FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, rule 13)
"PROCESS FOR PREPARING HIGHLY PURE AND FREE-FLOWING SOLID OF 7-ETHYLTRYPTOPHOL"
SK ENERGY AND CHEMICAL INC., of 22-10 Route 208 South, Fair Lawn, New Jersey, NJ 07410, U.S.A.,
The following specification particularly describes the invention and the manner in which it is to be performed.

WO2005/002573 PCT/US2004/021360
PROCESS FOR PREPARING HIGHLY PURE AND FREE FLOWINGSOLID OF 7 ETHYLTRYPTOPHOL
5 Background of the Invention
This invention relates to a purification process for the preparation of highly pure and free-flowing solid of 7-ethyltryptophol from the crude tarry 7-ethyltryptophol. 1-ethyltryptophol is the key intermediate of a potent anti-inflammatory and analgesic compound, Etodolac. Etodolac is a pyranocarboxylic acid, chemically designated as
10 (±) l,8-diethyl-l,3,4,9-tetrahydropyrano-[3,4-b]indole-l-aceticacid.
Two methods for the preparation of 7-ethyltryptophol are disclosed in U.S. Pat. No. 4,585,877 to Demerson et al. and PCT Publication WO 99/59,970 to Stevensen et al., in which 7-ethyltryptophol was prepared by the Fischer indole synthesis reaction of 2-ethylphenyl hydrazine hydrochloride and 2,3-dihydrofuran. A similar
15 process of making 7-ethyltryptophol by the reaction of 2-ethylphenylhydrazine
hydrochloride and 4-hydroxybutyraldehyde is disclosed in U.S. Pat No. 4,012.417 to Demerson et al.
Demerson et al., J. Med. Chem., 391(1976) also discloses the preparation of 7-ethyltryptophol by the reduction of 7-ethyl-3-indolyglyoxylate with UAIH4. The
20 glyoxylate is produced by the reaction of 7-ethylindole with oxalyl chloride, and the 7-ethylindole is made from 2-ethylaniline in a three-step process,
The method of making 7-ethyltryptophol by the reaction of 2-ethylphenylhydrazine hydrochloride and 2,3-dihydrofuran is cheaper and simpler than other methods . However, the reaction is not clean and produces a lot of impurities.
25 The 7-ethyltryptophol isolated from the reaction is a tarry solid or a sticky oil with a low purity unless flash column chromatography on silica gel was used for the purification {see U. S. Pat No. 4,585,877 to Demerson1 et al. and WO 99/59,970 to Sevensenetal.).
Purification by column chromatography is not economical and very difficult to
30 implement in industrial manufacture. Although other purification methods, such as
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WO200S/00M23 PCT/US2004/021360
crystallization and washing of a suspension or solution, are suitable ways to purify the products in manufacture production, to the best of our knowledge, no process For making highly pure and free-flowing solid of 7-ethyltryptophol has been developed so far except by using flash column chromatography.
5 Highly pure and free-flowing solid of 7-ethyitryptophol is desirable for the
preparation of etodolac in the terms of both convenience of material handling and product purity. There is thus a need for a simple and economical chemical process for making pure and free-flowing solid of 7-ethyltryptophol.
Summary of the Invention
10 According to the process of the present invention, crude 7-ethyltryptophol is
purified by dissolving the crude 7-ethyltryptophol (which may be a tarry solid or a - sticky oil) in an organic solvent, followed by washing with an aqueous solution of
acid at ambient temperature. After removing part or all of the solvent, preferably by
distillation, the product is solidified in an alkane solvent under cooling. The process
15 ' allows the formation of a free-flowing solid with an increased HPLC purity and assay.
Detailed Description of the Invention
Crude tarry 7-ethyltryptophol prepared by known methods contains many polar and non-polar impurities. In accordance with the present invention, there is
20 provided a novel process for making a highly pure and free-flowing solid of 7-ethyltryptophol from the crude tarry solid or sticky oil product. This provides an excellent intermediate for further synthesis, eliminating the preheating operation necessary for handling the tarry 7-ethyltryptophol and resulting in a high purity product which is useful as an intermediary for further synthesis. The process
25 comprises dissolving crude 7-ethyltryptophol prepared by the known methods in an organic solvent, dissolution of the crude preparation may be carried out at ambient temperature, and washing the resultant solution with an aqueous acid solution to remove most of the impurities, which are separated into the resulting aqueous fraction and removed. This is followed by removal of part or all of the organic
30 solvent and solidification of the remaining residue in an alkane solvent. In preferred

