hydrochloric acid. The layers were separated, and the aqueous layer was extracted with methyl ter.butyl ether(MTBE).To the combined organic layer 4N hydrochloric acid (HCl) (5-8 Vol) was added. The reaction mass was stirred for 6hrs at room temperature. The organic layer was evaporated to obtain crude compound. The crude compound was crystallized in toluene to obtain pure 4-acetyl-1-naphthoic acid (33-38% yield with HPLC purity>98%). Mass (m/z) 215 (M+H); 1H NMR (400 MHz, CDCl3) d 8.82 (m, 1H), 8.36 (m, 1H), 8.05 (d, J=7.2 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.48 (m, 2H), 2.61 (s, 3H).

Example 3.1: Preparation of 4-acetyl-1-naphthoic acid (I) where R is hydrogen, using Grignard reaction and sodium methyl carbonate.

In 100 mL 4-neck RBF 2-(4-bromonaphthalen-1-yl)-2-methyl-1, 3-dioxolane (1.0 eq),tetrahydrofuran (THF, 5-8 Vol) magnesium turning (1.1 eq), and iodine was added at room temperature. The reaction solution was heated to 65°C to 70°C for 3hrs.The reaction mixture was cooled to 25°C to 30°C.In another 100 mL RBF was sodium methyl carbonate(2.0 eq) and 50 mL THF was added. The reaction solution was stirred for 30 min. To this solution a Grignard reagent was added in 30 min and reaction mixture was stirred for 12 hrs at room temperature. The completion of reaction is monitored by TLC. After completion, the reaction mixture was quenched with 2N HCl and the organic layers were separated, and the aqueous layer was extracted with MTBE. The combined organic layer was treated with concentrated HCl. The reaction mixture was stirred for 6hrs. The organic layer was separated. The organic layer was evaporated to obtain crude compound. The crude compound was crystalized in toluene to obtain pure 4-acetyl-1-naphthoic acid (51-55 %, with HPLC purity >98%). Mass (m/z) 215 (M+H); 1H NMR (400 MHz, CDCl3) d 8.82 (m, 1H), 8.36 (m, 1H), 8.05 (d, J=7.2 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.48 (m, 2H), 2.61 (s, 3H).

Example 3.2: Preparation of 4-acetyl-1-naphthoic acid (I) where R is hydrogen using, Grignard reaction and sodium methyl carbonate.

In 4-neck RBF 2-(4-bromonaphthalen-1-yl)-2-methyl-1, 3-dioxolane (1.0 eq) THF (5 to 15Vol) magnesium turning (1.0-1.5 eq), and iodine was added. The solution was heated to 65°C to 70°C for 3hrs. The reaction mixture was cooled to room temperature. In another RBF sodium methyl carbonate (2.0 to 4.0 eq) and THF (5 to 15V) was added. The suspension was stirred for 30 min. To this solution the Grignard reagent was added, and reaction mixture was stirred for 12 hrs at room temperature. The completion of reaction is monitored by TLC. After completion, the reaction mixture was quenched with 2N HCl and the organic layers was separated, and the aqueous layer was extracted with MTBE To the combined organic layer concentrated HCl (1V to 5V) was added. The reaction mass was stirred for 6-12hrs. The organic layer was evaporated to afford crude product. The crude product was crystalized in toluene to afford pure 4-acetyl-1-naphthoic acid (58- 65 %with, HPLC purity >98%). Mass (m/z) 215 (M+H); 1H NMR (400 MHz, CDCl3) d 8.82 (m, 1H), 8.36 (m, 1H), 8.05 (d, J=7.2 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.48 (m, 2H), 2.61 (s, 3H).

Example 3.3: Preparation of ethyl 4-acetyl-1-naphthoate (I) where R is ethyl

In 4-neck RBF 4-acetyl-1-naphthoic acid (I, where R is hydrogen, 1.0 eq), sulfuric acid and ethanol (10-15 Vol) were added. The reaction solution was refluxed and monitored by TLC. After completion of reaction ethanol was distilled and water was added. The aqueous layer was extracted with ether and organic layer separated. The organic layer was distilled under vacuum to obtain ethyl 4-acetyl-1-naphthoate with 85-90 % yield with, HPLC purity >98%).

CLAIMS:

We claim:

1) A process for the preparation of 4-acetyl-1-naphthoic acid or its derivatives of formula (I),

which comprising the steps of:
a) reacting a 1-halonaphthalene of formula (II) with an acylating agent in presence of Lewis acid in a solvent to obtain 1-(4-halonaphthalen-1-yl) ethan-1-one of formula (III);

b) reacting a1-(4-halonaphthalen-1-yl) ethan-1-one of formula (III) with protecting group in presence of a catalyst in solvent to obtain compound of formula (IV);

c) reacting compound of formula (IV) with n-Butyllithium in presence of carbon dioxide; or Grignard reagent in presence of sodium methyl carbonate in a solvent to obtain compound of formula (V);

d) reacting compound of formula (V) with an acid.
2) A compound of formula (IV) and (V).

3) The process as claimed in claim 1, wherein acylating agent is selected from acetyl chloride, acetic anhydride in presence of Lewis acid.
4) The process as claimed in claim 1, wherein the Lewis acid is selected from aluminium chloride, boron trifluoride, and Zinc chloride.
5) The process as claimed in claim 1, wherein protecting group is selected from ethylene glycol, 2,2-dimethoxy propane, 1,3 propane diol, trimethyl orthoformate; and catalyst is selected from tertbutyl ammonium bromide (TBAB), benzyl trimethyl ammonium chloride, methyltricapryl ammonium chloride, methyltributyl ammonium chloride, p-toluene sulfonic acid (p-TSA),and methyltrioctyl ammonium chloride.
6) The process as claimed in claim 1, wherein compound of formula (V) is prepared by reacting compound (IV) with n-Butyllithium in presence of carbon dioxide, or a Grignard reagent in a solvent.
7) The process as claimed in claim 1, wherein solvent used in step (a) is chlorinated solvents selected from chloroform, dichloromethane, dichloroethane, carbon tetrachloride; and step (b) is a hydrocarbon solvent selected from toluene, n-hexane, n-heptane, cyclohexane, and o-xylene.
8) The process as claimed in claim 1, wherein solvent used in step (c) is ethereal solvent selected from tetrahydrofuran, diethyl ether, dibutyl ether, 2-methyl tetrahydrofuran, tert-butyl methyl ether and hydrocarbon solvent selected from toluene, hexane, n-heptane, and n-pentane.
9) The process as claimed in claim 1, wherein derivatives of compound (I) is obtained by reacting (I) where R is hydrogen with an alcohol in presence of acid where alcohol is selected from methyl alcohol, ethyl alcohol, propyl alcohol, and n-butanol.
10) The process as claimed in claim 1 and 9, wherein an acid is selected from sulfuric acid and hydrochloric acid.