Title of Invention	A PROCESS FOR THE PREPARATION OF 1,2,3,4-TETRAHYDRO-ß-CARBOLINE DERIVATIVES
Abstract	The present invention relates to a process for the production of 1,2,3,4-tetrahydro-ß-carboline derivatives. The invention provides a novel, simple and effective molecular iodine catalyzed process for the production of 1,2,3,4-tetrahydro-p-carboline derivatives, which comprises tryptamine, substituted aldehyde, molecular iodine and the reaction was carried out by stirring tryptamine and an aldehyde in the presence of catalytic amount of molecular iodine at room temperature and after completion, the solvent was removed under reduced pressure and the crude product was purified by column chromatography to afford pure 1,2,3,4-tetrahydro-p-carboline derivatives.

Title of Invention

A PROCESS FOR THE PREPARATION OF 1,2,3,4-TETRAHYDRO-ß-CARBOLINE DERIVATIVES

Abstract

The present invention relates to a process for the production of 1,2,3,4-tetrahydro-ß-carboline derivatives. The invention provides a novel, simple and effective molecular iodine catalyzed process for the production of 1,2,3,4-tetrahydro-p-carboline derivatives, which comprises tryptamine, substituted aldehyde, molecular iodine and the reaction was carried out by stirring tryptamine and an aldehyde in the presence of catalytic amount of molecular iodine at room temperature and after completion, the solvent was removed under reduced pressure and the crude product was purified by column chromatography to afford pure 1,2,3,4-tetrahydro-p-carboline derivatives.

