FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
COMPLETE SPECIFICATION
(SECTION 10)
A Process for the Preparation of 7-Formyl-indole
Glenmark Pharmaceuticals Limited an Indian Company, registered under the Indian company's Act 1957 and
having its registered office at B/2, Mahalaxmi Chambers 22, Bhulabhai Desai Road
Post Box No. 26511 Mumbai- 400 026, India
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION: AND THE MANNER IN, WHICH IT IS TO BE PERFORMED


Field of the Invention:
The present invention relates to process for the preparation of 7-formyl Indole of the formula I

Background of the Invention:
7-formyl-indole of the formula 1 is an important intermediate of several molecules with varying therapeutic efficiencies such as the Leukotriene antagonists (LTD4 antagonist) namely LY-302905 (US 5486612 to Eli Lilly and company) of the formula II which is in pre clinical trials.

II
III
The compound of formula I is also a useful intermediate in the preparation of some protein kinase inhibitors (WO 200075139 to BASF AG) of the formula III


Where q is -N=or CR2; X is S, O or NOR3; Y is -0-, -S-, -SO- or -S02-; R and R1 are each, independently H, a substituted or unsubstituted aliphatic, aromatic, heteroaromatic or aralkyl group R2 is H or a substitutent; R3 is H, or -C(0)R4; R4 is a substituted or unsubstituted aliphatic or aromatic group; n is an integer from 0 to 1.
The use of the compound of formula I as an intermediate is also known in the preparation of carbazole compounds (WO 0144247 to Eli Lilly and company, USA), These references are only a few to mention which clearly indicate the versatile utility of 7-formy-indole of the formula I.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to a new process for preparing 7-formyl-indole which comprises of synthetic steps shown in Scheme 6. In another aspect, the invention relates to usage of starting material of the formula 13 and intermediates of the formulae 14,15,16,17, and 19 in the process for the preparation of 7-formyl-indole of the formula I
PRIOR ART
There are a few reported methods for the synthesis of the compound of formula I.
(1) first method for the preparation of compound of formula I has been reported in Chem.
Pharm. Bull, Jpn., 4116, 34 (1986) is shown below in Scheme 1:


Scheme 1
This method consists of condensation of methyl 3-methyl-2-nitrobenzoate (1) with N,N-dimethyl formamide dimethyl acetal and subsequent reduction of the resulting 3-carbomethoxy-2-nitro-[3-aminostyrene (2) with titanium (III) chloride to produce the corresponding 7-carbomethoxyindole (3) in 57% yield. Reduction of 3 with lithium aluminum hydride followed by oxidation of the resulting benzyl alcohol (4) with manganese dioxide yielded 7-formyl-indole (I) in 64% yield. The major disadvantages of this process are as follows:
1. The source of 3-methyl-2-nitrobenzoate (1) was not disclosed. To our knowledge, it is not available commercially. One possibility of obtaining this starting material is via esterification of expensive but commercially available 3-methyl-2-nitro-benzoic acid [CAS No. 5437-38-7, Aldrich Cat. No. M6,040-6, US $43.60/25 g) of the formula 18.
2. Although yields appear to be good, it is a multi-step process and uses expensive starting materials and reagents.
3. Handling of reagents such as titanium(III) chloride or lithium aluminum hydride on a large scale would be expensive and hazardous.
(2) second method of making I [as reported in J. Org. Chem., 5106, 5J_ (1986)] is shown below in Scheme 2:


Scheme 2
This method consists of condensation of 3-bromo-2-nitrotoleune (5) with N,N-dimethyl formamide dimethyl acetal and subsequent reduction of the resulting 3-bromo-2-nitro-P-aminostyrene (6) with zinc in acetic acid yielded the corresponding 7-bromoindole (7) only in 29% yield. Lithiation of 7 followed by treatment with DMF yielded 7-formyl-indole (I) in 61% yield. The major disadvantages of this process are as follows:
1. The starting material of the formula 5 is not easily accessible
2. Handling of Potassium hydride and tert-butyllithium in large scale is expensive and hazardous.
3. Creation of low temperatures up to -78 °C on large scale synthesis is difficult and expensive.
(3) third method of making I [as reported in Synlett., 79-80 (1992)] is shown below in Scheme 3:

This method consists of treatment of ortho-bromo-nitrobenzene of the formula 9 with vinylmagnesium bromide to afford 7-bromoindole of the formula 7, which was converted to 7-formyl-indole of the formula I by following the procedure (with a slight modification) described

,nd
in the 2 method. Obviously, the major disadvantages of this process are as follows:

1 Handling of sodium hydride and butyllithium in large scale is expensive and hazardious.
2 Creation of low temperatures up to -78 °C on large scale preparation is difficult and expensive
(4) fourth method of making I [as reported in Synlett., 79-80 (1992)] is shown below in Scheme 4:

R,R (yield): -CH2CH2- (23%); -CH2CHPh- (35%); (CH3)2 (44%); (n-C5Hu)2 (39%); (n-C4H9)2 (68%)
Scheme 4

This method involves the conversion of ortho-nitrobenzaldehyde of the formula 9 to the corresponding dialkyl acetal of the formula 11 and treating the same with vinylmagnesium bromide to yield an intermediate (not identified) which upon treatment with aqueous hydrochloric acid/ tetrahydrofuran, afforded 7-formyl-indole (I) in 23-68% yields. The major disadvantage(s) of this process are as follows:
1. Low yields of 7-formyl-indole of the formula I
2. Usage of vinylmagnesium bromide in large-scale preparation is expensive and hazardous.
3. Creation of low temperatures up to -65 °C on large-scale preparation is difficult and expensive
(5) The fifth method of making 7-formyl-indole of the formula I [as reported in Helv. Chim. Acta., 5_1, 1616-1628 (1968)] is shown below in Scheme 5:

Scheme 5
This method involves conversion of 7-cyanoindole of the formula 12 to the corresponding 7-formyl-indole of the formula I using Nickel & Sodium hypophiosphite. Although this seems to be a promising approach, the limiting factor would the difficult to accessible starting material of the formula 12 which has to be synthesized first.
OBJECTIVES OF THE INVENTION:
In view of the potential usage of 7-formyl-indole of the formula I, as evident from the presence of analogous 7-subtituted-indoles in many potential drug candidates which are in various stages of clinical development, we developed a new process for the preparation of 7-formyl-indole of the formula I.

The primary objective of the present invention is to develop an efficient new process that is amenable to large-scale production of 7-formyl-indole of the formula I.
Another objective of the present invention is to utilize readily available/easily accessible starting materials and reagents in the process for the preparation of 7-formyl-indole of the formula I.
Yet another objective of the present invention is to avoid the usage of air-, and moisture-sensitive and expensive organometalhc reagents in the process for the preparation of 7-formyl-indole of the formula I.
Yet another objective of the synthesis is to avoid the usage of extremes in reaction temperatures (<-30 °C & >150 °C) in the process for the preparation of 7-formyl-indole of the formula I.
Also, another prime objective of this invention is to use 2-nitro-w-xylene of the formula 13 in the process for the preparation of 7-formyl-indole of the formula I.
Yet another objective of this invention is to use 3-methyl-2-nitrobenzaldiacetate of the formula 14 in the process for the preparation of 7-formyl-indole of the formula I.
Yet another objective of this invention is to use 3-methyl-2-nitrobenzaldehyde of the formula 19 in the process for the preparation of 7-formyl-indole of the formula I.
Yet another objective of this invention is to use 3-methyl-2-nitrobenzaldehyde dimethyl acetal of the formula 15 in the process for the preparation of 7-formyl-indole of the formula I.
Yet another objective of this invention is to use ?rans-P-pyrrolidino-3-dimethoxymethyl-2-nitrostyrene of the formula 16 in the process for the preparation of 7-formyl-indole of the formula I.
Yet another objective of this invention is to use 7-dimethoxyindole of the formula 17 in the process for the preparation of 7-formyl-indole of the formula I.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides an efficient process for the preparation of 7-formyl-indole of the formula I as shown below in Scheme 6:

Scheme 6
Thus, the method comprises of the following five steps:
• Step 1: One methyl group of 2-nitro-m-xylene of the formula 13 was selectively oxidized with readily available chromium trioxide in acetic anhydride to afford 3-methyl-2-nitro-benzaldiacetate of the formula 14 in 25-38% yields along with small amounts of over-oxidized product, 3-methyl-2-nitrobenzoic acid of the formula 18.
Oxidation of one methyl group in 2-nitro-w-xylene of the formula 13 can be done with other known oxidizing agents and the reaction can be performed in the presence of any acid anhydride ((RCO)2O, R = lower alkyl or aryl) to yield the corresponding compounds of the formula 14-G, where R = lower alkyl or aryl.


• Step 2: The benzaldiacetate of the formula 14 was converted directly to 3-methyl-2-nitro-benzaldehyde dimethyl acetal of the formula 15 in 59-96% yields by refluxing a methanolic solution of compound of the formula 14 in trimethyl orthoformate (10 eqs.) in the presence of p-toluenesulfonic acid (0.25 eq.) for 4.5 h. Formation of a small amount of methyl tosylate was also observed during the reaction.
Alternatively, the dimethyl acetal of the formula 15 was made in two steps from the compound of the formula 14. Thus, the compound of the formula 14 was first hydrolyzed in refluxing dilute hydrochloric acid to afford 3-methyl-2-nitrobenzaldehyde of the formula 19, which on refluxing in trimethyl orthoformate (10 eqs.) and methanol containing catalytic amount of P-toluenesulfonic acid yielded the dimethyl acetal of the formula 15. To our knowledge, no one has synthesized compounds of the formulae 14,15, and 19 starting from the compound of the formula 13. However, there is a known method [as reported in J. Heterocyclic Chem., 897, 23 (1986)] of synthesis of the compound of formula 19, which consists of conversion of 3-methyl-2-nitrobenzoic acid of the formula 18 to the compound of the formula 19 in three steps via the intermediate 3-methyl-2-nitrobenzyl alcohol of the formula 20 as shown below in the Scheme 7.


The 3-methyl-2-nitro-benzaldehyde dimethyl acetal of the formula 15 can be made from either the compound of the formula 14 as shown above in Step 1 or from 3-methyl-2-nitrobenzladehyde of the formula 19 as mentioned above in Step 2. Alternatively, any lower-dialkylacetals of the formula 15-G can be utilized in the synthesis or obtaining similar or even better yields in the remaining steps of process for making 7-formyl-indole of the formula I.

N02 RCT "OR R = lower-alkyl/ cycloalkyl/aralkyl
15-G
The 3-methyl-2-nitrobenzladehyde of the formula 19 can be made either by the two methods mentioned above or by a potential alternative route as shown below in Scheme 8.


13
Scheme 8 Thus, selective benzylic halogenation of one methyl group of 2-nitro-w-xylene of the
formula 13 using N-halosuccinimide would give the corresponding benzyl halide of the
formula 21, which on oxidation with hexamethylenetetramine (HMTA) in the presence of
aqueous acetic acid should give the aldehyde of the formula 19.
Step 3: The 3-methyl-2-nitro-benzaldehyde dimethyl acetal of the formula 15 was condensed
with N,N-dimethylformamide dimethyl acetal in DMF in the presence of pyrrolidine to
afford the corresponding frans-P-pyiTolidino-3-dimethoxymethyl-2-nitrostyrene of the
formula 16 in 53-70% yields. This reaction can also be conducted in the absence of
pyrrolidine to yield the corresponding trans-P-dimethylamino-3-dimethoxymethyl-2-
nitrostyrene of the formula 16. Alternatively, any di-lower alkyl/aralkyl acetal of the
formula 15-G can be condensed with any other N,N-di-

loweralkyl/cycloalkyl/aralkylformamide di-loweralkyl/aralyl acetals to afford the corresponding di-loweralkyl/aralkyl acetal of the formula 16-G. where R1 and R2 together form a C2-C7 cyclic ring

