This invention relates to a process for the preparation of the esters of 1,8-disubstituted -1,3,4,9-tetrahydropyrano (3,4-b)-indole-1-acetic acid of formula I as shown in the accompanied drawings, wherein R1 is selected from the group consisting of hydrogen, lower alkyl group having 1-6 carbon atoms, and lower alkenyl group having 1-6 carbon atoms, R2 is selected from the group consisting of lower alkyl group having 1-6 carbon atoms and aralkyl group in which the alkyl group is a lower alkyl group having 1-6 carbon atoms, R3 is selected from the group consisting of lower alkyl group having 1-6 carbon atoms, lower alkenyl group having 1-6 carbon atoms, cyclohexyl, phenyl and benzyl.
These esters are used as an intermediates for the preparation of the corresponding 1,8-dialkyl-1-3,4,9-tetrahydropyrano (3,4-b)-indole-1-acetic acids, which include etodolac, an anti-inflammatory and analgesic compound reported first by Demerson et al., US Patent No. 3,939,178.
Preparation of these esters has been previously described in US Patent Nos. 3,939,178; 4,012,417; 4,585,877; and several related patents. These esters are prepared from the corresponding 7-substituted tryptophol and alkyl propionylacetate. US Patent Nos. 3,939,178 and 4,012,417 disclose reaction of substituted tryptophols with keto ester to produce pyrano (3,4-b) indoles. Suitable solvents described are benzene, toluene, diethyl ether, dioxan, tetrahydrofuran, methylene dichloride, carbon tetrachloride and the like. Benzene and tetrahydrofuran are the preferred solvents.
Suitable acid catalysts which may be used for this condensation are the type of catalysts used in Fischer Indole Synthesis and include ß-toluenesulfonic acid, phosphorus pentoxide, boron trifluoride, zinc chloride, hydrochloric acid and sulfuric acid and the like. Preferred catalysts being ß -toluenesulfonic acid, boron trifluoride and phosphorus pentoxide. According to Example 477 of US Patent No.3,939,178, etodolac ethyl ester is produced by the reaction of 7-ethyltryptophol and the keto ester, ethyl propionyl acetate, using benzene as a solvent and ß-toluenesulfonic acid as the

catalyst. The product so obtained is purified by column chromatography, which is hydrolysed under alkaline conditions to give etodolac.
US Patent No.4,585,877 discloses reaction of the methyl ester of 3-methoxy-2-pentenoic acid with 7-ethyltryptophol using dichloromethane as a solvent and boron trifluoride ethereate as the catalyst.
The methods described in the prior art suffer from several disadvantages :
Firstly, the use of strong acid catalysts exposes the desired product to other acid catalysed reactions resulting in the formation of impurities. In order to minimise the impurities, the ester is either purified by column chromatography before hydrolysis or the hydrolyzed product is purified at the cost of the yields and overall efficiency of the process. Moreover, the purification by column chromatography is very cumbersome and is disadvantageous at a commercial scale because of its efficiency and higher manufacturing costs.
Secondly, the use of carcinogenic solvents like benzene, tetrahydrofuran and strong acids like p-toluenefonic acid, boron trifluoride ethereate or sulfuric acid at industrial scale involves health hazards and poses serious environmental problems.
For purposes of patient safety, it is highly desirable to limit the amount of residual solvents present in any medicament administered to a patient. With this objective in mind, International Regulatory bodies impose stringent limits on residual solvents and categorise solvents in various classes depending upon their toxicity. The solvents used in prior art have been categorised in Class I category, which are highly toxic.
The aim of the present invention is to provide an efficient process for the preparation of the esters of 1,8-disubstituted - 1,3,4,9-tetrahydropyrano (3, 4,6)-indole-1-acetic acid of formula I (as shown in the accompanied drawings), which process avoids the use of corrosive solvents, strong corrosive acids and gives a product of high purity and yield.

