Field of invention
The present invention relates to a process for the preparation of indole derivatives, particularly those, which are useful as pharmaceutical intermediates.
Background of the invention
Recent advances in medical science opens numerous opportunities in developing either a new therapy or it brings forth-new insights in the existing ones. The elaborate classification of serotonergic receptors; structural elucidation of the different types and sub-types of these receptors; their physiological role in humans, has lead to increased research interest in various disorders relating to central nervous system. Many substances in useful in these disorders preferably have indole nucleus. Also some indole derivatives are found to be useful in the treatment of various other disorders such as endocrine indications, cancer, immune system disorders, opthalmological diseases, and also therapeutic areas such as anti-inflammatory and dermatology.
Various 2,3-disubstituted indoles particularly those having 3-alkylamino substitutent in the side-chain are reported in literature. Examples include, US 5,817,689; US 5,756,507; US 5,571,833; US 5,436,264; US 5,276,051; US 5,179,211; US 5,030,640; US 4,839,377; US 4,672,067; US 4,544,663; US 4,803,218; US 3,669,960; US 3,472,870; EP 1,306,230 and PCT applications, WO 99/11619, WO 97/21703, WO 95/30655, WO 95/14004, WO 95/01334, WO 93/21178, WO 92/13856 and WO 90/05721.
As reported in the prior art the general methods to prepare 3-alkylamino substituted indoles using Fischer indole synthesis, involves at-least two steps, namely; initial formation of indole ring, which is followed by derivatization of conventional precursor for amines such as amide, cyano, acid chlorides, hydroxyl, chloro etc obtaining the desired 3-alkylamino substitution. In a typical conventional Fischer indole synthesis a substituted aryl hydrazine is condensed with a ketone or an aldehyde or its activated analogues such as ketals or acetals respectively.
US patent 6,133,453 describes a method to prepare 3-hydroxyalkyl indoles using hydrazines and dihydroflxran. US patent 5,179,211 describes a method wherein indole derivatives are prepared in aqueous medium in short reaction time and good yields.
Various processes to prepare substituted 3-aminoalkyl indole derivatives are described in the prior art. Though many of these are modifications of classical Fischer indole synthesis, only a few of these methods can be applied to prepare 3-aminoalkyl indole derivatives in one step. For example, a process used to prepare 3-hydroxyalkyl indoles in single step can not be extended to others which have strongly basic groups such as amines or highly electrophilic groups such as acid chlorides,
2

ketones, aldehydes and esters at 3-position of indole ring. Yet another one-pot synthesis employs relatively high dilution of solvents, preferably water, to maximize the purity of final product.
Hence we attempted to have an improved method to prepare substituted 3-aminoalkyl indole derivatives in one-pot, wherein initial non-cyclizing step is immediately followed by cyclization to give indole ring having the desired 3-aminoalkyl substitution. Accordingly, the process of this invention has number of advantages over the known art and is described in detail in the following specification.
From our extensive study, we have concluded that proper choice of solvents and co-solvents significantly reduces number and amount of impurities. Further, the by-products formed in the reaction can be easily removed without involving any additional operational cost and equipment, which is a considerable technical advantage from scale-up point of view.
The advantages of this invention as envisaged by us are as follows:
1. The process of this invention has much more broad scope for preparing substituted 3-
aminoalkyl indole intermediates than it was possible earlier with Fischer indole synthesis.
2. The present process is a one-pot process, wherein the desired substituted 3-aminoalkyl indole
intermediate is prepared by reacting the appropriately substituted ketone amines of varying
diversity with aryl hydrazines.
3. The process uses substituted ketone amines thus there is no additional derivatization or
deprotection step.
4. The above feature is especially useful when 3-aminoalkyl indoles are intermediates in a multi-
step synthesis.
5. Further the reaction time is shorter as compared to other methods without incurring any
additional operational changes or costly equipment.
6. The process of this invention allows more flexibility in terms of reaction conditions such as
solvent, reactants, catalyst etc.
7. The process does not require excessive cooling or heating.
8. The amounts of impurities formed are relatively less irrespective of nature and dilution of the
reaction medium.
9. As a result the process has good yields and purity as well.
10. The recovery of organic solvent/s used, is upto 80 %.

