J.

Atoms and Molecules/ 3(4); 2013 / 560563 Research Article

Patel VR & Desai HT

Journal of Atoms and Molecules

An International Online Journal
ISSN 2277 1247

A DEVELOPED PROCESS FOR THE SYNTHESIS OF TRYPTOPHOL, A KEY STARTING MATERIAL FOR INDORAMIN Vinodkumar R. Patel1* , Hemant T. Desai2
2

Research Scholar of CMJ University, Shilong, Meghalaya, India. GM (Operations), Nirma Limited (Healthcare Division), Sachana, ahmedabad-380009. Revised on: 13-08-2013 Accepted on: 20082013

Received on: 01-08-2013 ABSTRACT:

A developed process for the synthesis of tryptophol, a key starting material for Indoramin. Starting from commercially available indole. Firstly prepared (1H-indol-3yl)-oxo-acetyl chloride from indole by using oxalyl chloride and then prepared ethyl ester by using ethanol. Ethyl ester reduced by sodium borohydride and getting pure tryptophol without purification within 92% yield. the method is easy, inexpensive , without purification getting pure solid. The process is very clean, high yielding & high quality and operationally simple. KEY WORDS: indole, (1H-indol-3yl)-oxo-acetyl chloride,(1H-indol-3-yl)oxo-acetic acid ethyl ester, tryptophol, oxalyl chloride, indoramin. .

INTRODUCTION: Tryptophol is a chemical compound that induces sleep in humans1. It is formed in the liver after disulfiram treatment. It is also produced by the trypanosomal parasite in sleeping sickness. tryptophol are derivatives of indole class which contain a C-3 hydroxyethyl chain1,2. Tryptophol and its derivatives are communally extracted from various natural soures3. Some of the tryptophol derivatives exhibit biological activity4. Here tryptophol is one of the important chemical moiety and it has a also pharmaceutical importance. Tryptophol was prepared from indole . Tryptophol mainly used for the synthesis of Indoramin.

* Corresponding author Vinodkumar R. Patel, Email: vinod_patel88@yahoo.com Tel : + +91 - 9428047871

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J. Atoms and Molecules/ 3(4); 2013 / 560563 Indoramin hydrochloride works by blocking alpha receptors in certain areas of the body. Alpha receptors are found on the muscle in the prostate gland. This gland is found only in men and lies at the top of the tube connecting the bladder to the outside (urethra). The prostate gland often enlarges with advancing age (a condition called benign prostatic hyperplasia), pressing on the urethra and obstructing the flow of urine from the bladder. This can cause various urinary symptoms such as difficulty passing urine. By blocking the alpha receptors in the prostate gland, indoramin causes the muscle in the prostate gland to relax. This allows urine to flow freely past the prostate and relieves the urinary symptoms of this condition. Indoramin (trade names Baratol and Doralese) is a piperidine antiadrenergic agent. It is an alpha-1 selective adrenoceptor antagonist5 with direct myocardial depression action; therefore, it results in no reflex tachycardia. It is also used in benign prostatic hyperplasia (BPH).6 It is commonly synthesized from tryptophol.7 Indoramin is commonly prescribed as 20mg tablets when used in BPH.8 Tryptophol is the key starting material for the preparation of indoraminl. Here we are prepare tryptophol from indole with improve the yield and quality. So we are getting better yield and quality in preparation of tryptophol. The tryptophol preparation has been reported by several methods. One of the reaction of indole 3-acetic acid to tryptophol by reduction with using lithium aluminum hydride. The second method is indole to tryptophol by using firstly prepared acid chloride and then prepared ethyl ester and then prepared tryptophol by using reductive catalyst sodium borohydride with purification method fractional distillation at high temperature. However, upon attempting to repeat the reported procedure. While preparing the title All rights reserved 2011

Patel VR & Desai HT compound by the reported method, we observed the inconsistency in the process, low purity and low yield, formation of various impurities, tedious work-up. MATERIALS AND METHODS: Melting points were determined on Buchi 540 melting point apparatus and are uncorrected. FT-IR spectra were recorded as KBr pellet on Nicolet 380 FT IR instrument (model thermo electron corporation spectrum one), 1H and 13C CMR (proton decoupled) spectra were recorded on Varian 400 MHz spectrometer using DMSO-d6, and tetramethylsilane (TMS) as internal standard. Mass spectra were recorded on Agilent triple quadruple mass spectrometer equipped with turbo ion spray interface at 375C. Preparation of (1H-indol-3-yl)oxo-acetic acid ethyl ester To A solution of lindole (25g.) in methyl tertiary butyl ether (300 ml.) was added at 30.degree. to oxalyl chloride (20ml.) diluted with methyl tertiary butyl ether (100 ml.). After stirring for 1 hour the precipitate of lindolylglyoxylyl chloride was collected by filtration and treated with ethanol (200 ml.) to give the ethyl ester of indol-3-ylglyoxylic acid (37.0 g.) as a yellow powder m.p. 180.degree.-183.degree. yield : 80%. 1H NMR (DMSO): 1.34(t,3H), 4.35(q,2H), 7.27 (t,1H), 7.30(t,1H), 7.55(d,1H) ,8.15(d,1H), 8.43 (d,1H), 12.40 (broad s, 1H, NH), IR(cm-1) 3208, 3049, 2967, 2934, 2907, 1724, 1603, 1458, 1363, 1335, 1240, 1230, 1093, 1022, 941, 818, 759. Mass : 217.22. Preparation of 3-(2-Hydroxyethyl)indole (Tryptophol) (1H-indol-3-yl)oxo-acetic acid ethyl ester (37g.) was added to a stirred suspension of sodium borohydride (18.0g.) in isopropanol (300 ml). the exothermic reaction raising the temperature of the mixture from 20.degree. to www.jamonline.in 561