•


RO OR
R = R1 = R2 = Hydrogen, Lower alkyl, Cycloalkyl, or Arylalkyl
16-G
Step 4: The enamine of the formula 16 was reduced with Raney-Nickel in 1:1 THF/MeOH in the presence of hydrazine hydrate (1.5 eqs.) to afford the corresponding 7-dimethoxymethyl-indole of the formula 17 in 61-83% yields. Alternatively, other known reducing agents and catalysts can be in this transformation. Alterantively, usage of an acetal of the formula 15-G would give the corresponding 7-di-alkoxy/cycloalkoxy/aryloxy-methyl-indole of the formula 17-G.


RO OR R = lower-alkyl/ cycloalkyl/aralkyl
17-G
Step 5: The 7-dimethoxymethyl-indole of the formula 17 was subjected to mild hydrolysis condition (a brief treatment with 0.5 M HC1) to afford the corresponding 7-formyl-indole (~99% pure by HPLC) of the formula I in 91-96% yields. Similarly, any other acetal of the formula 17-G would give 7-formyl-indole of the Formula I. Alternatively, any other suitable mild hydrolytic condition can be used to convert 7-dimethoxymethyl-indole of the formula 17 to the corresponding 7-formyl-indole of the formula I.

The present invention is described in detail 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.
Example 1:
Preparation of 3-methyl-2-nitrobenzaldiacetate of the formula 14:
A mixture of 140 ml (151.48 g, 1.48 mol) of acetic anhydride (Thomas Baker, Lot No. PK/21/509/629-99/19) and 20 g (132 mmol) of 2-nitro-m-xylene (13, Lancaster, Batch No. 10048246) was placed in a 1-L, three necked flask equipped with a mechanical stirrer, dropping funnel, and a thermometer and the mixture was cooled to 0 °C . To this stirred solution was slowly added 29.3 ml (550 mmol) of concentrated sulfuric acid over a period of 20 min so that the temperature of the mixture remained below 5 °C. In the meantime, a cold solution of chromium trioxide (36.35 g, 366.6 mmol) in 97 ml of acetic anhydride was prepared by slowly dissolving small portions of chromium trioxide in pre-cooled acetic anhydride. This pre-cooled chromic acid solution was slowly added to the main reaction mixture over a period of 90 min while maintaining the mixture temperature between -10 °C and 0 °C. The mixture was then stirred at 0-5 °C for 1 h when TLC analysis of the mixture indicated >90% conversion. Stirring of the mixture beyond lh after the addition of chromic acid solution led to further oxidation to give varying amounts of 3-methyl-2-nitrobenzoic acid of the formula 18, which was isolated and identified (its proton-NMR data and melting point are given below).
The mixture was slowly poured into a beaker containing 1300 ml of crushed ice and the contents were stirred on magnetic stirrer for 20-25 min when the crude product was separated as a yellow sticky solid which was extracted with ethyl acetate (3 x 200 ml & 2 x 100 ml). The organic extracts were combined, washed with 1:1 mixture of saturated solutions of sodium bicarbonate and brine (4 x 100 ml), brine (4 X 150 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford the crude product as a yellow semi-solid (-80% pure by TLC). The crude product was purified by column chromatography using 5% ethyl acetate in petroleum ether as eluent to obtain a pure diacetate of the formula 14 as a light yellow solid, mp: 81-83 °C. Rf-: 0.35 (4:1 petroleum ether/ethyl acetate).

