“A NOVEL PROCESS FOR THE PREPARATION OF METHYL-1-BENZOFURAN-6-CARBOXYLATE”
FIELD OF THE INVENTION:
The present invention provides a novel process for the preparation of methyl-1-benzofuran-6-carboxylateof formula (II), which is a key intermediate for the synthesis of lifitegrast.
BACKGROUND OF THE INVENTION:
Lifitegrast is a leukocyte function antigen-1 (LFA-1) antagonist used to treat dry eye disease. Lifitegrast is presently marketed by Shire Dev LLC and is available as US under the trade name XIIDRA®. Lifitegrast is chemically known as (S)-2-(2-(Benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6carboxamido)-3-(3-methylsulfonyl)phenyl)propanoic acid of formula (I)
Formula (I)
U.S.Pat.No. US 8,084,047 disclose Lifitegrast or a pharmaceutically acceptable salt thereof and U.S. Pat. No. 8,378,105 discloses a process for the preparation of Lifitegrast of formula (I) by reacting methyl-1-benzofuran-6-carboxylate of formula (II) with sodium hydroxide (NaOH)/ tetrahydrofuran (THF)/methyl tert-butyl ether (MTBE)/hydrochloric acid (HCl) to get 1-benzofuran-6-carboxylic acid of formula (VII) and then treated with N-[(5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl) carbonyl]-3-(methylsulfonyl)-phenylmethyl ester L-Phenylalanine hydrochloride of

formula (VIII) in oxalyl chloride/ dimethylformamide (DMF)/N,N-diisopropylethylamine (DIPEA) to gives the N-[[2-(6-benzofuranylcarbonyl)-5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl]carbonyl]-3-(methylsulfonyl)-phenylmethyl ester L-Phenylalanine of formula (IX) which is hydrogenolysis with 10% Pd-C/HCOOH/triethylamine (Et3N) /MeOH/ tetrahydrofuran (THF) to afford the target Lifitegrast of formula (I). The above synthetic process is illustrated as per the following Scheme-I:

US ‘105 also discloses a process for the preparation of intermediate of formula (II) by reacting compound of formula (X) with tert-butyldimethylsilyl chloride (TBDMSiCl) /triethylamine (TEA) to give a compound of formula (XI) and then treated with sodium borohydride (NaBH4), followed by addition of aqueous HCl to give a benzofuran alcohol of formula (XII).
N-phenyl-bis(trifluoromethanesulfonimide) (Phenyl-bis-triflate) is reacted with benzofuran alcohol of formula (XII) to give a compound of formula (XIII) was then treated with palladium acetate (Pd(OAc)2)/Dimethylformamide (DMF)/MeOH/ carbon monoxide (CO) to give a compound of formula (II). The above synthetic process is illustrated as per the following Scheme-II:
Scheme-II
There are several disadvantages in making methyl-1-benzofuran-6-carboxylate of formula (II), which itself is more expensive and involves several steps for its synthesis by using cost effective reagents like N-phenyl-bis(trifluoromethanesulfonimide),

palladium acetate. The above process reagents or conditions are difficult to apply for industrially scale up.
US ‘105 also discloses a process for the preparation of intermediate of formula (XVII) by 2-(2-bromoethyl)-1,3-dioxolane of formula (XIV) with addition of triethyl phosphate to give a compound of formula (XV) and its reacted with furan-2-carbaldehyde in diethyl carbonate/ tetrahydrofuran and lithium diisopropylamide (LDA) is obtained from n-butyllithium / diisopropylamine/ at -78ºC to give a formula (XVI) and then treated with phosphoric acid (H3PO4) in ethanol/water to give a compound of formula (XVII). The above synthetic process is illustrated as per the following Scheme-III:
Scheme-III
There are several disadvantages in making ethyl-1-benzofuran-6-carboxylateof formula (XVII), which itself is more expensive and involves several steps for its synthesis. In the second step, lithium diisopropylamide (LDA) has a disadvantage that this compound is generally obtained through the reaction of diisopropylamine and n-butyl lithium at around -78ºC in a solvent such as tetrahydrofuran. Since, the LDA is very sensitive to moisture, hazardous nature and difficult to handle. So, the above process reagents and its conditions are not suitable for industrially scale up.