J. Atoms and Molecules/ 3(4); 2013 / 560563 55.degree.. After heating to reflux for 5 hours the mixture was cooled, diluted with water : Isopropanol (20 ml : 60 ml.). Adjusted pH of reaction mass 4.5 to 5. By using 10% HCl solution and then extracted the product by 300 ml dichloromethane at 25-30C. Washed the organic layer with 1% sodium carbonate solution (200 ml) at same temperature. The extract was concentrated under reduced pressure to an oil, which crystallized from 10% ethyl acetate in n-hexane solution (90 ml.)with cooling at 5-10C. to give the title compound as a white to pale brown crystals (24.6 gm),Yield : 90%. m.p. 57C 59C. Purity NLT 98% by HPLC. 1H NMR(300MHz, DMSO): 2.87 (t,2H)3.69 (q,2H), 4.68(t,1H,OH), 7.00(t,1H), 7.09(t,1H), 7.15(s,1H), 7.36(d,1H), 7.54(d,1H),

Patel VR & Desai HT 10.81(s,1H,NH) . C13 NMR: 29.31, 62.17, 111.73, 111.97, 118.56, 118.79, 121.21, 123.21, 127.86, 136.58. IR(cm-1) 3402, 3369, 3238, 3058, 2976, 2934, 2864, 2840, 1427, 1354, 1339, 1247, 1228, 1081, 1065, 930, 811, 754. Mass : 161.20. RESULTS AND DISCUSSIONS: As a part of our research involving synthetic process of tyrptophol improving method for a key intermediate of indoramin. In our study the reaction of indole with oxalyl chloride and then made ethyl ester of acid chloride and then reduction of ethyl ester was tested with different catalysts such as a Sodium borohydride, lithium aluminum hydride , platinum with H2 at 65-75C for 3 hrs (table-1).

Figure 1- chemical structures of tryptophol, Indole , Indoramin

H N
N

N H

OH

N H

HN

Tryptophol

Indole

Indoramin

Table 1- Reduction of (1H-indol-3-yl)oxo-acetic acid ethyl ester with in the presence of various catalyst. Sr. no. 1. 2. 3. Catalyst Sodium borohydride Lithium aluminum hydride platinum with H2 Conversion by TLC. 90-95% 75-80 % 60-62%

It was found that NaBH4 was superior to all the other catalysts examined and gave a good reaction conversion. During all reaction while All rights reserved 2011

preparing tryptophol formation of product observed (60-95% by TLC) . It was found that the reaction proceeded smoothly and gave an www.jamonline.in 562

J. Atoms and Molecules/ 3(4); 2013 / 560563 excellent reaction conversion (90-95 % by TLC) using NaBH4 as a reducing catalyst. In the preliminary study, the reduction stage of ethyl ester , if the sodium borohydride contains excess, a lot of impurities to form Scheme-1
O O O Cl
Oxalyl Chloride
Ethanol

Patel VR & Desai HT when the solution is warmed, and very little tryptophol is obtained. In summary, a simple and general method for the synthesis of tryptophol at 70C, which offers several advantages including good yield has been developed.

O OC2H5 OH N H
2-(1H-Indol-3-yl)-ethanol (Tryptophol)

NaBH4
N H
(1H-Indol-3-yl)-oxo-acetic acid ethyl ester

N H 1H-Indole

N H
(1H-Indol-3-yl)-oxo-acetyl chloride

ACKNOWLEDGEMENT The authors thank Dr. Hemant Desai for providing the best guidance and encouragement. REFERENCES: 1) Cornford, E. M.; Bocash, W. D.; Braun, L. D.; Crane, P. D.; Oldendorf, W. H.; MacInnis, A. J. (1979). "Rapid distribution of tryptophol (3-indole ethanol) to the brain and other tissues". Journal of Clinical Investigation 63 (6): 12411248. 2) Richard Seed, J.; Seed, T. M.; Sechelski, J. (1978). "The biological effects of tryptophol (indole-3-ethanol): Hemolytic, biochemical and behavior modifying activity". Comparative Biochemistry and Physiology Part C: Comparative Pharmacology 60 (2): 175. 3) Fenn P, Durbin R D & Kuntz J E, Phytochemistry, 16, 1977, 899, (b) Lacan 5)

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G, Magnus V, Jericevic B, Kunst L & Iskric S, Plant Physiol, 76, 1984,889,(c) mantle P G & Weedon CM, Phytochemistry,36,1994,1209. Fernando I N, Francis P L & Smith I, J Neural Transm, 56,1983,33. Pierce V, Shepperson NB, Todd MH, Waterfall JF (February 1986). "Investigation into the cardioregulatory properties of the alpha 1-adrenoceptor blocker indoramin". Br. J. Pharmacol. 87 (2): 433441. PMC 1916533. PMID 3955309. "Indoramin 20mg tablets". Medicines.org.uk. April 20, 2011. Retrieved September 30, 2012. Ullman's encyclopedia of Industrial Chemistry, Sixth Edition, 2002. "Indoramin hydrochloride". National Health Service (UK). Retrieved September 30, 2012.

How to cite this article: Patel VR, Desai HT A developed process for the synthesis of tryptophol, a key starting material for Indoramin J. Atoms and Molecules, 3(4), 2013: 560 563. All rights reserved 2011 www.jamonline.in 563