FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patent Rules, 2003
Provisional Specification
(See section 10 and rule 13)
A Novel Process of Manufacturing 3-Methylindole
Moraya Global Private Limited
Plot A-42, Street No. 2, MIDC, Andheri (e), Mumbai 400 093,
Maharashtra State, India
An Indian company registered under the Companies Act, 1956
The following specification describes the invention:

A NOVEL METHOD FOR MANUFACTURING 3-METHYLINDOLE
Field of invention:
The present invention relates to perfumery industry. In particular the present invention relates to a method of preparation of 3-Methylindole
Background of invention:
3-methylindole, also known as skatole, is found in naturally occuring substances such as coal-tar, beet-root, nectranda-wood, and faeces. 3-methylindole finds extensive use in perfumes as a as a fragrance and also as a fixative. Recently, it is being used to develop newer drug molecules for the treatment of osteoporosis, etc.
A number of methods are available for the manufacture of 3-methylindole.
In 1883, Fischer (see Reference 1) synthesised 3-methylindole by cyclization of phenylhydrazone of propionaldehyde. In what is widely accepted as the general method of skatole manufacture, he reported a 35% yield. Arbusonti and Tichwinsky (see Reference 2) disclosed improvements to Fischer's method whereby they claimed to have obtained 73% yield.
It has also been claimed by Gesellschaft fur Teerver- Wertung (see Reference 3) disclosed further improvement of Fischer's process by using methyl naphthalene and Zinc chloride, whereby the yield was reported to have been 80%.
One of the drawbacks of both of these methods is that they take a long time to complete, each of the entire processes lasting for a period of approximately 1 week. A further drawback is that they comprise several steps that need starting, stopping and monitoring, thereby making them cumbersome. The methods use Phenylhydrozone as a raw material which is hazardous itself and emits ammonia which is a hazardous gas. The reaction progress in these methods is monitored by
cessation of ammonia and no reliable instrumental methods of monitoring the
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same are available. The crude extraction, distillation and separation processes that are a part of these methods are also lengthy and cumbersome processes.
According to another general method ( see Reference 4) a reaction of coal-Tar with sodium and sodamide leads to production of 3-methylindol
This method is an obsolete technique because of growing depletion of coal tar reserves.
A number of other publications (see references 5 and 6) have described synthesis of 3-methylindole from indolyl acetic acid which can be degraded to 3-methylindole when heated to its melting point
The drawbacks of this method are that the raw materials used in the method are expensive, the method is multi-step and therefore cumbersome, and the yields are low.
US patent 4473699 (Reference 7) described the preparation of 3-methylindole from 2-(cyanomethyl) cyclohexanone which is catalytically reduced at high temperatures using Group VIII or Group lb metals of the Periodic Table of elements (as described in Lange's Handbook of Chemistry, 11 Edition). In one of the illustrative examples therein a skatole yield of 45% has been reported.
Yet another publication, by L Marion and W L Ashford (see Reference 8) describes a method of manufacture of skatole wherein a skatole yield of 68% has been reported. The method produces skatole by intramolecular condensation of o-ethylformanilide by heating with potassium tert-butoxide.
The drawback of this method is that it is of more academic interest than of industrial application.
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A recent publication by Iana Gueorguieva, et al (see Reference 9) describes a method of preparation of 3-methylindole by hydroborations and cyclization from 1,2,3-benzodioxiborole and 1-ethoxy-l-alkyne, through a multi-step process.
Because of the growing demand of 3-Methylindole in the perfumery and Pharma-chemical industries, there is a need for a process of making 3-Methylindole that uses non-hazardous raw materials and that completes in shorter time than existing methods.
Objects and advantages of the present invention:
Accordingly, there are several objects and advantages of the present invention.
One object of the present invention is to provide an easy to handle and low cost method of manufacturing skatol.
Another object of the present invention is to provide a low-cost method of manufacture of skatole.
Yet another object of the present invention is to provide a method of manufacture of skatole using widely available raw materials.
A still further object of the present invention is to provide a method of manufacture of 3-methylindole of high level of purity (about 99%) and a high level of yield (about 90%).
Summary of the invention:
The present invention provides a novel method of manufacturing 3-methylindole. The invention discloses an easy to handle and low cost method that provides high yields of skatole. The main raw ingredient used in the manufacture of skatole is 3-indole acetic acid, a substance which itself is easily manufactured by a number of methods well known to the person skilled in the art.
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Brief description of the figures:
Figure 1 shows the basis of the existing methods of manufacturing skatole. Figure 2 shows the method of the present invention.
Detailed description of the invention:
The present invention provides a method of manufacture of 3-methylindole.
This method comprises two broad steps. The first step comprises decarboxylation and the second the separation of pure skatole.
Dry yellowish crude Indole Acetic Acid is mixed with Diethylene Glycol in a suitable reactor equipped with a heavy stirrer. The mixture is heated to and maintained at a certain temperature which results in Indole Acetic Acid rapidly giving out carbon dioxide. This step of carboxylation is followed by leaving the solution to cool down to room temperature (20° -25° C). It is then diluted with water which leads to separation of skatole in the mixture. The skatole in the mixture is then centrifuged and washed. The crude 3-Methylindole derived by this process is found to be of high purity.
The crude 3-Methylindole is mixed with water and transferred to distillation chamber. Distillation is carried out at a suitable temperature and a small suction. Skatole is collected in liquid form. The overall yield of skatole obtained by the process of this invention is high.
In the preferred embodiment of the present invention, the stirrer is of the type of an anchor made of stainless steel. The reactor is made of stainless steel. The decarboxylation temperature is preferably approximately 180 degrees and the time taken to raise the solution to this temperature level is about 2 hours. The temperature is maintained at this level for about an hour after which heating is stopped. The Indole Acetic acid used in the preferred embodiment has a melting point preferably of 160 degrees and acidimetry of 98%. The suction used at the
distillation stage is preferably 0.5mm of Hg.
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One of the advantages of the method of the present invention is that it used readily available raw materials, which are also non-hazardous. The process is a two step process that makes the method a less cumbersome task. The entire process completes within two to three days as compared with the week long processes of the prior art. The method is simple and highly reproducible.
Example:
A 200 L stainless steel reactor equipped with an anchor shaped heavy duty stainless steel stirrer, Thermowell stainless steel air-condensor, and oil-heating system is provided. 100 Kg of dry yellowish crude Indole Acetic Acid (IAA) of a melting point of 160 degrees and acidimetry of 98%, and 200 litres of DiEthylene Glycol was charged in the reactor. The mixture was stirred and heated with hot oil for 2 hours to raise its temperature to 180 degrees. Heating was continued for further one hour to maintain the temperature of the mixture at 180 degrees. Heating was stopped and the hot reaction mixture was allowed to cool down to the room temperature (20-25 degrees). It was diluted with water and stirred. Skatole which was separated was removed by centrifugation and washed with water. This crude skatole was found to be of 99% purity according to the GLC tests run on a sample. The crude skatole was vacuum distilled at 0.5 mm of HG suction and at 120-130 degrees temperature. The purified 3-methylindole was collected. The overall theoretical yield was recorded at 88%.
REFERENCES
1) Fischer and jourdan,ber,16(1883) 2241 (from text book "Pefumery And Flavouring Synthetics" by Paul Z. Bedoukian ,second, revised edition ppl93).
2) A.e.arbusow and w.m.tichwinsky, ber,1910,43, 2301 (from "Synthetic Perfumes Their Chemistry and Prepration" by T.F.West, H.J. Strausz, andD.H.R.Bartonp.311).
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3) Gesellschaft fur Teerverwertung D.R.P. 230.138 1911 (from "Synthetic Perfumes Their Chemistry and Prepration" by T.F.West, H.J. Strausz, and D.H.R.Barton p.311).
4) Gesellschaft fur Teerverwertung and O.kruber, D.R.P. 515.543/1930 (from "Synthetic Perfumes Their Chemistry and Prepration" by T.F.West, H.J. Strausz, and D.H.R.Barton p.311).
5) Kermack, Perkin and Robinson, J.C.S., 1921.119.1622 (from "Synthetic Perfumes Their Chemistry and Prepration" by T.F.West, H.J. Strausz, and D.H.R.Barton p.311).
6) F.E. King and P. Liecuyer, J.C.S.. 1934.1902 (from "Synthetic Perfumes Their Chemistry and Prepration" by T.F.West, H.J. Strausz, and D.H.R.Barton p.311).
7) Van der Stoel Roland E (NZ); Janssen Petrus H.J (NZ); Van de Moesdijk Cornelis G M (NZ); u.s. p. 4473699. 1984.
8) L.marion and w.r.ashford,lan. J.research, 1945,23,26 (from "Synthetic Perfumes Their Chemistry and Prepration" by T.F.West, H.J. Strausz, and D.H.R.Barton p.311).
9) Iana Gueorguieva, Meagan Mass, Kurun Oberoi, Jeff Simon, "3-step synthesis of 3-methyl indole (skatole) via hydroboration and cyclization", organic chemistry. H.H. 2006,271,1-12.
10) Organic synthesis coll. Vol 5, p 655.
11) Practical organic chemistry including qualitative organic analysis, Arthur I. Vogel, iii edition, 1956, p. 10/2.
Dated this 16th day of October, 2006

Mr. Vijay Sharatchandra Tase (Patent Agent for the Applicant) Registration No. IN/PA 987
To
The Controller of Patents,
The Patent Office Branch at Mumbai
7

Applicant: Moraya Global Privet Limited.

No. Of Sheets-2 Sheet No. - 1

Step -1

NH - NH,- HCL

CHO

CH,COONa
METHANOL

NH-N = CH I CH2 - CH,

Phenyl Hydrazine Hydrochloride

CH, Propionaldehyde

Phenyl Hydrazone

Step - II

NH-N = CH I CH2 - CH,
Phenyl Hydrazone _j-

DEG ZnC1>
N,

+ Ammonia

H20 + Nacl + CH,COOH
Step - III


Purification

-*• Pure Skatole

Figure 1 : Existing Process

(Vijay Sharatchandra Tase)
Patent agent for the applicant
Registration no. IN/PA 987

Applicant: Moraya Global Privet Limited. No. Of Sheets - 2
Sheet No. - 2
Step -1

CH2COOH DEG
/\ 180°C

H

H SKATOLE

Step - II
CH,


H

VAC - DISTN
PURIFICATION

3-METHYL INDOLE
Figure 2 : The Process of the Present Invention

(Vijay Sharatchandra Tase)
Patent agent for the applicant
Registration no. IN/PA 987
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