Full Text	FIELD OF THE INVENTION The present invention relates to a process for the production of 1,2,3,4-tetrahydro-β-carboline derivatives. More particularly it relates This new process involves the preparation of various substituted tetrahydro-p-carbolines, by the Pictet-Spengler condensation of tryptamine with aldehydes catalysed by molecular iodine represented as: (Formula Removed) wherein, R is C6H5, p-NO2C6H5, p-CIC6H5, p-BrC6H5, p-MeOC6H4, or benzopyranyl groups. BACKGROUND OF THE INVENTION The tetrahydro-p-carboline moiety is a central feature of many indole alkaloids and natural products and the Pictet-Spengler condensation continues to be the most widely used method of synthesising this crucial tricyclic ring system. Numerous compounds from this class have received considerable attention because they show a broad spectrum of pharmacological activities. Tetrahydro-p-carboline template possess multiple sites for modification allowing it ideally suited to combinatorial elaboration. The World Drug Index for instance, contains over 200 listings of this heterocycle, which is usually assembled by the Pictet-Spengler reaction. Thus the synthesis of this heterocyclic nucleus is of much current interest. Combinations of various reactions with Pictet-Spengler condensation in a sequential/tandem fashion has been studied by several research groups and successfully utilized in organic synthesis. Reference may be made to H. Wang, A. Ganesan, Tetrahedron Lett. 1997, 38, 4327 and M. Nakagawa, H. Fukushima, T. Kawate, M. Hongu, S. Kodato, T. Une, M. Taniguchi, T. Hino, Tetrahedron Lett. 1986, 27, 3235._wherein the authors reported an efficient one-pot synthesis of acylated tetrahydro-β-carboline enroute to dimethoxyfumitremorgin C through ..acvlation of the imine with Fmoc-L-proline and acid chloride. The drawbacks are the product is reported to form via a two-step one-pot reaction sequence in which the tetrahydro-p-carbolines were separated by chromatography subjected to removal of the Fmoc group with simultaneous diketopiperazine cyclisation, yielding the natural product and its epimer. (Scheme 1). (Scheme Removed) Another reference may be made to R. Rill. Cesati, J. A. Katzenellenbogen, Organic Lett. 2000, 2, 3635.. wherein Katzenellenbogen reported a vinylogous Pictet-Spengler cyclisation as the key step aiming to prepare breast tumor imaging agents. Another references may be made to a) C. J. Braestrup, Neurochem. 1981, 37, 333; b) M. Cain, R. W. Weber, F. Guzman, J. M. Cook, S. A. Baruk, K. C. Rice, J. Crawley, S. Paul, P. Skolnick, J. Med. Chem. 1982, 25, 1081. c) M. S. Allen, T. J. Hagen, M. L. Trudell, P. W. Codding, P. Skolnick, J. M. Cook, J. Med. Chem. 1988, 31, 1854. wherein the Pictet-Spengler reaction has also been employed as the key reaction in the preparation of Β-carboline-3-carboxylic acid esters which are active at the benzodiazepine receptor. The 3-substituted β-carbolines were prepared from 3-amino-β-carboline in one-step via diazotization, followed by reaction with the appropriate nucleophile in order to determine their binding affinity for benzodiazepine receptors. (Scheme-2). (Scheme Removed) Also references may be made to a) J. P. Mayer, D. Bankaitis-Davis, J. Zhang, G. Beaton, K. Bjergarde, C. M. Andersen, B. A. Goodman, C. J. Herrera, Tetrahedron Lett. 1996, 37, 5633. b) P. P. Fantauzzi, K. M. Ynager Tetrahedron Lett. 1998, 39, 1291. c) X. Li, L. Zhang, W. Zhang, S. E. Hall, J. P. Tarn, Organic Lett. 2000, 2, 3075 wherein the preparation of tetrahydro-carbolines on solid support using strong acidic condition is described particularly the condensation of a polymer bound tryptophan with an aldehyde at room temperature under acidic conditions. Use of 1 mol% trifluoroacetic acid/methylene chloride in polystyrene based supports exhibit excellent swelling properties in solvents. (Scheme 3). (Scheme Removed) Also, in another reference C. -Y. Wu, C. -M. Sun, Synlett 2002, 1709, wherein Fmoc-protected tryptophan was directly anchored to MeO-PEG-OH via an ester linkage in the presence of DCC and DMAP. One-pot condensation of polymer bound tryptophan with a variety of aldehydes has been carried out under microwave irradiation to provide immobilized 1,2,3,4-tetrahydro-p-carboline derivatives. The desired products were then liberated from the soluble matrix in good yields. Still another reference may be made to N. Srinivasan, A. Ganesan. J. Chem. Soc. Chem Commun. 2003, 916, wherein various metal triflate catalyzed one-pot Pictet-Spengler reaction of tryptamine and tryptophan methyl ester with aliphatic and aromatic aldehydes were performed in short reaction times with the aid of microwave irradiation. The drawbacks are, normally the reaction needed one day or longer at room temperature. Also, the addition of 50 mol% [bmin]CI-AICl3 N = 0.5, suggests that ionic liquids are additives for slow Lewis acid catalysed processes (Scheme 4). (Scheme Removed) Still another reference may be made to R. Tsuji, M. Yamanaka, A. Nishida, M. Nakagawa, Chemistry Letters 2002, 428, wherein the Pictet-Spengler reaction of tryptamine with p-nitrobenzaldehyde using 5 mol% Yb(OTf)3 and 100 mol% TMSCI was carried out. The drawback is that the reaction did not proceed with benzaldehyde (Scheme 5). (Scheme Removed) Still another reference may be made to P. D. Baily, S. P. Hollinshead, Z. Dauter, J. Chem. Soc. Chem. Commun., 1985, 7507 wherein optically active 1,3-disubstituted 1,2,3,4-tetrahydro-□-carbolines were formed by the reaction of various N,N-substituted (S)-tryptophan methyl esters with methyl propynoate or dimethyl butynedioate respectively. (Scheme 6). (Scheme Removed) However, in references a) R. Grigg, H. Q. N. Gunaratne, E. McNaghten, J. Chem. Soc. Perkin Trans 1 1983, 185. b) H. C. Hiemstra, H. Bieraugel, M. Wijnberg, U. K. Pandit, Tetrahedron 1983, 39, 