11. Various indole derivatives substituted in 2nd and 3rd position can be prepared in a single step.
12. Though reactions of Fischer Indole type, exclude generally strongly basic and highly
electrophilic group. The method of this invention answers this deficiency in the prior art as the
hydrazine is treated with N,N-disubstituted compounds without any loss in yields or purity of
the product. The process disclosed in this invention may be advantageously applied to prepare
various analogues of indoles.
Summary Of The Invention
The present invention relates to the process for the preparation of compounds of general formula (I),

General formula (I)
which comprises of reacting a phenyl hydrazine of the formula (II) or its salt represented by the formula (IF), each of which has at-least one ortho-position unsubstituted,

with a ketone amine represented by the formula (III),


wherein,
R represents hydrogen, C1-C10 alkyl5 C2-100 alkenyl, C2-C10 alkynyl3 phenyl-(-R5)6b CH2-phenyl-(-R5)a SO2-phenyl(-R5)a, C(O)R9, C(O)OR6, (H2)qNR7R8 C(O)NR7R8 (CH2)mHet, (CH2)O(CH2)oCH3 (CH2)m(C3-C10)cycloalkyl3 (C3-C10)cycloalkyl, wherein o is 0 or 1, m is 1 or 2, a is 1 to 4, b is 1 to 5, q is 2 or 3;
R1 represents C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, phenyl-(-R5)b -(CH2)-phenyl(-R5)a (CH2)mHet, (CH2)m(C3-C10)cycloa]kyl, (C3-C10)cycloalkyl and the like;
R2 represents C1-C6 alkyl, phenyl-(-R5)b -(CH2)-phenyl(-R5)b -(CH2)mHet; wherein Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group containing nitrogen, oxygen and sulfur; and also includes mono or bicyclic group, which may be further attached to above defined heterocycles;
R3 represents hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C(O)R9, C(O)OR6; optionally, R2 and R3 together may form a part of cyclic structure along with the intervening nitrogen; the heterocycle may have either one, two or three double bonds; optionally it may also contain one to three heteroatom selected from the group of oxygen, nitrogen and sulfur, and includes ring fused with any carbocyclic or heterocyclic ring, which can be saturated or unsaturated;
R4 represents hydrogen, C1-C10 alkyl, and is attached to any one or more than, one carbon atoms present in the side chain;
R5 represents either same or different substitutents such as hydrogen, halogen, hydroxy, -X-R8 (X = -O-, -NH-, -S-), nitro, ammo, -N6R7, -NHC(O)R1, -OC(O)R1, -OC(O)R1, -C(O)R1, trifluoromethyl, trifluoromethoxy, -SO2N(R)(R), -CN, -CO(O)R6, C1C4 alkyl, phenyl, -O-CHrO;
R6 represents hydrogen, C1-C10 alkyl, -C(O)OR12 phenyl-(-R5)bs -(CH2)-phenyl-(-R5)b5 -(CH2)mHet, and is attached to any one or more than one carbon atoms present in the side chain;
R? represents hydrogen, C1-C10 alkyl;
R« represents hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, phenyl-(-R5)b CH2)b phenyl-(-R5)b -(CH2)b Het;
R9 represents hydrogen, hydroxy, 0R8, NR6R7;
R10 and R11 each independently represents hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, aryl, ar(C1-C4)alkyl, hydroxy, -X-R8 (X = O,NH5 S), nitro, amino, -NR6R7 NHC(0)R1, OC(O)1, OC(O)Ri, C(O)Ri, trifluoromethyl, trifluoromethoxy, SO2N(R)(R), (CH2)nSO2N(R)(R)3 -CN, -CO(O)R6, phenyl, O-CH2-O-; R10 and R11together with the two adjacent carbon atoms of phenyl ring