In general, molar equivalent proportions of 7-alkyltryptophol and p-ketoester is used. More preferably, 0.9-1.2 molar ratio of p-keto ester with respect to 7-alkyltryptophol is used but varying amounts of molar ratios are within the scope of this invention.
The present invention provides a process for the preparation of the esters of 1, 8-disubstituted -1,3,4,9-tetrahydropyrano-(3,4-b)-indole-1 -acetic acid of Formula I as shown in the accompanied drawings, wherein R1, R2 and R3 have the meanings as defined above, the said process comprising the reaction of 7-alkyltryptophol of Formula II as shown in the accompanied drawings, wherein R1 has the meaning as defined earlier, with a ß-ketoester of the Formula III, as shown in the accompanied drawings, wherein R2 and R3 have the usual meanings as defined above, in a hydroxylic solvent, comprising at least one alkanol solvent having 1-4 carbon atoms, containing hydrogen chloride gas, and subsequently recovering the product of Formula I.
The term hydroxylic solvent means any lower alkanol and includes those primary secondary and tertiary alcohols, Suitable lower alkanol solvents include metanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and t-butanol. Preferably, methanol is used as a solvent. Mixture of two or more lower alkanols can also be used.
The concentration of hydrogen chloride gas may range from 1% w/v to 20% w/v. However, a range of 5% to 15% w/v is generally preferred. The amount of solvent is at least 1 part by volume per part of the starting material, 7-substituted tryptophol. Higher amounts of solvents and generally upto 20 parts by volume can be used. However, a range of 5-10 parts by volume is generally preferred. Amounts higher than 20 parts are not useful from an economic point of view because large size reactor would be required.
Generally, the reaction is carried out in a temperature range of -20°C to the boiling point of the reaction mixture. Preferred temperature range includes between about 0°C to about 30°C. Persons skilled in the art will appreciate that the temperature range is given as a guide and may vary with the choice of solvent.

The reaction is typically accomplished within about 3-8 hours. However, the length of time required for reaction may vary depending on such factors as temperature of the reaction, volume of reaction mixture and size of batch and container and presence or absence of stirring.
In general, the reaction product directly crystallizes out of the reaction medium and is recovered by filtration to get substantially pure product of Formula I (as shown in the accompanied drawings). Methods known in the art may be used with the process of this invention to enhance any aspect of this process. For example, the reaction mixture may be extracted with a solvent such as pentane or hexane. Such a solvent has the characteristic that the desired product is soluble in it and it does not form a homogeneous mixture with a hydroxylic solvent and the solvent is then removed to get the desired product. The product so obtained is hydrolysed by using methods known in the art to get the corresponding acid, e.g. etodolac.
The present invention is illustrated by, but is by no means limited to, the following examples:
EXAMPLE 1
Preparation of Methyl 1,8-diethyl-1,3,4,9-tetrahydropropyrano(3,4-b)-indole-1-acetate
To a solution of 7-ethyltryptophol (12.0g) in methanolic hydrogen chloride (5% w/v, 100.0 ml), methyl 3-oxopentanoate (9.1g) was added in one lot, at 25°C. The reaction mixture was stirred at 25-30°C for 7 hours. The reaction mixture was then cooled to 0°C, and stirred at 0-5°C for 3 hours. The product was filtered, washed with methanol and dried to afford the title compound (16.7g, 89%), m.p. 128-130°C; purity : 99.7%.

EXAMPLE 2
Preparation of Methyl 8-methyl-1-n-propyl-1,3,4,9-tetrahydropyrano (3,4-b)-indole-1-acetate
To a solution of 7-methyltryptophol (10.0g) in methanolic hydrogen chloride (5% w/v, 100.0 ml), methyl 3-oxohexanoate (9.1g) was added in one lot, at 25°C. The reaction mixture was stirred at 25-30°C for 7 hours. The reaction mixture was extracted with hexane (100.0 ml). Hexane was concentrated to about 20ml and methanol (10 ml) was added. The mixture was stirred at 5-10°C for 2 hours. The product was filtered, washed with methanol, and dried to afford the title compound (13.7g, 80%); purity: 98.1%.
EXAMPLE 3 Preparation of Methyl 1, 8-diethyl-1,3,4,9-tetrahydropyrano (3,4-b)-indole-1-acetate
To a solution of 7-ethyltryptophol (12.0g) in 1-butanolic hydrogen chloride (5% w/v, 100.0 ml), methyl 3-oxopentanoate (9.1 g) was added in one lot, at 25°C. The reaction mixture was stirred at 25-30°C for 7 hours. The reaction mixture was extracted with hexane (100.0 ml). Hexane was concentrated to about 20 ml and methanol (10 ml) was added. The product was filtered, washed with methanol and dried to afford the titled compound (14.7 g, 79%), m.p. 128-130°C; purity : 96.2%.

