“A PROCESS FOR THE PREPARATION OF 1-BENZOFURAN-6-CARBOXYLIC ACID BY EMPLOYING NOVEL INTERMEDIATE”
FIELD OF THE INVENTION:
The present invention provides a process for the preparation of 1-benzofuran-6-carboxylic acid of formula (II) by employing novel intermediate of [2-formyl-5-(methoxycarbonyl) phenoxy] acetic acid of formula (VI).
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)
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 1-benzofuran-6-carboxylic acid of formula (II) withN-[(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 (TEA) /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 (VII) and it was hydrolyzed with lithium hydroxide (LiOH) in presence of methanol to afford the compound of formula (II). The above synthetic process is illustrated as per the following Scheme-II:
There are several disadvantages in making 1-benzofuran-6-carboxylic acid 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, lithium hydroxide are expensive. . 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 (II) by
2-(2-bromoethyl)-1,3-dioxolane of formula (XIV) with addition of triethyl phosphate
(P(OEt)3) to give a compound of formula (XV) and its reacted with furan-2-
carbaldehyde in diethyl carbonate/ tetrahydrofuran (THF) 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), further it was hydrolyzed in
presence of sodium hydroxide in methanol to get a compound of formula (II).
The above synthetic process is illustrated as per the following Scheme-III:
There are several disadvantages in making 1-benzofuran-6-carboxylic acid of formula (II), 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 1-benzofuran-6-carboxylic acid 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 novel method for the preparation of 1-benzofuran-6-carboxylic acid of formula (II) by employing novel intermediate of formula (VI). 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 process for the preparation of 1-benzofuran-6-carboxylic acid of formula (II) by employing novel intermediate of [2-formyl-5-(methoxycarbonyl) phenoxy] acetic acid of formula (VI).
Accordingly, one aspect of the present invention provides a compound of [2-formyl-5-(methoxycarbonyl) phenoxy] acetic acid of formula (VI).
In another aspect of the present invention provides a process for the preparation of 1-benzofuran-6-carboxylic acid of formula (II),

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 (VII); and

hydrolysis with hydrochloric acid in presence of an alcohol solvent to produce 1-benzofuran-6-carboxylicacid of formula (II).
In yet another aspect of the present invention provides a process for the preparation of methyl-1-benzofuran-6-carboxylate of formula (VII), comprising as follows:
a) reacting of methyl-4-formyl-3-hydroxy benzoate 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); and
b) reacting with a mixture of acetic anhydride, acetic acid and anhydrous alkali metal acetate to produce methyl-1-benzofuran-6-carboxylate of formula (VII).
DETAILEDDESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of 1-benzofuran-6-carboxylic acid of formula (II) by employing novel intermediate of [2-formyl-5-(methoxycarbonyl) phenoxy] acetic acid of formula (VI). The present invention is also provides commercially and industrial applicable process for the preparation of 1-benzofuran-6-carboxylic acid of formula (II).

Accordingly, one aspect of the present invention provides a compound of [2-formyl-5-(methoxycarbonyl) phenoxy] acetic acid of formula (VI).
In another aspect of the present invention provides a process for the preparation of 1-benzofuran-6-carboxylic acid of formula (II),
Formula (IV)
reacting of formula (IV) with thionylchloride in presence of a methanol to produce methyl-4-formyl-3-hydroxy benzoate of formula (V);
O
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 (VII)
c) reacting of methyl-4-formyl-3-hydroxy benzoate 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); and
d) reacting with a mixture of acetic anhydride, acetic acid and anhydrous alkali metal acetate to produce methyl-1-benzofuran-6-carboxylate of formula (VII).
According to the embodiment of the present invention, the compound of formula (IV) comprises by reacting 3-hydroxy benzoic acid with chloroform and aqueous alkali metal hydroxide in presence of an alcohol solvent to produce 4-formyl-3-hydroxy benzoic acid of formula (IV). The reaction mixture was heated to 75- 90°C, added drop wise addition of chloroform to maintain a gentle refluxing, completion of addition of chloroform, stir for 1 hour at same temperature. The

resultant alcohol solvent in a reaction was removed under reduced pressure; adjust pH 2-3 by using 1M HCl. The product was extracted with ethyl acetate, dried over anhydrous Na2SO4 and evaporated under reduced pressure to get a residue, further it was recrystallized with ethyl acetate and hexane to isolate the 4-formyl-3-hydroxy benzoic acid of formula (IV) with high purity.
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 (VII). 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 (VII) with high purity, which is under hydrolysis with hydrochloric acid in presence of an alcohol solvent to produce 1-benzofuran-6-carboxylicacid of formula (II).
The reaction mass of formula (II) was heated to reflux, stir the reaction mixture for 7-10 hrs at reflux temperature, distilled out the alcohol solvent completely under reduced pressure. The reaction mass was cooled to room temperature and adjusted the pH to 7-8 using 20% NaOH solution, stir the reaction mass for 2-4hrs at room temperature. The resulted compound was filtered and recrystallized by using ethyl acetate to get 1-benzofuran-6-carboxylicacid of formula (II) with high purity.
According to the above embodiment of present invention, wherein the alkali metal hydroxide is selected form sodium hydroxide or potassium hydroxide; the chloroacetic acid is chloro ethanoic acid; the alcohol solvent is selected from methanol, ethanol or isopropanol; the alkali metal acetate is selected from sodium acetate or potassium acetate.
In a preferred embodiment of the present invention, the 1-benzofuran-6-carboxylicacid 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 (10gm, 0.072mol) in methanol (100 ml) was treated with potassium hydroxide (30.0gm, 0.53mol) in water (150 ml). The reaction mixture was heated to 80°C, added drop wise addition of chloroform (23.6gm) to maintain a gentle reflux and stir for 1 hr at same temperature. The resultant solvent in a reaction mixture was removed under reduced pressure; cool to room temperature and adjust pH 2-3 by using 1M HCl. The compound was extracted with ethyl acetate, dried over anhydrous Na2SO4 and evaporated under reduced pressure to get a residue, further it was purified by using ethylacetate to get 4-formyl-3-hydroxy benzoic acid (8gm) of formula (IV) with high purity. Yield: 67% Chromatography Purity (by HPLC): 98%
Example-2:
Preparation of 4-formyl-3-hydroxy benzoic acid (IV):
3-Hydroxy benzoic acid (100gm, 0.72mol) in methanol (1000 ml) was treated with sodium hydroxide (300.0gm, 5.3mol) in water (1500 ml). The reaction mixture was heated to 80°C, added drop wise addition of chloroform (236gm) to maintain a gentle reflux and stir for 2 hour at same temperature. The resultant solvent in a reaction mixture was removed under reduced pressure; cool to room temperature and adjust pH 2-3 by using 1M HCl. The compound was extracted with ethyl acetate, dried over anhydrous Na2SO4 and evaporated under reduced pressure to get residue, further it was purified by using a mixture of ethylacetae and N-hexane to get 4-formyl-3-hydroxy benzoic acid (90gm) of formula (IV) with high purity. Yield: 75% Chromatography Purity (by HPLC): 98%

Example-3:
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-4:
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-5:
Preparation of methyl-1-benzofuran-6-carboxylate (VII):
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 (VII). Yield: 81% Chromatography Purity (by HPLC): 99%
Example-6: Preparation of 1-benzofuran-6-carboxylicacid (II):
Methyl-1-benzofuran-6-carboxylate (100gm, 0.568mol) was dissolved into methanol (1000ml) and then added dil.HCl solution (500ml) at ambient temperature. The reaction mixture was heated to reflux temperature, stir for 10hrs at same temperature and distilled out the methanol completely under reduced pressure. The reaction mass was cooled to room temperature, adjusted the pH to 7-8 using 20% NaOH solution, and stir for 2hrs at room temperature. The resultant material was filtered and it was recrystallized by using ethyl acetate to get 1-benzofuran-6-carboxylicacid (75gm) of formula (II) with high purity. Yield: 81% Chromatography Purity (by HPLC): 99%

Claim:
1. A compound of [2-formyl-5-(methoxycarbonyl) phenoxy] acetic acid of formula (VI).
2. A process for the preparation of 1-benzofuran-6-carboxylic acid of formula (II),
Formula (IV)
reacting of formula (IV) with thionylchloride in presence of a methanol to produce methyl-4-formyl-3-hydroxy benzoate of 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);

O 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 (VII); and
a) reacting of methyl-4-formyl-3-hydroxy benzoate 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); and
b) reacting with a mixture of acetic anhydride, acetic acid and anhydrous alkali metal acetate to produce methyl-1-benzofuran-6-carboxylate of formula (VII).

4. The process as claimed in claim 2 & 3, wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide.
5. The process as claimed in claim 2, wherein the alcohol solvent is methanol, ethanol or isopropanol.

6. The process as claimed in claim 2 & 3, wherein the chloroacetic acid is chloro ethanoic acid.
7. The process as claimed in claim 2 & 3, wherein the alkali metal acetate is sodium acetate or potassium acetate.