form a cyclic structure containing 5 to 8 carbon atoms, which may contain 1 to 3 double bonds, optionally it may contain one to three hetero atoms selected from the group containing oxygen, sulfur and nitrogen;
n is 1 to 4 and relates only to carbon atoms;
said process comprising of one-pot reaction in the presence of acidic catalyst and a suitable solvent, and if desired, removing in any known manner , water formed in the reaction.
The compounds of formulae (I) may have one or more asymmetric carbon. Hie process of invention also includes preparation of such chiral compounds of formula (I) using the corresponding chiral oxo amines wherein the reaction proceeds with complete retention of configuration at the asymmetric carbon atom.
Similarly the compounds of formula (I) may also posses geometric isomerisnu wherein also the process of this invention can be used to prepare such compounds.
Suitable phenyl hydrazines for the process according to this invention are : phenyl hydrazine, 4-methylphenyl hydrazine, 4-ethylphenyl hydrazine, 4-propylphenyl hydrazine, 4-dodecylphenyl hydrazine, 4-methoxyphenyl hydrazine, 2,5-dimethylphenyl hydrazine, 3,4-dimethylphenyl hydrazine, 4-ethoxyphenyl hydrazine, 4-benzyloxyphenyl hydrazine, 4-chlorophenyl hydrazine, 4-bromophenyl hydrazine, 4-fluorophenyl hydrazine, 4-iodophenyl hydrazine, 5-chloro-2-methylphenyl hydrazine, 4-(l-(lv3-oxazolidine-2-one-4-yl)methyIene)phenyl hydrazine and 2,4-dichlorophenyl hydrazine.
Suitable ketones for the process according to the invention are: N,N-dimethyl-4-oxo-
pentanamine, N,N-diethyl-4-oxo-pentanamine, N-methyI,N'-ethyI-4-oxo-pentanamine, N,N,2-
trimethyl-4-oxo-pentanamine, N,N,3-trimethyl-4-oxo-pentanamine, N,N,2-triethyI-4-oxo-
pentanamine, N,N,3-triethyI-4-oxo-pentanamine, N,N-dimethyl-5-oxo-hexanamine, N,N-diethyl-5-
oxo-hexanamine, N-methyI,N'-ethyl-5-oxo-hexanamine, N3N,2-trimethyl-5-oxo-hexanamine, N,N,3-
trimethyl-5 -oxo-hexanamine, N,N,2-triethyl-5 -oxo-hexanamine, N,N, 3 -triethyl-5 -oxo-hexanamine,
N?N-dimethyl-6-oxo-heptanamine? N?N-diethyl-6-oxo-heptanamine, N-methyl,N'-ethyl-6-oxo-
heptanamine, N,N,2-trimethyl-6-oxo-heptanamine, N,N,3-trimethyl-6-oxo-heptanamine, N,N,2-
triethyl-6-oxo-heptanamine, N,N,3-triethyl-6-oxo-heptanamine, N,N-dimethyl
benzoylpropanamine, N,N-diethyl benzoylpropanamine, N,N-dimethyI (4-
bromobenzoyl)propanamine, N,N-dimethyl benzoylbutanamine, N,N-diethyl
benzoylpentanamine, N,N-dimethyl (4-bromobenzoyl)butanamine and N,N-dimethyl (4-methylbenzoyl)pentanamine.
DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of compounds of general formula (I),

which comprises of reacting a phenyl hydrazine of the formula (II) or its salt represented by the formula (II'), each of which has at-least one ortho-position unsubstituted,

with a ketone amine represented by the formula (III),

wherein,
R represents hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, phenyl-(~R5)b, CH2-phenyl-(-R5)as SO2-phenyl(-R5)a, C(O)R9s C(O)OR6, (CH2)qNR7R83 C(O)NR7 R8 (CH2)mHets (CH2)mO(CH2)oCH3, (CH2)m(C3-C10 cycloalkyl, (C3-C)cycloalkyl3 wherein o is 0 or 1, m is 1 or 2, a is 1 to 4, b is 1 to 5S q is 2 or 3;
7

R1 represents C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, phenyl-(-R5)b, "(CH2)-phenyl(-R5)a (CH2)mHet, (CH2)m(C3-C10)cycloalkyl, (C3-C10)cycloalkyl and the like;
R2 represents C1C6 alkyl, phenyl-(-R5)b, -(CH2)-phenyl(-R5)m, -(CH2)mHet; wherein Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group containing nitrogen, oxygen and sulfur; and also includes mono or bicyclic group, which may be further attached to above defined hctcrocycles,
R3 represents hydrogen, C1-C10 alkyl, C2-Ci0 alkenyl, C2-Ci0 alkynyl, C(O)R9? C(O)OR$; optionally, R2 and R3 together may form a part of cyclic structure along with the intervening nitrogen; the heterocycle may have either one, two or three double bonds; optionally it may also contain one to three heteroatom selected from the group of oxygen, nitrogen and sulfur, and includes ring fused with any carbocyclic or heterocyclic ring, which can be saturated or unsaturated;
R4 represents hydrogen, C1-C10 alkyl, and is attached to any one or more than one carbon atoms present in the side chain;
R5 represents either same or different substitutents such as hydrogen, halogen, hydroxyl, -X-R« (X = -O-> -NH-, -S-), nitro, amino, -NReR?, -NHC(O)R}, -OC(O)RU -OC(O)RU -C(O)RU trifluoromethyl, trifluoromethoxy, -SO2N(R)(R), -CN, -CO(O)R6, d-C4 alkyl, phenyl, -O-CH2-O-;
R« represents hydrogen, CrCi0 alkyl, -C(O)ORl3 phenyl-(-R5)b, -(CH2)-phenyH-R5)b, -(CH2)mHet, and is attached to any one or more than one carbon atoms present in the side chain;
R7 represents hydrogen, Q-Cio alkyl;
Rg represents hydrogen, C1-C10 alkyl, C2-Ci0 alkenyl, C2-Ci0 alkynyl, phenyl-(-R5)b, -(CH2)b- phenyl-(-R5)b5 -(CH2)b- Het;
R9 represents hydrogen, hydroxyl, OR«, NReR?;
Rio and Rn each independently represents hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, aryl, arCCrC^alkyl, hydroxyl, -X-Rg (X = O, NH, S), nitro, amino, -NReR?, NHC(O)Ri, OC(O)Rb OC(O)Rb C(O)Rb trifluoromethyl, trifluoromethoxy, SO2N(R)(R), (CH2)nSO2N(R)(R), -CN, -CO(O)R6, phenyl, O-CH2-O-; Rio and Rn together with the two adjacent carbon atoms of phenyl ring form a cyclic structure containing 5 to 8 carbon atoms, which may contain 1 to 3 double bonds, optionally it may contain one to three hetero atoms selected from the group containing oxygen, sulfur and nitrogen;
n is 1 to 4 and relates only to carbon atoms;