'H-NMR of diacetate of the formula 14 (300 MHz, CDC13): 5 2.11 (s, 6H, (OCOCH3)2), 2.35 (s, 3H, CH3), 7.33-7.38 (m, lHarom), 7.41 (d, 2Harom, J = 4.8 Hz), 7.72 (s, lHmethine)
1H-NMR of benzoic acid derivative of the formula 18 (300 MHz, CDC13): 8 2.27 (s, 3H, CH3), 7.58 (unsymmetrical t, 1Harom, J = 7.8 Hz & 7.5 Hz), 7.68 (d, lHarom, J = 7.5 Hz), 7.82 (d, lHarom, J = 7.8 Hz). M.P.: 220-222 °C (reported6: 220-222.5 °C)
Example 2:
Preparation of 3-methyl-2-nitrobenzaldehyde dimethyl acetal of the formula 15:
Triethyl orthoformate (53.38 ml, 488 mmol, 10 eqs.) and p-toluenesulfonic acid (2.32 g, 12.2 mmol, 0.25 eq.) were added to a stirred solution of diacetate of the formula 14 (13.03 g, 48.8 mmol, 1 eq.) in 60 ml of anhydrous methanol at RT under nitrogen atmosphere, and the mixture was stirred at RT for 5 min. The reaction flask was then placed in an oil bath that was pre-heated to 70 °C. The mixture was refluxed at that temperature for 4.5 h when TLC of the mixture indicated completion of the reaction with the formation of dimethyl acetal of the formula 15 as the major product (>90%) along with a minor product (<10%) that was isolated and characterized as methyl-p-toluenesulfonate.
The mixture was concentrated in vacuo and the reddish yellow colored oily residue thus obtained was re-dissolved in ethyl acetate (250 ml). The organic layer was washed with saturated sodium bicarbonate (100 ml), brine 92 x 100 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo to give 14.6 g of crude product as a yellow oil. The crude product was purified by column chromatography using 1:9 ethyl acetate/petroleum ether as eluent (added 0.1% triethylamine as stabilizer to the eluent), to afford 9.93 g (96.5%) of pure dimethyl acetal of the formula 15 as a light yellow oil. Rf. 0.56 (4:1 petroleum ether/ethyl acetate).
'H-NMR of dimethyl acetal of the formula 15 (300 MHz, CDC13): 5 2.32 (s, 3H, CH3), 3.33 (s, 6H, (OCH3)2), 5.56 (s, lHmethine), 7.26 (d, lHarom, J = 7.5 Hz), 7.37 (t, lHarom, J = 8.1 Hz & 7.5 Hz), 7.51 (d, lHarom, J = 7.8 Hz)

Example 3:
Preparation of 3-methyl-2-nitrobenzaldehyde of the formula 19:
To a stirred solution of benzaldiacetate of the formula 14 (0.25 g, 0.94 mmol) in 0.5 ml of ethanol at RT was added 2.18 ml of water andl.32 ml of cone, hydrochloric acid. The mixture was stirred at RT for 5 min and at reflux temperature (oil bath temperature at 75-80 °C) for 40 min when TLC analysis of the mixture indicated completion of the reaction. The mixture was cooled in ice bath and separated light yellow precipitate was filtered. The precipitate was washed with cold water (4 ml) and dried in vacuum desiccator. The product of the formula 19 was obtained as light yellow solid, mp: 58-60 °C "(reported5: 59-61 °C); yield: 108 mg (70%).
'H-NMR of aldehyde of the formula 19 (300 MHz, CDC13): 5 2.41 (s, 3H, CH3), 7.57 (unsymmetrical d, 2Harom, J = 4.8 Hz), 7.76-7.81 (m, lHarom), 9.93 (s, lHaidehyde); M.P.: 58-60 °C
Example 4:
Preparation of 3-methyl-2-nitrobenzaldehyde dimethyl acetal of the formula 15:
A mixture of 3-methyl-2-nitrobenzaldehyde of the formula 19 (90 mg, 0.55 mmol), trimethyl orthoformate (0.5 ml), and p-toluenesulfonic acid (5 mg) in anhydrous methanol (0.6 ml) was stirred at RT for 5 min and at reflux temperature (oil bath temperature at 75-80 °C) for 1.5 h when TLC of the mixture indicated completion of the reaction. The mixture was cooled to RT and basified with saturated sodium bicarbonate and extracted with ethyl ether (2x10 ml). The ether extracts were combined, washed with 1:1 mixture of saturated sodium bicarbonate and brine (2x5 ml), brine (3x10 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford dimethyl acetal of the formula 15 as a light yellow oil, yield: 112 mg (97%). 'H-NMR of this sample is identical to that obtained in Example 2.
Example 5:
Preparation of rra/is-P-pyrrolidino-3-dimethoxymethyl-2-nitrostyrene of the formula
16:

A mixture of dimethyl acetal of the formula 15 (12.3 g, 58 mmol), N,N-dimethyl formamide dimethyl acetal (14.2 ml, 108 mmol, 1.86 eqs., Lancaster Lot No. S29698945) and pyrrolidine (8.9 ml, 108 mmol, 1.86 mmol, Lancaster Lot No. S31566109) in 40 ml DMF was placed in a 250-ml RB flask equipped with a reflux condenser. The reaction flask was then placed in an oil bath preheated to -130 °C. With in 10 min of heating and stirring, the mixture changed colors from yellow to red to black. The temperature of the bath was raised to 140-145 °C and the mixture was stirred and refluxed at that temperature for 4 h when TLC analysis of the mixture indicated about 50% conversion. Another portion of pyrrolidine (8.9 ml, 108 mmol) was added to the mixture and it was further stirred and refluxed at 140-145 °C for 3 h when TLC analysis of the mixture indicated completion of the reaction. The mixture was concentrated in vacuo to give a black solid residue, which was triturated with 20 ml of cold methanol and filtered. The red-colored precipitate was washed with 10 ml of cold methanol and dried the material in vacuum desiccator. The pure product of the formula 16 was obtained as a red shinning crystals, m.p: 85-88 °C; Yield: 11.6 g (68.2%); Rf: 0.21 (1:4 ethyl acetate/petroleum ether).
'H-NMR of enamine of the formula 16 (300 MHz, CDC13): 5 1.85-1.95 (m, 4H, N(CH2CH2)2), 3.20-3.28 (m, 4H, N(CH2CH2)2), 3.31 (s, 6H, (OCH3)2), 4.84 (d, lHvinyiic, J -13.2 Hz), 5.50 (s, lHmethine), 7.09 (d, lHvinylic, J = 13.2 Hz), 7.15-7.26 (m, 2Harom), 7.35 (dd, lHarom,J=1.2,7.5Hz)
Example 6;
Preparation of 7-dimethoxymethyl-indole of the formula 17:
To a stirred solution of 7 g (23.9 mmol) of trans-P-pyrrolidino-3-dimethoxymethyl-2-nitrostyrene of the formula 16 in 66 ml of 1:1 methanol/THF was added Raney-Ni (1.4 g,) under nitrogen atmosphere followed by the first installment of hydrazine hydrate (1.75 ml, 35.9 mmol, 1.5 eqs.) (Note: Addition of hydrazine hydrate should be done slowly to control the exothermic reaction. Towards the end of the addition, the mixture temperature rises to about 50 °C. Stirring was continued and after 30 min, 2nd installment of hydrazine hydrate (1.75 ml) was added. The mixture was stirred for another 15 min when the red-colored mixture turned to amber green, and TLC of the mixture indicated completion of the reaction.

The mixture was cooled to RT and filtered through celite bed and the catalyst was washed several times with methanol. The filtrate was concentrated on rotavap and the residue was re-dissolved in ethyl acetate, dried (anhydrous sodium sulfate), and concentrated in vacuo to give a thick oily residue which was purified by column chromatography using 5% ethyl acetate in petroleum ether as eluent. The pure product was obtained as a light yellow oil. Yield: 3.2 g (69.9%). Rf: 0.40 (4:1 petroleum ether/ethyl acetate).
'H-NMR of 7-dimethoxymethyl-indole of the formula 17 (300 MHz, CDCI3; & 3.38 (s, 6H, (OCH3)2), 5.68 (s, lHmethine), 6.52 (t, 1H, J = 2.4, 3.0 Hz, H-3), 7.07 (t, 1H, J = 7.5 Hz, H-5), 7.16 (d, 1H, J = 7.5 Hz, H-6), 7.19 (t, 1H, J = 2.7 Hz, H-2), 7.60 (d, 1H, J = 7.8 Hz, H-4), 9.04 (brs, lH,NHindole)
Example 7;
Preparation of 7-formyl-indole of the formula I:
2.7 ml of 0.5M HCl was added over 5 min to a pre-cooled (ice-bath) and stirred solution of 2.7 g (14.1 mmol) of 7-dimethoxymethyl-indole of the formula 17 in 22.5 ml of THF under nitrogen atmosphere and the mixture was stirred for 15 min when TLC of the mixture indicated completion of hydrolysis. The mixture was poured into 25 ml of saturated sodium bicarbonate and extracted with diethyl ether (2 x 25 ml). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 2.09 g of practically pure product (>99% pure by HPLC) as a yellow solid, mp: 86-87 °C (reported3: 86.7-87 °C); Rf: 0.50 (1:4 ethyl acetate/petroleum ether). The product was re-crystallized from petroleum ether to afford 7-formyl-indole of the formula I as yellow crystals, mp: 86-87 oC (99.6% pure by HPLC).
'H-NMR of 7-Formyl-Indole of the formula I (300 MHz, DMSO-d*): 6 6.58 (t, 1H, J = 2.4 Hz, H-3), 7.22 (t, 1H, J = 7.2, 7.8 Hz, H-5), 7.39 (t, 1H, J = 2.7 Hz, H-2), 7.72 (d, 1H, J = 7.2 Hz, H-4), 7.93 (d, 1H, J = 7.5 Hz, H-6), 10.12 (s, lHaldehyde), 11.51 (br s, 1H, NHinddole)

ADVANTAGES OF THE INVENTION:
1. The present invention discloses an efficient new process that is amenable to large-scale production of 7-formyl-indole of the formula I.
2. The present invention utilizes readily available/easily accessible starting materials and reagents in the process for the preparation of 7-formyl-indole of the formula I.
3. The present invention avoids the usage of air-, and moisture-sensitive and expensive organometallic reagents in the process for the preparation of 7-formyl-indole of the formula I.
4. The present invention avoids the usage of extremes in reaction temperatures (<-30 °C & >150 °C) in the process for the preparation of 7-formyl-indole of the formula I.

We claim:
1. A process for the preparation of 7-formyl-indole of the formula I

Which comprises:
Step 1: Selective oxidation of one methyl group of 2-nitro-w-xylene of the formula 13 with chromium trioxide in the presence of acetic anhydride/sulfuric acid to afford 3-methyl-2-nitro-benzaldiacetate of the formula 14 and 3-methyl-2-nitrobenzoic acid of the formula 18.

Step 2: Conversion of 3-methyl-2-nitro-benzaldiacetate of the formula 14 to 3-methyl-2-nitro-benzaldehyde dimethyl acetal of the formula 15. Alternatively, this process was also carried out in two-steps via intermediacy of 3-methyl-2-nitrobenzaldehyde of the formula 19.
Step 3: Condensation of 3-methyl-2-nitro-benzaldehyde dimethyl acetal of the formula 15 with N,N-dimethylformamide dimethyl acetal in DMF in the presence of pyrrolidine to afford the corresponding trans-p-pyrrolidino-3-dimethoxymethyl-2-nitrostyrene of the formula 16.


Step 4: Reduction of trans-p-pyrrolidino-3-dimethoxymethyl-2-nitrostyrene of the formula 16 to afford 7-dimethoxymethyl-indole of the formula 17.

Step 5: Hydrolysis of 7-dimethoxymethyl-indole of the formula 17 afforded the corresponding 7-formyl-indole of the formula I.
2. The process according to step 1 of claim 1, wherein the reaction is carried out at temperature range between -20 & 40 °C and over a period of 0.5-6.0 h.
3. The process according to step 1 of claim 1, wherein the acid anhydride is selected from lower alkanoic acid anhydrides, such as acetic anhydride, propionic anhydride, butyric anhydride and the like
4. The process according to step 1 of claim 1, wherein the selective oxidation of one methyl group of 2-nitro-m-xylene of formula 13 is done by any conventional oxidizing agents such as chromium trioxide, potassium permanganate and other manganese oxides.
5. The process according to step 2 of claim 1, wherein the reaction mixture is refluxed for 1-6 h, then cooled to 0-20 °C.