Aforesaid reasons above there is a need to produce methyl-1-benzofuran-6-carboxylate of formula (II) synthetically by industrially applicable method to ensure the availability with high purity.
Hence, there is consequently a need development for new methods to sort out prior art existing methods. So, our inventors have developed a method for the preparation of methyl-1-benzofuran-6-carboxylate of formula (II). The present invention is providing a simple, cost effective with high purity and good yield on industrial applicable process.
SUMMARY OF THE INVENTION
The present invention provides a novel process for the preparation of methyl-1-benzofuran-6-carboxylate of formula (II).
Accordingly, one aspect of the present invention provides a novel process for the preparation of methyl-1-benzofuran-6-carboxylate of formula (II),
Formula (II)
which comprises:
reacting of 3-hydroxy benzoic acid with hexamine and glacial acetic acid in presence of aqueous sulfuric acid to produce 4-formyl-3-hydroxy benzoic acid of formula (IV) at suitable temperature;
reacting of formula (IV) with thionylchloride in presence of an methanol to produce methyl-4-formyl-3-hydroxy benzoate of formula (V);

Formula (V)
treating of formula (V) with chloroacetic acid in presence of an alkali metal hydroxide and water to produce of [2-formyl-5-(methoxycarbonyl) phenoxy] acetic acid formula (VI);
Formula (VI)
reacting of formula (VI) with a mixture of acetic anhydride, acetic acid and anhydrous alkali metal acetate to produce methyl-1-benzofuran-6-carboxylate of formula (II).
In another aspect of the present invention provides a process for the preparation of 4-formyl-3-hydroxy benzoic acid of formula (IV) by reacting of 3-hydroxy benzoic acid with hexamine and glacial acetic acid in presence of aqueous sulfuric acid at suitable temperature.
DETAILEDDESCRIPTION OF THE INVENTION
The present invention provides a novel process for the preparation of methyl-1-benzofuran-6-carboxylate of formula (II). The present invention is also provides commercially and industrial applicable process for the preparation of methyl-1-benzofuran-6-carboxylate of formula (II), which is a key intermediate for the synthesis of Lifitegrast.

Accordingly, one aspect of the present invention provides a novel process for the preparation of methyl-1-benzofuran-6-carboxylate of formula (II),
Formula (II)
which comprises:
reacting of 3-hydroxy benzoic acid with hexamine and glacial acetic acid in presence of aqueous sulfuric acid to produce 4-formyl-3-hydroxy benzoic acid of formula (IV) at suitable temperature;
Formula (V)
treating of formula (V) with chloroacetic acid in presence of an alkali metal hydroxide and water to produce of [2-formyl-5-(methoxycarbonyl) phenoxy] acetic acid formula (VI);
reacting of formula (VI) with a mixture of acetic anhydride, acetic acid and anhydrous alkali metal acetate to produce methyl-1-benzofuran-6-carboxylate of formula (II).

In another aspect of the present invention provides a process for the preparation of 4-formyl-3-hydroxy benzoic acid of formula (IV) by reacting of 3-hydroxy benzoic acid with hexamine and glacial acetic acid in presence of aqueous sulfuric acid at suitable temperature.
According to the embodiment of the present invention, the compound of formula (IV) comprises by reacting 3-hydroxy benzoic acid is reacted with hexamine and glacial acetic acid in presence of aqueous sulfuric acid. The reaction mixture was heated to 130°C and stir at same temperature for 2-3 hrs. The mixture was allowed to cool at 75-80°C, followed by addition of aqueous sulfuric acid and allow to stir the reaction mass at 105-110°C for 30 to 90 minutes.
The resultant mixture was cooled to 75-80°C and then adjusted pH 4-5 using aqueous sodium hydroxide to separate the organic layer, cooled to 50°C, added methanol, allowed to cool0-5°C and stir for 1 hr. The resultant product was filtered, washed with cold methanol at (0-5°C) to produce crude product. The obtain crude product was suspended in methanol (approximately 1:1; w/v), heated for 30 min at 50-55°C, stir and then the solution was cooled to 0-5° stir for 1-hr. The precipitated product was collected by vacuum filtration and washed with cold methanol to get 4-formyl-3-hydroxy benzoic acid of formula (IV).
According to the embodiment of the present invention, the compound of formula (VI) comprises by reacting 4-formyl-3-hydroxy benzoic acid of formula (IV) with thionylchloride in presence of methanol to produce methyl-4-formyl-3-hydroxy benzoate of formula (V). The reaction mixture was heated to reflux temperature, stirred the reaction mass for 5-6 hrs and distilled out thionyl chloride completely under reduced pressure to obtained crude product. The reaction mass was allow to cool at 25-30ºC, followed by slow addition of water, stir for 1hr and extract the product with methylene chloride. The resultant methyl-4-formyl-3-hydroxy benzoate of formula (V) was obtained by concentrated the methylene chloride solvent completely under vacuum.
Methyl-4-formyl-3-hydroxy benzoate of formula (V) is treating with chloroacetic acid in presence of an alkali metal hydroxide and water to produce of [2-formyl-5-(methoxycarbonyl) phenoxy] acetic acid formula (VI). The mixture was stirred slowly and heated to reflux for 3 hours and then solution was acidified with

concentrated hydrochloric acid, which is allow to cool at 15-25 °C and stir the reaction mass for 1 hr at same temperature. The obtain precipitated product was filtered and washed with water to get [2-formyl-5-(methoxycarbonyl) phenoxy] acetic acid of formula (VI) with high purity and yield.
According to the embodiment of the present invention, the compound of formula (II) by reacting 2-formyl-5-(methoxycarbonyl) phenoxy] acetic acid formula (VI) with a mixture of acetic anhydride, acetic acid and anhydrous alkali metal acetate to produce methyl-1-benzofuran-6-carboxylate of formula (II). The reaction mixture was heated to reflux for 8-10 hrs, quenched with ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with cold dilute sodium hydroxide solution, until the aqueous layer is basic. The resultant ethyl acetate layer was concentrated under reduced pressure to obtained crude and then it was recrystallized by using ethyl acetate and hexane to get methyl-1-benzofuran-6-carboxylate of formula (II) with high purity.
According to the above embodiment of present invention, wherein the hexamine is hexamethylenetetramine; the alkali metal hydroxide is selected form sodium hydroxide or potassium hydroxide; the chloroacetic acid is chloro ethanoic acid; the alkali metal acetate is selected from sodium acetate or potassium acetate.
Yet another embodiment, the methyl-1-benzofuran-6-carboxylate of formula (II) is converted to Lifitegrast of formula (I) according to the process disclosed in U.S. Pat. No. 8,378,105.
According to the present invention, the aforesaid methods should in particular be more industrially scalable, allow the desired compounds to be obtained with high yields, and use cheaper reagents which are simpler to handle and industrial applicable.
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

EXPERIMENTAL PROCEDURE:
Example-1:
Preparation of 4-formyl-3-hydroxy benzoic acid (IV):
3-Hydroxy Benzoic acid (125gm,0.90mol) and hexamethylenetetramine (170 gm, 1.21 mol, 2 eq) were added to glacial acetic acid (300 ml), heated to 125-130° and stir the reaction mixture at same temperature for 3hrs. The reaction mixture was allow to cool at 75-80°C, followed by addition of aqueous sulfuric acid of 33% (w/w) (300 ml) and allow to stir at 105-110°C for 30-60 min. The resulted mixture was allow to cool at 75-80°C to separate the layers, adjust pH 4-5 using aqueous sodium hydroxide; further added methanol (100 ml) and allowed to stir at 0-5°C for 1 hr. The resultant product was collected by vacuum filtration and the solid was washed with 30 ml of cold (0-5°C) methanol. The resultant crude product was suspended in methanol (approximately 1:1; w/v), heated to 50-55°C for 30 min and stir the solution at 0-5°C for 1 hr. The resultant product was collected by vacuum filtration and washed with 20 ml of cold methanol to get 4-formyl-3-hydroxy benzoic acid (112gm) of formula (IV). Yield: 75%
Example-2:
Preparation of methyl-4-formyl-3-hydroxy benzoate (V):
4-Formyl-3-hydroxy benzoic acid (100gm, 0.60 mol) was dissolved in a methanol (1000ml), followed by slow addition of thionylchloride (200g, 1.69mol), the reaction mixture was heated to reflux temperature and stirred for 5-6 hrs at same temperature. Thionylchloride in a reaction mass was distilled out completely under reduced pressure to obtained crude product of methyl-4-formyl-3-hydroxy benzoate, cooled to 25-300C and slowly added water (800 ml) to reaction mass. The resultant mass was stir for 1hr, extracts the material with methylene chloride and concentrated the methylene chloride completely under vacuum to get methyl-4-formyl-3-hydroxy benzoate (85gm) of formula (V) with high purity. Yield: 78% Chromatography Purity (by HPLC): 99%

Example-3:
Preparation of [2-formyl-5-(methoxycarbonyl) Phenoxy] acetic acid (VI):
A mixture methyl-4-formyl-3-hydroxy benzoate (106gm, 0.58mol), chloroacetic acid (94.5gm, 1.0 mol) and water (200ml) were added to a solution of sodium hydroxide pellets (80.0gm, 2.0mol) in distilled water (200ml). The reaction mixture was stirred slowly and heated to reflux for 3 hours, the solution was acidified with 190 ml. of concentrated hydrochloric acid and then acidic mixture was cooled to 20°C.The resultant precipitated product was filtered and washed with water to get [2-formyl-5-(methoxycarbonyl) Phenoxy] acetic acid (100gm) of formula (VI) with high purity. Yield: 74%. Chromatography Purity (by HPLC): 97%.
Example-4:
Preparation of methyl-1-benzofuran-6-carboxylate (II):
Crude[2-formyl-5-(methoxycarbonyl) Phenoxy] acetic acid(90.0g, 0.37mol),anhydrous powdered sodium acetate (180g, 2.19mol) were added into a mixture of acetic anhydride (450 ml) and glacial acetic acid (450 ml) and heated it to gentle reflux for 8 hours. The reaction is complies (checked by TLC), quench with ice water (2.5 lit),extracted with ethyl acetate (600ml) and then wash with cold dilute 5% sodium hydroxide solution, until the aqueous layer is basic. The resultant ethyl acetate layer was washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulphate and it was concentrated under reduced pressure to obtain crude methyl-1-benzofuran-6-carboxylate, which was recrystallized by using ethyl acetate and hexane to get a pure methyl-1-benzofuran-6-carboxylate (55gm) of formula (II). Yield: 81% Chromatography Purity (by HPLC): 99%

Claim:
1. A novel process for the preparation of methyl-1-benzofuran-6-carboxylate of formula (II),
which comprises:
reacting of 3-hydroxy benzoic acid with hexamine and glacial acetic acid in presence of aqueous sulfuric acid to produce 4-formyl-3-hydroxy benzoic acid of formula (IV) at suitable temperature;
treating of formula (V) with chloroacetic acid in presence of an alkali metal hydroxide and water to produce of [2-formyl-5-(methoxycarbonyl) phenoxy] acetic acid formula (VI);
reacting of formula (VI) with a mixture of acetic anhydride, acetic acid and anhydrous alkali metal acetate to produce methyl-1-benzofuran-6-carboxylate of formula (II).

2. A process for the preparation of 4-formyl-3-hydroxy benzoic acid of formula (IV) by reacting of 3-hydroxy benzoic acid with hexamine and glacial acetic acid in presence of aqueous sulfuric acid at suitable temperature.
3. The process as claimed in claim 1 & 2, wherein the hexamine is hexamethylenetetramine.
4. The process as claimed in claim 1 & 2, where in the suitable temperature range is between 125-135°C.
5. The process as claimed in claim 1, wherein the chloroacetic acid is chloro ethanoic acid.
6. The process as claimed in claim 1, wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide.
7. The process as claimed in claim 1, wherein the alkali metal acetate is sodium acetate or potassium acetate.