and the said process wherein comprises of an one-pot reaction in the presence of acidic catalyst and a suitable solvent, optionally having a suitable mechanism to remove water formed in the reaction.
Examples of suitable salts of phenyl hydrazine represented by the general formula (IV) includes the hydrochloride salt, the hydrobromide salt, the salts of H2SO4, HNO3, H3PO4 and the like, prepared by reacting phenyl hydrazine of formula (II) with the corresponding mineral acids.
Halogen when mentioned is fluorine, chlorine, bromine or iodine.
Suitable acid catalysts include mineral acids as well as organic acids, characterized in that glacial acetic acid, perchloric acid, trifluoroacetic acid, trichloroacetic acid, monochloroacetic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, orthophosphoric acid, polyphosphoric acid and the like. Optionally Lewis acids such as aluminum chloride, titanium tetrachloride, zinc chloride etc. can be used as a catalyst in some cases.
Preferable acid catalysts used include trifluoroacetic acid, sulfuric acid, orthophosphoric acid or glacial acetic acid in suitable concentrations and optionally the acid catalyst used may be dissolved in an aqueous solvent.
Suitable mechanism for removing water from a reaction mixture includes those described in the literature and known to a skilled artisan. Dehydrating agents such as sulfuric acid, molecular sieves, or removing water by azeotropic distillation are examples of techniques described in the prior art.
The process comprises of reacting the phenyl hydrazine compound of formula (II) or its salt (IP) with the ketone amine compound of formula (III) in presence of suitable solvent and an acid catalyst. The reaction may be carried out at temperature ranging between 60 °C to the reflux temperature of the solvent/s used, for about half-hour to 4 hours. Optionally, water formed in the reaction may be removed using the techniques known in the art. The reaction may be conducted in an inert atmosphere.
Phenyl hydrazine of formula (II) or its salt (IP) and ketone amine of formula (HI) can be present in 1: 1 molar ratios to 1: 5 molar ratio of each other. The compound of formula (II) or its corresponding salt (IP), optionally may be first dissolved in a solvent, and then added to the reaction mixture and the vice-versa.
Suitable solvents for the phenyl hydrazine of formula (II) or its salt (IP) include ethers, alcohols, nitroalkanes, acetonitrile, dimethylsulfoxide, dimethyl formamide, and hexamethylphosphoramide. While suitable solvents for the ketone amine of formula (III) includes inert solvents, such as, hydrocarbons, chlorinated hydrocarbons or acyclic ethers and the mixtures thereof.