3981, wherein protic acid catalysed Pictet-Spengler reactions of tryptamine often feature harsher conditions and poor yields. So, most of these methods have their own merits as well as limitations. Therefore, a need still exists for versatile, simple and environmentally friendly processes, whereby tetrahydro-β-carbolines may be synthesized under mild conditions. OBJECTS OF THE INVENTION The main object of the present invention is to provide a novel, simple and effective molecular iodine catalyzed process for the production of 1,2,3,4-tetrahydro-β-carboline derivatives. Another object of the present invention is to provide 1 mol% of the catalyst to perform the synthesis. Yet another object of the present invention is to carry out the Pictet-Spengler reaction without effecting the substituents in the aromatic ring and without any side product formation. Still another object of the present invention is to perform the reaction in one-pot and at ambient temperature. SUMMARY OF THE INVENTION Accordingly, the present invention provides a process for the preparation of 1,2,3,4-tetrahydro-p carboline derivative, which comprises: reacting tryptamine with a substituted aldehyde with a molar ratio of tryptamine to aldehyde of 1:1, in the presence of catalytic amount of molecular iodine, in an organic solvent, under stirring, for a period of 3-5 hrs, distilling off the solvent from the above said reaction mixture and adding 5% Na2S207 solution to the resultant distillate and extracting the desired resultant product with ethyl acetate, followed by drying, evaporation and purification by known method to obtain the desired product. In an embodiment of the present invention the substituted aldehyde used is selected from the group consisting of acetaldehyde, methoxy aldehyde, benzaidehyde, p-nitrophenylaldehyde, p-chlorophenyl aldehyde, p-bromophenyl aldehyde and benzopyranyl aldehyde. In yet another embodiment the organic solvent used is selected from acetonitrile and ethylacetate. In yet another embodiment the product 1,2,3,4 tetrahydro-p-carboline derivative obtained is represented by the group of following compounds: 1 -(phenyl)-1,2,3,4-tetrahydro-p-carboline, 1 -(p-nitropheny l)-1,2,3,4-tetrahydro-p-carboline,1 -(p-chlorophenyl)-1 ,2,3,4-tetrahydro-p-carboline,1 -(p-methylphenyl)-1,2,3,4-tetrahydro-p-carboline,1 -(p-methoxyphenyl)-1 ,2,3,4-trahydro-p-carboli ne , 1 -(p-bromophenyl)-1 ,2,3,4-tetrahydro-p-carboline, and l-(benzopyranyl)-1,2,3,4-tetrahydro-p-carboline. In still another embodiment the yield of the product obtained is in the range of 80-91%. DETAILED DESCRIPTION OF THE INVENTION The present process appears to be superior as well as novel for the preparation of 1,2,3,4-tetrahydro-p-carboline derivatives. The present invention provides a novel, simple and effective molecular iodine catalyzed process for the production of 1,2,3,4-tetrahydro-p-carboline derivatives, which comprises tryptamine, substituted aldehyde, molecular iodine and the reaction was carried out by stirring tryptamine and an aldehyde in the presence of "catalytic amount of molecular iodine at room temperature and after completion, the solvent was removed under reduced pressure and the crude product was purified by column chromatography to afford pure Scheme 7 (Scheme Removed) 1,2,3,4-tetrahydro-p-carboline derivatives 4. (Scheme 7) In another embodiment to the present invention, the process avoids the need for isolation of any intermediates, thereby avoiding any losses during such isolation.The process includes catalytic molecular iodine greatly that enhances the efficiency of the Pictet-Spengler condensation.The catalyst selectively produces various 1,2,3,4-tetrahydro-p-carbolines without affecting the nitro, chloro, methyl and bromo groups present in the substrates.The catalyst used is very cheap, less hazardous and the method is eco-friendly. The following examples are given by way of illustration of the working of the invention in a actual practice and therefore should not be construed to limit the scope of the present invention. Example 1 1-(Phenyl)-1,2,3,4-tetrahydro-β-carboline, 4a (R = Ph) A mixture of tryptamine (0.16 g, 1 rnmol), and benzaldehyde (0.106 g, 1 mmol) were added in a 50 ml round bottomed flask containing catalytic amount of molecular iodine (0.012 g) in acetonitrile (15 ml). This was than allowed to stir for 3.5 h. After completion of the reaction -.solvent was distilled off and added 5% Na2S2O7 solution. The product was extracted with ethylacetate (3 x 20 ml) and then dried over anhydrous Na2SO4, which upon evaporation subjected to column chromatography (1:6 hexane:ethylacetate) to get the pure product 4a mp 204 °C in 90% yield. Analysis of the crude mixture did not indicate the formation of any other products. Similarly other substituted carbonyl compounds and tryptamine were reacted together with molecular iodine. Example 2 1-(p-Nitrophenyl)-1,2,3,4-tetrahydro-β-carboline, 4b (R = p-NO2Ph) A mixture of tryptamine (0.16 g, 1 mmol), and p nitrobenzaldehyde (0.152 g, 1 mmol) were added in a 50 ml round bottomed flask containing catalytic amount of molecular iodine (0.012 g) in acetonitrile (15 ml). This was than allowed to stir for 4.5 h. After completion of the reaction solvent was distilled off and added 5% Na2S2O7 solution. The product was extracted with ethylacetate (3 x 20 ml) and then dried over anhydrous Na2SO4, which upon evaporation subjected to column chromatography (1:6 hexane:ethylacetate) to get the pure product 4b mp 168-170 °C in 91% yield. Analysis of the crude mixture did not indicate the formation of any other products. Example 3 1-(p-Chlorophenyl)-1,2,3,4-tetrahydro-β-carboline, 4c (R = p-CIPh) A mixture of tryptamine (0.16 g, 1 mmol), and p chlorobenzaldehyde (0.141 g, 1 mmol) were added in a 50 ml round bottomed flask containing catalytic amount of