6. The process according to step 2 of claim 1, wherein the di-acetate of the formula 14 is refluxed in the presence of -1:1 v/v mixture of 5-10 equivalents of trialkylorthoformate/alcohol such as trimethyl orthoformate/methanol, triethylortho-formate/ethanol, tripropylorthoformate/propanol, tribenzylorthoformate/benzyl alcohol, and the like
7. The process according to step 2 of claim 1, wherein the reaction is conducted in the presence of catalytic amount of an acid such as p-toluenesulfonic acid, camphur suphonic acid, or a lewis acid or a montmorillonite clay.
8. The process according to step 3 of claim 1, wherein the reaction is conducted at temperature range of 100-160 °C and over a period of 1-6 h
9. The process according to step 3 of claim 1, wherein the compound of the formula 15 is treated with N,N-dialkylformamide dialkyl acetal in the presence/absence of secondary amines such as pyrrolidine, piperidine and the like.
10. The process according to step 3 of claim 1, wherein the reaction is carried out in the presence of a solvent such as DMF, THF and the like.
11. The process according to step 4 of claim 1, wherein the reaction is carried out at temperature range of 20-60 °C and over a period of 1-4 h
12. The process according to step 4 of claim 1, wherein the compound of the formula 16 is reduced with a known reducing agents such as titanium chloride, zinc in acetic acid and catalysts such as Raney-Nickel or Pd/C in the presence of 0-10 equivalents of hydrazine hydrate.
13. The process according to step 4 of claim 1, wherein the reaction is conducted in solvents such as THF, Methanol, or a mixture of these (~1:1) solvents.

14. The process according to step 5 of claim 1, wherein the reaction was conducted at -10 to 5 oC, and over a period of 5 min to 30 min.
15. The process according to step 5 of claim 1, the compound of formula 17 is treated with small amounts of very dilute acids such as hydrochloric acid, toluenesulfonic acid, trifluoro acetic acid and the like.
16. The process according to step 5 of claim 1, wherein the reaction is conducted in the presence of solvents such as THF, dioxane, methanol and the like
17. The process according to step 2 of claim 1, wherein the dimethyl acetal of the formula 15 is made from aldehyde of the formula 19.
18. The process according claim 17, wherein the aldehyde of the formula 19 is made from diacetate of the formula 14.
19. The process according to claim 17-18, wherein the aldehyde of the formula 19 is made directly by selective oxidation of one methyl group of 2-nitro-w-xylene of the formula 13.
20. The process according to claim 19, wherein the selective oxidation of one methyl group is done by conventional oxidizing agents such as chromium trioxide, potassium permanganate, eerie (III) ammonium nitrate (CAN) and other manganese oxides.
21. The process according to claim 19, wherein the aldehyde of the formula 19 is made by the oxidation of the corresponding benzyl halide of the formula 21, which in turn is made by selective benzylic halogenation of one methyl group of 2-nitro-m-xylene of the formula 13.


22. The process according to claim 21, wherein the benzylic mono-halogenation of 2-nitro-w-xylene of the formula 13 is done by reagents such as N-bromosuccinimide in the presence of UV light or radical initiators such as dibenzoyl peroxide and the like.
23. The process according to claim 22, the benzylic halogenation is done in solvents such as carbon tetra-halides and the like.
24. The process according to claim 21, wherein the oxidation of benzyl halides of the formula 21 to the corresponding aldehyde of the formula 19 is done by reagents such as hexamethylenetetramine (HMTA) and the like
25. The process according to claim 23, wherein the oxidation reaction is done in solvents such as acetic acid and the like
26. The process for the preparation of the compound of formula I as defined in claim 1 substantially as herein described with reference to Example 1-7.