Suitable substitutents for either hydrazine derivative or the ketone amine compound are those which are compatible with the reaction, i.e., do not significantly reduce the yield of reaction and d< not cause a significant amount of side reactions.
Suitable acid catalysts include organic as well as mineral acids characterized in that glacia acetic acid, trifluoroacetic acid, trichloroacetic acid, monochloroacetic add, perchloric acid benzenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like The preferred acid catalyst is dissolved in protic or polar solvents such as alcohols or ethers, foi example, methanol, ethanol, propanol; ethers such as tetrahydrofuran, diisopropyi ether; and even water upto 50 % may be present in some cases.
The acid employed can be present in the mole ratio of 1 to 10 mole equivalents per mole of ketone amine. The particular molar proportions employed will depend upon the concentration of the acid employed as illustrated in the examples.
Preferable acid catalysts used in the process of this invention include trifluoroacetic acid, sulfuric acid or glacial acetic acid in suitable concentrations and optionally dissolved in a solvent may be used to carry out the process of this invention.
The concentration of acid catalyst employed in the reaction can vary from about 10 % to 100 % or from 10 % to 75 % with the range 15 to 75 % representing the preferred range of concentration. Where higher concentrations are employed, it is preferred to employ inert organic solvents such as toluene, xylene, or chlorobenzene.
The initial step of hydrazone formation requires a little amount of acidic catalyst and results into formation of 1 mole equivalent of water. The latter may be removed, if desired, using various techniques known in the art such as using either a dehydrating condition, molecular sieves or by distillation.
Because the reaction is exothermic, the reagents are typically mixed slowly, e.g., drop-wise. The optimal reaction time and temperature depends on factors such as the solvent and concentration, which the skilled artisan will be able to adjust so as to maximize the yield of the product. Generally, after mixing the reaction is maintained at temperatures ranging from room temperature to reflux temperature of the solvent employed until completion of the reaction. It is known fact that the mode of addition of one reactant in another can accelerate the rate of reaction or at least minimize the formation of undesired components thus improving the economy of the process.
In the process according to this invention it is possible initially to introduce either the phenyl hydrazine or ketone amine initially, together with the acid compound, in the solvent, and bring the mixture to the reflux temperature and then to add the reactant which is not added till then. It is frequently advantageous to introduce phenyl hydrazine initially. It is advantageous to introduce the

ketone amine at elevated temperature but before the reaction mixture reaches its maximum temperature.
It is also possible to add the phenyl hydrazine and the ketone amine simultaneously to the solvent, which is at the reflux temperature and contains the acid compound; in this case also it can be advantageous to introduce small amount of phenyl hydrazine in the beginning of the reaction and latter add the two components simultaneously. This method of simultaneous addition is particularly suitable for a continuos operation. In all cases, the formation of the phenyl hydrazone and its cyclisation to give indole, with the elimination of NH3, take place in immediate succession.
After termination of the process according to the invention the aqueous portion is isolated, neutralized, the substituted indole derivative is obtained in organic phase; if required, the indole can be purified further in a manner well known to those skilled in the art.
The reaction may be monitored by conventional techniques such as gas chromatography, thin layer chromatography etc or any other convenient technique known in the field of art. After it is confirmed that the reaction is complete the reaction mixture is allowed to cool slowly to room temperature.
The product may be isolated by addition of reaction solvent to an aqueous solvent, which may contain pH-modifying agents. Water is such preferred solvent, and the reaction mixture is latter neutralized with a suitable base such as sodium carbonate, liquid ammonia and the like. Latter solvents are evaporated under reduced pressure then extracted with low boiling organic solvent such as ethyl acetate, diethyl ether or methylene dichloride and the like. The residue, if needed, may be further purified by using column chromatography over a silica gel column using a solvent system containing ether, hexane, pentane, ethyl acetate, alcohols etc. or mixtures thereof. Again evaporating the solvent/s in an inert atmosphere under vacuum to obtain pure product, the structure of which is confirmed by characterizing with IR spectra, Mass spectra, NMR spectra, and melting point.
The following is the list of compounds prepared by the process of this invention,
1. N,N-dimethyl-2-(2-methylindol-3 -yl)ethylamine
2. N,N-dimethyl-2-(2,5-dimethylindol-3 -yl)ethylamine
3. N,N-dimethyl-2-(5-fluoro-2-methylindol-3-yl)ethylamine
4. N,N-dimethyl-2-(5-chloro-2-methylindol-3-yl)ethylamine
5. N,N-dimethyl-2-(5-bromo-2-methylindol-3-yl)ethylamine
6. N,N-dimethyl-2-(5-methoxy-2-methylindol-3-yl)ethylamine

7. N3N-dimethyl-2-(2-phenylindol-3 -yl)ethylamine
8. N5N-dimethyl-2-(5 -methyl-2-phenylindol-3 -yl)ethylamine
9. N,N-dimethyl-2-(5-fluoro-2-phenylindol-3-yl)ethylamine
10. N,N-dimethyl-2-(5-chloro-2-phenylindol-3 -yl)ethylamine
11. N,N-dimethyl-2-(5-bromo-2-phenylindol-3-yl)ethylamine
12. N5N-dimethyl-2«(5-methoxy-2-phenylindol-3-yl)ethylamine
13. N,N-dimethyl-2-{5-(l,3-xazolidine
The present will now be described with reference to the following e illustrative examples which should not be construed as the limiting scope of this invention.
EXAMPLES EXAMPLE 1 : Preparation of N,N-dimethyI"2-(2-methylindol-3-yl)ethylamine
In a reaction flask provided with Dean-Stark apparatus, 10.8 g of phenyl hydrazine, 15.48 g of N,N-dimethyl-4-oxo pentanamine, and 150 mL of toluene was charged under an inert atmosphere. Latter 55.6 g of ortho phosphoric acid is added. The reaction mixture was then refluxed for 4 hrs by continuous stirring while monitoring the reaction and the temperature continuously. After completion, the reaction mixture was cooled and diluted with 200 mL water and pH was adjusted to about 10 -11 using aqueous ammonia solution at low temperatures. The product was extracted with ethyl acetate 2 x 75 mL; organic layer washed with brine 1 x 30 mL and dried over anhydrous magnesium sulfate and the solvent was evaporated to dryness under reduced pressure. The residue was triturated with n-hexane and the separated solids are collected by filtration and chromatographed over a column of silica gel by elution with the ethyl acetate : methanol (9:1) to get the title compound 15.8 g, 75.15 %), melting range: 96-98 °C.
The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1.
EXAMPLE 2:
Preparation of N,N-dimethyl-2-(2,5-dimethylindol-3-yI)ethylamine
To a reaction flask containing 150 mL aqueous sulforic acid (10 %), warmed to 50-60 °C, under an inert atmosphere, 3.05 g of p-methylphenyl hydrazine was added. Latter the temperature was heated to 90 °C, 3.89 g of N,N-dimethyl-4-oxo-pentarnine was added drop-wise within 15 minutes. The

reaction mixture was then refluxed for 4-5 hrs by continuous stirring while monitoring the reaction and the temperature continuously. After completion, the reaction mixture was quenched in 40 mL water and raised to the pH of about 10 using aqueous ammonia solution at low temperatures. The product was extracted with ethyl acetate 2 x 25 mL; organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated to dryness under reduced pressure. The residue was chromatographed over a column of silica gel by elution with the ethyl acetate : methanol (9:1) to get the title compound (3.09 g, 57.65 %), melting range: 126-129 °C (uncorrected).
The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1.
EXAMPLE 3 :
Preparation of N,N-dimethyI-2"(5-fluoro-2-methyIindoI-3-yI)ethyIamine
4-Fluorophenyl hydrazine was used and the procedure as given in example 2 is followed to obtain the title compound.
The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data was given in Table 1.
EXAMPLE 4:
Preparation of N,N-dimethyl-2-(5-chloro-2-methylindol-3-yl)ethylamine
4-Chlorophenyl hydrazine was used and the procedure as given in example 2 is followed to obtain the title compound.
The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data was given in Table 1.
EXAMPLE 5 :
Preparation of N,N,-dimethy-2-2(5-bromo-2-methyIindol-3-yl)ethyIamine
4-Bromophenyl hydrazine was used and the procedure as given in example 1 is followed to obtain the title compound.
The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1.

EXAMPLE 6 :
Preparation of N,N-dimethyl-2-(5-methoxy-2-methylindol-3-yl)ethylamine
To a reaction flask, 9 mL acetic acid, 14 g of p-methoxyphenylhydrazine hydrochloride and 10.32 g of N3N-dimethyl-4-ox.o pentanamine hydrochloride were added, under an inert atmosphere and die reaction mixture was warmed slowly till temperature reached 40-50 °C. After consumption of the reactants, a mixture of 9 mL acetic acid and 4 mL sulfuric acid were added dropwise, keeping the temperature below 60 °C, while continuously stirring the reaction mixture in about half an hour. Later, , the reaction mixture was refluxed for about 3 to 4 hours, and continuously monitoring reaction and temperature. After the reaction was complete, the mixture was poured to 90 mL ice-cold water and the pH was adjusted to about 10 using sodium carbonate. The product was extracted with 2 x 50 mL methylene dichloride. The organic solution was dried over sodium sulfate and the solvent is evaporated to dryness under reduced pressure. The residue was chromatographed over a column of silica gel and eluted with ethyl acetate to get the title compound (14.5 g, yield = 78.2 %, melting range : 89 °C to 90 °C (uncorrected), purity = 98.5 % by HPLC).
The product obtained is characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1.
EXAMPLE 7 : Preparation of N,N-dimethyl-2-(2-phenylindol-3-yl)ethyIamine
To a reaction flask provided with Dean-Stark apparatus, 2.16 g of phenyl hydrazine, 3.8 g of N,N-dimethyl-4-oxo-4-phenyl butanamine, 12 g of ortho phosphoric acid and 50 mL of toluene were charged under an inert atmosphere. The reaction mixture was then refluxed for 4 hrs by continuous stirring and removing water azeotropically, monitoring the reaction and the temperature continuously. After completion, the reaction mixture was cooled and diluted with 50 mL water. The toluene layer was separated and recycled. The pH of the bottom aqueous layer was adjusted to about 10-11 using saturated sodium carbonate solution. The product was extracted with ethyl acetate 2 x 25 mL; organic layer washed with brine 1 x 30 mL and dried over anhydrous magnesium sulfate and the solvent is evaporated to dryness under reduced pressure. The residue was triturated with n-hexane and the separated solids were dried. The compound obtained weighs 4.1 g (77.65 %), melting range: 112 -
The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1.

EXAMPLE 8:
Preparation of N,N-dimethyl-2-(5-methyI-2-phenyIindoI-3-yI)ethyIamine
4-Mcthylphenyl hydrazine was used and procedure given m example 7 is followed Lu obtain the title compound.
The product obtained was characterized by IR spectra NMR spectra and Mass spectra. The corresponding data was given in Table 1.
EXAMPLE 9:
Preparation of N,N-dimethyI-2-(5-fluoro-2-phenylindol-3-yI)ethylamine
To a reaction flask provided with a Dean Stark apparatus, 3.17 g orthophosphoric acid, 1.0 g of p-Fluorophenyl hydrazine l/2sulphate and 1.0 g of N,N-dimethyl-4-oxo-4-phenylbutanamine and toluene (25 mL) were added, under an inert atmosphere and the reaction mixture was heated to reflux. Latter, the reaction mixture was refluxed for about 4 to 5 hours. After completion of reaction, the toluene layer was separated and the residue was triturated with 30 mL water and the pH of aqueous layer was adjusted to about 10 using sodium carbonate. The product was extracted with 2 x 20 mL methylene dichloride. The organic solution was dried over sodium sulfate and the solvent was evaporated to dryness under reduced pressure. The residue was chromatographed over a column of silica gel and eluted with the ethyl acetate to get the title compound (1.32 g, yield = 82 %, melting range : 104 °C to 105 °C (uncorrected)).
The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1.
EXAMPLE 10;
Preparation of N,N-dimethyl-2-(5-chloro-2-phenylindoI-3-yl)ethylamine
4-Chlorophenyl hydrazine was used and procedure given in example 7 was followed to obtain the title compound.
The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1.
EXAMPLE 11:
Preparation of N,N-dimethyl«2-(5rbromo-2-phenylindoI-3-yI)ethyIamine
4-Bromophenyl hydrazine was used and procedure given in example 7 is followed to obtain the title compound.

The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1.
EXAMPLE 12:
Preparation of N,N-dimethyl-2-(5-methoxy-2-phenylindoI-3-yl)ethylamine
4-Methoxyphenyl hydrazine was used and procedure given in example 6 is followed to obtain the title compound.
The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1.
EXAMPLE 13: Preparation of N,N-dimethyl-2-{5-(l,3-oxazoIidine-2.one-4-yI-methyI)-2-methylindol-3-yl}ethylamine
The corresponding hydrazine derivative was used and procedure given in example 7 was followed to obtain the title compound.
The product obtained was characterized by IR spectra^ NMR spectra and Mass spectra. The corresponding data is given in Table 1.


WE CLAIM:
1. A "Fischer Indole synthesis" process for the preparation of compounds represented by the general formula I,

which comprises of reacting a phenyl hydrazine of the formula (II) or its salt represented by the formula (IF), each of which has at-least one orther-position unsubstituted,

with a ketone amine represented by the formula (III), in "one pot" along with an acidic catalyst i.e., phosphoric acid and its derivatives and organic solvent such as tolouene, xylene;
wherein,
R represents hydrogen, C1-C4 alkyl;
R1represents C1,C4 alkyl, (C3-Cl4)cyc1on1kyl;
R2 represents C1-C4 alkyl;
R3 represents hydrogen, C1-C4 alkyl;
R5 represents either same or different substitutents such as hydrogen, halogen, hydroxy, -X-Rg (X
= -O-, -NH-, -S-), nitro, amino;
R6 represents hydrogen, C1-C4 alkyl;
R10 and R11 each independently represents hydrogen, halogen, C1C4 alkyl, C1C4 haloalkyl, aryl,
ar(C1-C4)alkyl, hydroxyl, -X-R (X = O, NH, S), nitro, amino, -NR1R2, trifluoromethyl,
trifluoromethoxy, n is 1 to 4 and relates only to carbon atoms;

said process characterised by a)of a reaction vessel having not more than 15 volumes of organic solvent (having boiling point more than 100° C) b) in the presence of phosphoric acids as a acidic catalyst c) the complete conversion of reactant to product is over within 6 hours wherein water formed in the reaction is removed using any suitable method preferably either azeotrophic distillation or molecular sieves.
2. The process as claimed in claim 1, wherein in said compound of formula (HI), R2 and R3 each independently include, C1-C4 alkyl, exemplified by methyl, ethyl, isopropyl, butyl, sec-butyl, tert-butyl and iso-butyl.
3. The process as claimed in claim 1 or 2 , wherein R4 is hydrogen, C1-C4 alkyl; wherein R$ is hydrogen or C1-C4 alkyl..
4. The process as claimed in claim 3,, wherein R4 is hydrogen, C1-C3 alkyl; wherein
R6 is preferably hydrogen and C1C3 alkyl.
5. The process as claimed in claim 4, wherein R4 and R6 both together are hydrogen.
6. The process as claimed in any preceding claim , wherein said compound of formula (II) or its salt (IF)comprises a hydrochloride salt, hydrobromide salt, salts of H2SO4, HNO3, or H3PO4.
7. The process as claimed in any preceding claim, wherein the compound of formula (II) or its salt (IF) and the compound of formula (III) are present in 1: 1 molar ratios to 1:5 molar ratio of each other.
8. The process as claimed in claim 1, wherein the said acid catalyst includes phosphoric acid, orthophosphoric acid, and polyphosphoric acid.
9. The process as claimed in claim 8, wherein the preferred acid catalyst is orthophosphoric acid.
10. The process as claimed in claim 9, wherein the concentration of said acid is 1 to 100 %. The process as claimed in claim 1, wherein the preferred acid is in mole ratio of 1 to 10 mole equivalents per mole of ketone amine.
11. The process as claimed in claim 12, wherein the preferred acid is in mole ratio of 1 to 6 mole equivalents per mole of ketone amine.
12. The process as claimed in any preceding claim, wherein the solvent of Ihe reaction is selected from toluene, xylene, chloroform and the mixtures thereof.
13. The process as claimed in any preceding claim , wherein the reaction of said compound of formula (II) and the said compound of formula (III) is conducted at a temperature of 60 °C to the reflux temperature of the solvent mixture used.
14. The process as claimed in any preceding claim , wherein water formed in the reaction is removed by azeotrophic distillation, molecular sieves or Molecular sieves.
15. The process as claimed in claim 1, wherein the compound of formulae (I) is selected from:

i. N,N-dimethyl-2-(2-methylindol-3-yl)ethylamine ii. NsN-dimethyl-2-(5-bromo-2-methylindol-3-yI)ethylainine
iii. N,N-dimethyl-2-(2-phenyIindol-3-yl)ethylaniine
iv. N,N-dimethyl-2-5-methyl-2-phenylindoI-3-yl)ethyIamine
v. N,N-dimethyl-2-(5-fluoro-2-phenylindol-3-yl)ethylamine
vi. N,N-dimethyl-2-(5-chloro-2-henylindol-3-yl)ethylamine
vii, N,N-dimethyl-2-(5-bromo-2-phenylindoI-3-yl)ethylamine
viii. N,N-imethyl-2-{5-1,3-xazolidine-2K)ne-4-yl-methyl)-2-mcthylindol-3-yl}ethylamine.
16. The process as claimed in claim 1, wherein R10 is hydrogen, fluorine, chlorine, bromine or iodine; methyl, methoxy, trifluoromethyl, trifluoromethoxy, benzyloxy or l,3-oxazolidine-2-one- 4-yl-methyL
17. The process as claimed in any preceding claim, wherein the said compound of formula (III) is selected from , N,N-dimethyl-4-oxo-pentanamine, N,N-diethyl-4-oxo-pentanamine, N- methyl,N*-ethyl-4-oxo-pentanamine, N,N,2-trimethyl-4-oxo-pentanamine, N,N,3-trimethyl-4-oxo- pentanamine, N,N,2-triethyl-4-oxo-pentanamine, N,N-dimethyl benzoylpropanamine, N,N-diethyl benzoylpropanamine,
18. The process a any preceding claim, wherein the said compound of formula (II) is selected from , phenyl hydrazine, 4-methylpheriyI hydrazine, 4-ethylphenyl hydrazine, 4-propylphenyI hydrazine, 4-methoxyphenyl hydrazine, 2,5-dimethyIphenyl hydrazine, 3,4-dimethyIphenyl hydrazine, 4-ethoxyphenyl hydrazine, 4-benzyIoxyphenyl hydrazine, 4-chlorophenyI hydrazine, 4- bromophenyl hydrazine, 4-fluorophenyl hydrazine, 4-iodophenyI hydrazine, 5-chloro-2- methylphenyl hydrazine, 4-(l-(l,3-oxazolidine-2-one-4-yl)methylene)phenyl hydrazine and 2,4- dichlorophenyl hydrazine.
Dated this the 14th day of November 2006