molecular iodine (0.012 g) in acetonitrile (15 ml). This was than allowed to stir for 4.0 h. After completion of the reaction solvent was distilled off and added 5% Na2S2O7 solution. The product was extracted with ethylacetate (3 x 20 ml) and then dried over anhydrous Na2SO4, which upon evaporation subjected to column chromatography (1:6 hexane:ethylacetate) to get the pure product 4c mp 208 °C in 89% yield. Analysis of the crude mixture did not indicate the formation of any other products. Example 4 1-(p-Methylphenyl)-1,2,3,4-tetrahydro-β-carboline,4d (R = p-MePh) A mixture of tryptamine (0.16 g, 1 mmol), and p methylbenzaldehyde (0.120 g, 1 mmol) were added in a 50 ml round bottomed flask containing catalytic amount of molecular iodine (0.012 g) in acetonitrile (15 ml). This was than allowed to stir for 4.0 h. After completion of The reaction solvent was distilled off and added 5% Na2S2O7 solution. The product was extracted with ethylacetate (3 x 20 ml) and then dried over anhydrous Na2SO4, which upon evaporation subjected to column chromatography (1:6 hexane:ethylacetate) to get the pure product 4d mp 192-193 °C in 87% yield. Analysis of the crude mixture did not indicate the formation of any other products. Example 5 1-(p-Methoxyphenyl)-1,2,3,4-tetrahydro-β-carboline, 4e (R = p-MeOPh) A mixture of tryptamine (0.16 g, 1 mmol), and p methoxybenzaldehyde (0.137 g, 1 mmol) were added in a 50 ml round bottomed flask containing catalytic amount of molecular iodine (0.012 g) in acetonitrile (15 ml). This was than allowed to stir for 4.0 h. After completion of the reaction solvent was distilled off and added 5% Na2S2O7 solution. The product was extracted with ethylacetate (3 x 20 ml) and then dried over anhydrous Na2SO4, which upon evaporation subjected to column chromatography (1:6 hexane:ethylacetate) to get the pure product 4e mp 206 °C in 88% yield. Analysis of the crude mixture did not indicate the formation of any other products. Example 6 1-(p-Bromophenyl)-1,2,3,4-tetrahydro-β-carboline, 4f (R = p-BrPh) A mixture of tryptamine (0.16 g, 1 mmol), and p bromobenzaldehyde (0.191 g, 1 mmol) were added in a 50 ml round bottomed flask containing catalytic amount of molecular iodine (0.012 g) in acetonitrile (15 ml). This was than allowed to stir for 4.0 h. After completion of the reaction solvent was distilled off and added 5% Na2SO2O7 solution. The product was extracted with ethylacetate (3 x 20 ml) and then dried over anhydrous Na2SO4, which upon evaporation subjected to column chromatography (1:6 hexane:ethylacetate) to get the pure product 4f in 91% yield. Analysis of the crude mixture did not indicate the formation of any other products. Example 7 1-(Benzopyranyl)-1,2,3,4-tetrahydro-β-carboline, 4g (R = benzopyranyl) A mixture of tryptamine (0.16 g, 1 mmol), and 3-formylchromone (0.175 g, 1 mmol) were added in a 50 ml round bottomed flask containing catalytic amount of molecular iodine '0.012 g) in acetonitrile (15 ml). This was than allowed to stir for 4.5 h. After completion of the reaction solvent was distilled off and added 5% Na2S2O7 solution. The product was extracted with ethylacetate (3 x 20 ml) and then dried over anhydrous Na2SO4, which upon evaporation subjected to column chromatography (1:6 hexane:ethylacetate) to get the pure product 4g mp 191 °C in 80% yield. Analysis of the crude mixture did not indicate the formation of any other products. ADVANTAGES OF THE INVENTION 1 The method is very simple and can be carried out at one-pot reaction and at room temperature. 2 The reaction time is 3.5 to 4.5 hrs . 3 The work-up procedure is very simple and molecular iodine catalyzes the Pictet- Spengler condensation without effecting any substituents in the aromatic ring and without any side product formation as observed by earlier workers. 4 1 mol% of the catalyst is found to be optimal to perform this reaction. More or less than 1 mol% catalyst is not effective, rather the reaction results side product formation and incompletion 5 The product obtained from the reaction mixture is pure and the yield is 80-91%. 6 In this process acetonitrile is used as the solvent. 7 Also, the process is efficient, mild and selective over the existing methods and the catalyst is less hazardous and inexpensive. We claim: 1. A process for the preparation of 1,2,3,4-tetrahydro-p carboline derivative, which comprises: reacting tryptamine with a substituted aldehyde with a molar ratio of tryptamine to aldehyde of 1:1, in the presence of catalytic amount of molecular iodine, in an organic solvent, under stirring, for a period of 3-5 hrs, distilling off the solvent from the above said reaction mixture and adding 5% Na2S207 solution to the resultant distillate and extracting the desired resultant product with ethyl acetate, followed by drying, evaporation and purification by known method to obtain the desired product. 2. A process as claimed in claim 1, wherein the substituted aldehyde is selected from the group consisting of acetaldehyde, methoxy aldehyde, benzaldehyde, p-nitrophenylaldehyde, p-chlorophenyl aldehyde, p-bromophenyl aldehyde and benzopyranyl aldehyde. 3. A process as claimed in claim 1 , wherein the organic solvent is selected from acetonitrile and ethylacetate. 4. A process as claimed in claim 1, wherein the product 1,2,3,4 tetrahydro-p- carboline derivative obtained is represented by the group of following compounds: 1-(phenyl)-1 ,2,3,4-tetrahydro-p-carboline, 1-(p-nitrophenyl)-1 ,2,3,4-tetrahydro-P-carboline,1-(p-chlorophenyl)-1,2,3,4-tetrahydro-p-carboline,1 -(p-methylphenyl)-l ,2,3,4-tetrahydro-p-carboline,1 -(p-methoxyphenyl)1,2,3,4-trahydro-p-carboli ne, 1-(p-bromophenyl)-1,2,3,4-tetrahydro-p-carboline, and 1-(benzopyranyl)-1,2,3,4-tetrahydro-p-carboline. 5. A process as claimed in claim 1, wherein the yield of the product obtained is in the range of 80-91%.