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WO 2005/00232T
embodiments, all or substantially all of the organic solvent is removed via distillation and solidification of the remaining residue is accomplished via trituration in the alkane solvent under cooling with vigorous stirring.
The organic solvent utilized to dissolve the crude product can be any solvent
5 in which 7-ethyltryptophol is soluble. Preferably, the solvent is one that has a good solubility for 7-ethyltryptophol at ambient temperature and good layer separation with aqueous acid solution. Examples of suitable organic solvents which can be used to dissolve the crude 7-ethyltryptophol include, without intended limitation, dichloromethane, t-butyl methyl ether, diethyl ether, toluene, 1,2-dichloroethane,
10 benzene, ethyl acetate and t-butyl acetate. The amount of the organic solvent used in the purification is at least sufficient to completely dissolve the crude 7-ethyltryptophol, but preferably the organic solvent may be present in greater than equimolar amounts.
The aqueous solutions of acids used for the washing step include, without
15 intended limitation, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid and suitable organic acids, such as acetic acid. The concentration of the aqueous acid solution can be in the range of 0.1 to ION, preferably, from about 1 N to 2 N. The washing to remove impurities is carried out by mixing the solution of 7-ethyltryptophol and the aqueous acid solution and stirring at a temperature lower
20 than 100° C or the boiling point of the organic solvent. However, in order to avoid any reaction between 7-ethyltryptophol and the acid, the washing is preferably earned out at a temperature from about 10° C to25°C. When said preferred temperature range is employed, the stirring time is typically about 30 to 60 min for each washing.
The number of washings and the time of each will depend on I) the volume and
25 concentration of the aqueous acid solution used for each washing; and 2) the concentration of 7-ethyltryptophol in the organic solution. After washing and removal of the aqueous phase, the organic solvent is removed from the resultant solution of 7-tryptophol. Preferably this is accomplished via distillation under vacuum to remove from about 50-100 % of the organic solvent, preferably removing
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WO 2005/002523
as much as possible. In most preferred embodiments, all or substantially all of the organic solvent is removed via distillation. The distillation temperature should be higher than 50°C if the solvent is completely removed, At this temperature, the 7-ethyltryptophol is in a melted state and, therefore, stirring will not be impeded during
5 the distillation.
Solidification of the 7-ethyltryptophol is preferably performed by triturating the; resultant residue with an alkane solvent to at a temperature of 50° C or higher, but lower than the boiling point of the alkane solvent, The most commonly employed alkane solvents for the solidification are pentane, hexane, cyclohexane, heptane and
10 petroleum ether, but any of other alkane solvents can be used as well, Preferably, the mixture is slowly cooled under vigorous stirring to 5 °C or lower, preferably from about -20 to 5°C. and then stirring is continued for one to two hours. The resultant mixture is filtered and the recovered solid is washed with the alkane solvent and then dried under vacuum at ambient temperature. The obtained solid is free-flowing and
15 its HPLC purity and assay are usually 20% higher than those of the crude product.
The following examples serve to illustrate the present invention and are not, in any way, to be considered as a limitation thereof.
Example 1
20 Two hundred grams of crude 7-ethyltryptophol, which has an HPLC purity
and assay of 83.0% and 75.4% respectively, were dissolved in 1400 mL of dichloromethane at room temperature. The solution was successively washed at room temperature with three 600 mL portions of 1 N aqueous solution of HC1, 600 mL of saturated sodium bicarbonate solution and 400 mL of brine. After completely
25 removing the solvent by evaporating on a rotary vapor at 50-55° C, 350 mL of
hexane was added at 50~55°C under vigorous stirring. The mixture was then slowly cooled to 0—5°C over 1 h and stirred at 0~-5°C for another 2 h. After filtering, the solid was washed with 200 ml of hexane and dried at 25~30° C under vacuum overnight to give 164 g (82% recovery) of the solid product. HPLC purity and assay:
30 96.2% and 88.4%, respectively.