EXAMPLE 4 Preparation of Methyl 1,8-diethyl-1,3,4,9-tetrahydropyrano(3,4-b)-indole-1-acetate
To a solution of 7-ethyltryptophol (12.0g) in a mixture of methanolic hydrogen chloride (10% w/v, 50.0 ml) and tolune (50ml), methyl 3-oxopentanoate (9.1g, 0.07 mole) was added in one lot, at 25°C. The reaction mixture was stirred at 25-30°c for 7 hours. The reaction mixture concentrated to about 20 ml under reduced pressure. Methanol (50 ml) was added to the concentrate and the solution was extracted with hexane (100ml). Hexane was concentrated to about 20 ml and methanol (10 ml) was added. The product was filtered, washed with methanol and dried to afford the title compound (15.8 g, 84%), m.p. 128-130°C, purity : 97.8%.

WE CLAIM :
1. A process for the preparation of the esters of 1,8-disubstituted 1,3,4,9-
tetrahydropyrano (3,4-b) - indole-1-acetic acid of Formula I as shown in the
accompanied drawings, wherein RI is selected from the group consisting of
hydrogen, lower alkyl group having 1-6 carbon atoms, and lower alkenyl group
having 1-6 carbon atoms, R2 is selected from the group consisting of lower alkyl
group having 1-6 carbon atoms and aralkyl group in which the alkyl group is a
lower alkyl group having 1-6 carbon atoms, R3 is selected from the group
consisting of lower alkyl group having 1-6 carbon atoms, lower alkenyl group
having 1-6 carbon atoms, cyclohexyl, phenyl and benzyl, the said process
comprising
a. the reaction of 7-alkyltryptophol of Formula II as shown in the
accompanied drawings with a ß-Ketoester of Formula III as shown in
the accompanied drawings, wherein R1, R2 and R3 have the
meanings as defined above, in a hydroxylic solvent, comprising at
least one alkanol having 1-4 carbon atoms, containing hydrogen
chloride gas, and
b. recovering the product of Formula I as shown in the accompanied
drawings from the reaction mixture of step (a) by conventional
procedures such as filtration or extraction.
2. A process as claimed in claim 1 wherein R2 is methyl in the compound of
Formula I as shown in the accompanied drawings.
3. A process as claimed in claim 1 wherein RI is ethyl in the compound of Formula I
as shown in the accompanied drawings.
4. A process as claimed in claim 1 wherein R3 is ethyl in the compound of Formula I
as shown in the accompanied drawings.

5. A process as claimed in claim 1 wherein the hydroxylic solvent is methanol,
ethanol, n-propanol, isopropanol, n-butanol, or t-butanol.
6. A process as claimed in claim 1 wherein the concentration of hydrogen chloride
gas in a hydroxylic solvent is 1-20% w/v.
7. A process as claimed in claim 1 wherein the reaction temperature is in the range
-20°C to 80°C.
8. A process as claimed in claim 7 wherein the reaction temperature is in the range
0°C to 30°C.
9. A process as claimed in claim 1 wherein said hydroxylic solvent contains
hydrogen chloride gas at the time said reactants are dissolved therein.
10. A process as claimed in 1 wherein said hydrogen chloride gas is added to the
reaction mixture after the said reactants are dissolved in the said hydroxylic
solvent.
11. A process as claimed in claim 1 wherein the extraction of the esters of 1,8-
disubstituted 1,3,4,9-tetrahydropyrano(3,4-b)-indole-1-acetic acid of Formula I as
shown in the accompanied drawings, is done by using an extraction solvent
characterized in that it does not form a homogeneous mixture with the said
hydroxylic solvent and in which extraction solvent the desired product of Formula
I is soluble, and subsequently recovering the product of Formula I by removing
the extraction solvent by conventional means.
12. The process of claim 10 wherein the said solvent is selected from pentane and
hexane.

13. A process for the preparation of etodolac wherein the methyl ester of 1,8-diethyl
1,3,4,9-tetrahydropyrano(3,4-b)-indole-1 -acetic acid prepared by using a process
as claimed in claim 1 is hydrolyzed by using conventional procedures.
14. A process for the preparation esters of 1,8-disubstituted 1,3,4,9-
tetrahydropyrano(3,4-b)-indole-1-acetic acid of Formula I, as shown in the
accompanied drawings, as claimed in claim 1 substantially as herein described
and illustrated by the examples herein.