Full Text

FIELD OF THE INVENTION
The present invention relates to a process for the production of 1,2,3,4-tetrahydro-β-carboline derivatives.
More particularly it relates This new process involves the preparation of various substituted tetrahydro-p-carbolines, by the Pictet-Spengler condensation of tryptamine with aldehydes catalysed by molecular iodine represented as:
(Formula Removed)
wherein, R is C6H5, p-NO2C6H5, p-CIC6H5, p-BrC6H5, p-MeOC6H4, or benzopyranyl groups.
BACKGROUND OF THE INVENTION
The tetrahydro-p-carboline moiety is a central feature of many indole alkaloids and natural products and the Pictet-Spengler condensation continues to be the most widely used method of synthesising this crucial tricyclic ring system. Numerous compounds from this class have received considerable attention because they show a broad spectrum of pharmacological activities. Tetrahydro-p-carboline template possess multiple sites for modification allowing it ideally suited to combinatorial elaboration. The World Drug Index for instance, contains over 200 listings of this heterocycle, which is usually assembled by the Pictet-Spengler reaction. Thus the synthesis of this heterocyclic nucleus is of much current interest. Combinations of various reactions with Pictet-Spengler condensation in a sequential/tandem fashion has been studied by several research groups and successfully utilized in organic synthesis.
Reference may be made to H. Wang, A. Ganesan, Tetrahedron Lett. 1997, 38, 4327 and M. Nakagawa, H. Fukushima, T. Kawate, M. Hongu, S. Kodato, T. Une, M. Taniguchi, T. Hino, Tetrahedron Lett. 1986, 27, 3235._wherein the authors reported an efficient one-pot synthesis of acylated tetrahydro-β-carboline enroute to dimethoxyfumitremorgin C through
..acvlation of the imine with Fmoc-L-proline and acid chloride. The drawbacks are the product is reported to form via a two-step one-pot reaction sequence in which the tetrahydro-p-carbolines were separated by chromatography subjected to removal of the Fmoc group with simultaneous diketopiperazine cyclisation, yielding the natural product and its epimer. (Scheme 1).
(Scheme Removed)
Another reference may be made to R. Rill. Cesati, J. A. Katzenellenbogen, Organic Lett. 2000, 2, 3635.. wherein Katzenellenbogen reported a vinylogous Pictet-Spengler cyclisation as the key step aiming to prepare breast tumor imaging agents.
Another references may be made to a) C. J. Braestrup, Neurochem. 1981, 37, 333; b) M. Cain, R. W. Weber, F. Guzman, J. M. Cook, S. A. Baruk, K. C. Rice, J. Crawley, S. Paul, P. Skolnick, J. Med. Chem. 1982, 25, 1081. c) M. S. Allen, T. J. Hagen, M. L. Trudell, P. W. Codding, P. Skolnick, J. M. Cook, J. Med. Chem. 1988, 31, 1854. wherein the Pictet-Spengler reaction has also been employed as the key reaction in the preparation of Β-carboline-3-carboxylic acid esters which are active at the benzodiazepine receptor. The 3-substituted β-carbolines were prepared from 3-amino-β-carboline in one-step via diazotization, followed by reaction with the appropriate nucleophile in order to determine their binding affinity for benzodiazepine receptors. (Scheme-2).
(Scheme Removed)
Also references may be made to a) J. P. Mayer, D. Bankaitis-Davis, J. Zhang, G. Beaton, K. Bjergarde, C. M. Andersen, B. A. Goodman, C. J. Herrera, Tetrahedron Lett. 1996, 37, 5633. b) P. P. Fantauzzi, K. M. Ynager Tetrahedron Lett. 1998, 39, 1291. c) X. Li, L. Zhang, W. Zhang, S. E. Hall, J. P. Tarn, Organic Lett. 2000, 2, 3075 wherein the preparation of tetrahydro-carbolines on solid support using strong acidic condition is described particularly the condensation of a polymer bound tryptophan with an aldehyde at room temperature under acidic conditions. Use of 1 mol% trifluoroacetic acid/methylene chloride in polystyrene based supports exhibit excellent swelling properties in solvents. (Scheme 3).
(Scheme Removed)
Also, in another reference C. -Y. Wu, C. -M. Sun, Synlett 2002, 1709, wherein Fmoc-protected tryptophan was directly anchored to MeO-PEG-OH via an ester linkage in the presence of DCC and DMAP. One-pot condensation of polymer bound tryptophan with a variety of aldehydes has been carried out under microwave irradiation to provide immobilized 1,2,3,4-tetrahydro-p-carboline derivatives. The desired products were then liberated from the soluble matrix in good yields.
Still another reference may be made to N. Srinivasan, A. Ganesan. J. Chem.
Soc. Chem Commun. 2003, 916, wherein various metal triflate catalyzed one-pot
Pictet-Spengler reaction of tryptamine and tryptophan methyl ester with aliphatic and
aromatic aldehydes were performed in short reaction times with the aid of microwave
irradiation. The drawbacks are, normally the
reaction needed one day or longer at room temperature. Also, the addition of 50 mol% [bmin]CI-AICl3 N = 0.5, suggests that ionic liquids are additives for slow Lewis acid catalysed processes (Scheme 4).
(Scheme Removed)
Still another reference may be made to R. Tsuji, M. Yamanaka, A. Nishida, M. Nakagawa, Chemistry Letters 2002, 428, wherein the Pictet-Spengler reaction of tryptamine with p-nitrobenzaldehyde using 5 mol% Yb(OTf)3 and 100 mol% TMSCI was carried out. The drawback is that the reaction did not proceed with benzaldehyde (Scheme 5).
(Scheme Removed)