5

•WO 3005/002523
Example 2
Two hundred grams of crude 7-ethyltryptophol, which had an HPLC purity and assay of 76.7% and 62.2%, respectively, were dissolved in 1400 mL of t-butyl
5 methyl ether at room temperature. The solution was successively washed at room temperature with three 600 mL portions of 1 N aqueous solution of HCI.600 mLof saturated sodium bicarbonate solution and 400 mL of brine, After completely removing the solvent by evaporating on a rotary vapor at 50-55°C, 350 mL of hexane was added at 50-55° C under vigorous stirring. The mixture was then slowly
10 cooled to 0—5° C over 1 hour and stirred at 0—5 ° C for another 2 hours. After filtering, the solid was washed with 200 mL of hexane and dried at 25-30° C under vacuum overnight to give 168 g (84% recovery) of the solid product. HPLC purity and assay: 96.9% and 86%, respectively.
15 Example 3
Twenty grams of crude 7-ethyltryptophol, which had an HPLC purity and assay of 76.7% and 62.2%, respectively, were dissolved in 150 mL of toluene at room temperature. The solution was successively washed at room temperature with three 80 mL portions of 1 N aqueous solution of HC1, 80 mL of saturated sodium
20 bicarbonate solution and 60 mL of brine. After evaporating on a rotary vapor at 50° C to a volume of 30-35 mL, 60 mLof hexane was added and stirred at refluxing for 20 min. The mixture was then slowly cooled to -10° C over 1 h and stirred at -10° C for another 2 h. After filtering, the solid was washed with 20 mL of hexane and dried at 25-30°C under vacuum overnight to give 11.2 g (56% recovery) of the solid product.
25 HPLC purity and assay: 95.3% and 87.2%, respectively.
6

-PCT/US
WHAT IS CLAIMED IS:
1. A process for preparing highly pure 7-ethyitryptophol, comprising:
a) dissolving crude 7-ethyltryptophol in an organic solvent in which 7-ethyltryptophol is soluble;
b) treating the solution formed in step (a) by addition of an aqueous acid solution to form separate aqueous and organic phases;
c) separating said aqueous phase from said organic phase;
d) at least partially removing said organic solvent from said organic phase;
e) solidifying the residue produced in step (d) by adding an alkane solvent; and
f) recovering highly pure solid 7-ethyltryptophol from the mixture of step(e).

2. The process in accordance with Claim 1, wherein said organic solvent in step (a) is selected from the group consisting of chloroform, dichloromethane, toluene. benzene, t-butyl methyl ether, diethyl ether, dioxane, ethyl acetate and isopropyl acetate.
3. The process in accordance with Claim 1, wherein said aqueous acid solution added in step (b) comprises an acid selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and acetic acid.
4. The process in accordance with Claim 1, wherein the concentration of said aqueous acid solution added in step (b) is from about 0.1 N to about 10 N.
5. The process in accordance with Claim 1, wherein the treatment with aqueous acid solution in step b) is conducted at a temperature of from about 10° C to about 50" C.
6. The process in accordance with Claim 1, wherein the treatment with aqueous acid solution at step b) comprises mixing and stirring together said organic solution and said aqueous acid solution such that at least a majority of impurities present in the mixture are contained in said separate aqueous phase.

7

2005/002523 rCT/UC:U01.'O213CO
7. The process in accordance with Claim 1, wherein at the organic solvent is removed in step d) by distillation.
8. The process in accordance with Claim 1, wherein the alkane solvent added to the residue in step e) has a low solubility for 7-ethyltryptophol.
9. The process in accordance with Claim 8, wherein said alkane solvent is selected from the group consisting of pentane, hexane, heptane, cyclohexane and petroleum ether.
10. The process in accordance with Claim 1, wherein said solidification in step (e) comprises trituration conducted under cooling conditions.
11. The process in accordance with Claim 10, wherein said cooling conditions comprise lowering the temperature during solidification to a range of about -20 to 5 °C.
12. The process in accordance with Claim 1, wherein said highly pure solid 7-ethyltryptophol is recovered from the mixture of step e) by filtration.
13. The process in accordance with Claim 1 wherein said crude 7-ethykryptophol comprises a tarry solid, or a sticky oil.
14 The process in accordance with Claim 1, wherein the treatment in said organic solvent in step a) is conducted at ambient temperature.
15. A process for preparing highly pure 7-ethyltryptophol substantially as herein described with reference to the foregoing examples.
Dated this 2nd day of January, 2006.
MEHUA GHOSH
OF K & S PARTNERS
AGENT FOR THE APPLICANTS
8

ABSTRACT
PROCESS FOR PREPARING HIGHLY PURE AND FREE-FLOWING SOLID OF 7
ETHYLTRYPTOPHOL
An industrial purification process for preparing a highly pure and free-flowing soli of 7-ethyl tryptophol. Crude 7-ethyltryptophol, prepared by known procedures is dissolved i an organic solvent and washed with aqueous acid solutions to form an aqueous phase and a organic phase. After at least partially removing the solvelit from the organic phase, it i triturated with alkane solvent under cooling to solidify the residue. A highly pure and fret flowing solid of 7-ethyltryptophol is recovered therefrom.
9