Still another reference may be made to P. D. Baily, S. P. Hollinshead, Z. Dauter, J. Chem. Soc. Chem. Commun., 1985, 7507 wherein optically active 1,3-disubstituted 1,2,3,4-tetrahydro-□-carbolines were formed by the reaction of various N,N-substituted (S)-tryptophan methyl esters with methyl propynoate or dimethyl butynedioate respectively. (Scheme 6).
(Scheme Removed)
However, in references a) R. Grigg, H. Q. N. Gunaratne, E. McNaghten, J. Chem. Soc. Perkin Trans 1 1983, 185. b) H. C. Hiemstra, H. Bieraugel, M. Wijnberg, U. K. Pandit, Tetrahedron 1983, 39, 3981, wherein protic acid catalysed Pictet-Spengler reactions of tryptamine often feature harsher conditions and poor yields. So, most of these methods have their own merits as well as limitations.
Therefore, a need still exists for versatile, simple and environmentally friendly processes, whereby tetrahydro-β-carbolines may be synthesized under mild conditions.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide a novel, simple and effective molecular iodine catalyzed process for the production of 1,2,3,4-tetrahydro-β-carboline derivatives.
Another object of the present invention is to provide 1 mol% of the catalyst to perform the synthesis.
Yet another object of the present invention is to carry out the Pictet-Spengler reaction without effecting the substituents in the aromatic ring and without any side product formation.
Still another object of the present invention is to perform the reaction in one-pot and at ambient temperature.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for the preparation of 1,2,3,4-tetrahydro-p carboline derivative, which comprises: reacting tryptamine with a substituted aldehyde with a molar ratio of tryptamine to aldehyde of 1:1, in the presence of catalytic amount of molecular iodine, in an organic solvent, under stirring, for a period of 3-5 hrs, distilling off the solvent from the above said reaction mixture and adding 5% Na2S207 solution to the resultant distillate and extracting the desired resultant product with ethyl acetate, followed by drying, evaporation and purification by known method to obtain the desired product.
In an embodiment of the present invention the substituted aldehyde used is selected from the group consisting of acetaldehyde, methoxy aldehyde, benzaidehyde, p-nitrophenylaldehyde, p-chlorophenyl aldehyde, p-bromophenyl aldehyde and benzopyranyl aldehyde.
In yet another embodiment the organic solvent used is selected from acetonitrile and ethylacetate.
In yet another embodiment the product 1,2,3,4 tetrahydro-p-carboline derivative obtained is represented by the group of following compounds: 1 -(phenyl)-1,2,3,4-tetrahydro-p-carboline, 1 -(p-nitropheny l)-1,2,3,4-tetrahydro-p-carboline,1 -(p-chlorophenyl)-1 ,2,3,4-tetrahydro-p-carboline,1 -(p-methylphenyl)-1,2,3,4-tetrahydro-p-carboline,1 -(p-methoxyphenyl)-1 ,2,3,4-trahydro-p-carboli ne , 1 -(p-bromophenyl)-1 ,2,3,4-tetrahydro-p-carboline, and l-(benzopyranyl)-1,2,3,4-tetrahydro-p-carboline.
In still another embodiment the yield of the product obtained is in the range of 80-91%.
DETAILED DESCRIPTION OF THE INVENTION
The present process appears to be superior as well as
novel for the preparation of 1,2,3,4-tetrahydro-p-carboline derivatives. The
present invention provides a novel, simple and effective molecular iodine
catalyzed process for the production of 1,2,3,4-tetrahydro-p-carboline
derivatives, which comprises tryptamine, substituted aldehyde, molecular iodine
and the reaction was carried out by stirring tryptamine and an aldehyde in the presence of "catalytic amount of molecular iodine at room temperature and after completion, the solvent was removed under reduced pressure and the crude product was purified by column chromatography to afford pure
Scheme 7
(Scheme Removed)
1,2,3,4-tetrahydro-p-carboline derivatives 4. (Scheme 7) In another embodiment to the present invention, the process avoids the need for isolation of any intermediates, thereby avoiding any losses during such isolation.The process includes catalytic molecular iodine greatly that enhances the efficiency of the Pictet-Spengler condensation.The catalyst selectively produces various 1,2,3,4-tetrahydro-p-carbolines without affecting the nitro, chloro, methyl and bromo groups present in the substrates.The catalyst used is very cheap, less hazardous and the method is eco-friendly.
The following examples are given by way of illustration of the working of the invention in a actual practice and therefore should not be construed to limit the scope of the present invention.
Example 1
1-(Phenyl)-1,2,3,4-tetrahydro-β-carboline, 4a (R = Ph)
A mixture of tryptamine (0.16 g, 1 rnmol), and benzaldehyde (0.106 g, 1 mmol) were added in a 50 ml round bottomed flask containing catalytic amount of molecular iodine (0.012 g) in acetonitrile (15 ml). This was than allowed to stir for 3.5 h. After completion of the reaction
-.solvent was distilled off and added 5% Na2S2O7 solution. The product was extracted with ethylacetate (3 x 20 ml) and then dried over anhydrous Na2SO4, which upon evaporation subjected to column chromatography (1:6 hexane:ethylacetate) to get the pure product 4a mp 204 °C in 90% yield. Analysis of the crude mixture did not indicate the formation of any other products. Similarly other substituted carbonyl compounds and tryptamine were reacted together with molecular iodine.
Example 2
1-(p-Nitrophenyl)-1,2,3,4-tetrahydro-β-carboline, 4b (R = p-NO2Ph)
A mixture of tryptamine (0.16 g, 1 mmol), and p nitrobenzaldehyde (0.152 g, 1 mmol) were added in a 50 ml round bottomed flask containing catalytic amount of molecular iodine (0.012 g) in acetonitrile (15 ml). This was than allowed to stir for 4.5 h. After completion of the reaction solvent was distilled off and added 5% Na2S2O7 solution. The product was extracted with ethylacetate (3 x 20 ml) and then dried over anhydrous Na2SO4, which upon evaporation subjected to column chromatography (1:6 hexane:ethylacetate) to get the pure product 4b mp 168-170 °C in 91% yield. Analysis of the crude mixture did not indicate the formation of any other products.
Example 3
1-(p-Chlorophenyl)-1,2,3,4-tetrahydro-β-carboline, 4c (R = p-CIPh)
A mixture of tryptamine (0.16 g, 1 mmol), and p chlorobenzaldehyde (0.141 g, 1 mmol) were added in a 50 ml round bottomed flask containing catalytic amount of molecular iodine (0.012 g) in acetonitrile (15 ml). This was than allowed to stir for 4.0 h. After completion of the reaction solvent was distilled off and added 5% Na2S2O7 solution. The product was extracted with ethylacetate (3 x 20 ml) and then dried over anhydrous Na2SO4, which upon evaporation subjected to column chromatography (1:6 hexane:ethylacetate) to get the pure product 4c mp 208 °C in 89% yield. Analysis of the crude mixture did not indicate the formation of any other products.
Example 4
1-(p-Methylphenyl)-1,2,3,4-tetrahydro-β-carboline,4d (R = p-MePh)
A mixture of tryptamine (0.16 g, 1 mmol), and p methylbenzaldehyde (0.120 g, 1 mmol) were added in a 50 ml round bottomed flask containing catalytic amount of molecular iodine
(0.012 g) in acetonitrile (15 ml). This was than allowed to stir for 4.0 h. After completion of The reaction solvent was distilled off and added 5% Na2S2O7 solution. The product was extracted with ethylacetate (3 x 20 ml) and then dried over anhydrous Na2SO4, which upon evaporation subjected to column chromatography (1:6 hexane:ethylacetate) to get the pure product 4d mp 192-193 °C in 87% yield. Analysis of the crude mixture did not indicate the formation of any other products.
Example 5
1-(p-Methoxyphenyl)-1,2,3,4-tetrahydro-β-carboline, 4e (R = p-MeOPh)
A mixture of tryptamine (0.16 g, 1 mmol), and p methoxybenzaldehyde (0.137 g, 1 mmol) were added in a 50 ml round bottomed flask containing catalytic amount of molecular iodine (0.012 g) in acetonitrile (15 ml). This was than allowed to stir for 4.0 h. After completion of the reaction solvent was distilled off and added 5% Na2S2O7 solution. The product was extracted with ethylacetate (3 x 20 ml) and then dried over anhydrous Na2SO4, which upon evaporation subjected to column chromatography (1:6 hexane:ethylacetate) to get the pure product 4e mp 206 °C in 88% yield. Analysis of the crude mixture did not indicate the formation of any other products.
Example 6
1-(p-Bromophenyl)-1,2,3,4-tetrahydro-β-carboline, 4f (R = p-BrPh)
A mixture of tryptamine (0.16 g, 1 mmol), and p bromobenzaldehyde (0.191 g, 1 mmol) were added in a 50 ml round bottomed flask containing catalytic amount of molecular iodine (0.012 g) in acetonitrile (15 ml). This was than allowed to stir for 4.0 h. After completion of the reaction solvent was distilled off and added 5% Na2SO2O7 solution. The product was extracted with ethylacetate (3 x 20 ml) and then dried over anhydrous Na2SO4, which upon evaporation subjected to column chromatography (1:6 hexane:ethylacetate) to get the pure product 4f in 91% yield. Analysis of the crude mixture did not indicate the formation of any other products.
Example 7
1-(Benzopyranyl)-1,2,3,4-tetrahydro-β-carboline, 4g (R = benzopyranyl)
A mixture of tryptamine (0.16 g, 1 mmol), and 3-formylchromone (0.175 g, 1 mmol) were added in a 50 ml round bottomed flask containing catalytic amount of molecular iodine
'0.012 g) in acetonitrile (15 ml). This was than allowed to stir for 4.5 h. After completion of the reaction solvent was distilled off and added 5% Na2S2O7 solution. The product was extracted with ethylacetate (3 x 20 ml) and then dried over anhydrous Na2SO4, which upon evaporation subjected to column chromatography (1:6 hexane:ethylacetate) to get the pure product 4g mp 191 °C in 80% yield. Analysis of the crude mixture did not indicate the formation of any other products.
ADVANTAGES OF THE INVENTION
1 The method is very simple and can be carried out at one-pot reaction and at room
temperature.
2 The reaction time is 3.5 to 4.5 hrs .
3 The work-up procedure is very simple and molecular iodine catalyzes the Pictet-
Spengler condensation without effecting any substituents in the aromatic ring and
without any side product formation as observed by earlier workers.
4 1 mol% of the catalyst is found to be optimal to perform this reaction. More or less
than 1 mol% catalyst is not effective, rather the reaction results side product
formation and incompletion
5 The product obtained from the reaction mixture is pure and the yield is 80-91%.
6 In this process acetonitrile is used as the solvent.
7 Also, the process is efficient, mild and selective over the existing methods and the
catalyst is less hazardous and inexpensive.

We claim:
1. A process for the preparation of 1,2,3,4-tetrahydro-p carboline derivative, which comprises: reacting tryptamine with a substituted aldehyde with a molar ratio of tryptamine to aldehyde of 1:1, in the presence of catalytic amount of molecular iodine, in an organic solvent, under stirring, for a period of 3-5 hrs, distilling off the solvent from the above said reaction mixture and adding 5% Na2S207 solution to the resultant distillate and extracting the desired resultant product with ethyl acetate, followed by drying, evaporation and purification by known method to obtain the desired product.
2. A process as claimed in claim 1, wherein the substituted aldehyde is selected from the group consisting of acetaldehyde, methoxy aldehyde, benzaldehyde, p-nitrophenylaldehyde, p-chlorophenyl aldehyde, p-bromophenyl aldehyde and benzopyranyl aldehyde.
3. A process as claimed in claim 1 , wherein the organic solvent is selected from acetonitrile and ethylacetate.
4. A process as claimed in claim 1, wherein the product 1,2,3,4 tetrahydro-p- carboline derivative obtained is represented by the group of following compounds:
1-(phenyl)-1 ,2,3,4-tetrahydro-p-carboline, 1-(p-nitrophenyl)-1 ,2,3,4-tetrahydro-P-carboline,1-(p-chlorophenyl)-1,2,3,4-tetrahydro-p-carboline,1 -(p-methylphenyl)-l ,2,3,4-tetrahydro-p-carboline,1 -(p-methoxyphenyl)1,2,3,4-trahydro-p-carboli ne, 1-(p-bromophenyl)-1,2,3,4-tetrahydro-p-carboline, and 1-(benzopyranyl)-1,2,3,4-tetrahydro-p-carboline.
5. A process as claimed in claim 1, wherein the yield of the product obtained is in the range of 80-91%.

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Patent Number

252485

Indian Patent Application Number

1549/DEL/2006

PG Journal Number

21/2012

Publication Date

25-May-2012

Grant Date

17-May-2012

Date of Filing

30-Jun-2006

Name of Patentee

COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH

Applicant Address

ANUSANDHAN BHAWAN, RAFI MARG, NEW DELHI.

Inventors:

#	Inventor's Name	Inventor's Address
1	DR. DIPAK PRAJAPATI	RRL JORHAT.
2	DR. RAMESH CH. BARUAH	RRL JORHAT

PCT International Classification Number

C07D 471/16

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA