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Synthesis of 9-Substituted Derivatives of tert-Butyl 6-(9h-Purin-6-Ylthio) Hexylcarbamate

Venkateswara Rao P1*, Ravindhranath K2 and Ravi Kumar K3

1R.V.R and J.C. College of Engineering, Guntur, AP, India

2Dept of Engg. Chemistry and P G Chemistry, Bapatla Engineering College, Baptla, AP, India

3RA Chem Pharma Limited, R&D Division, Prasanth Nagar, Hyderabad, AP, India

*Corresponding Author:
Venkateswara Rao P
R.V.R and J.C. College of Engineering
Guntur, AP, India
Tel: +919490642727
E-mail: [email protected]

Received date: March 05, 2013; Accepted date: April 27, 2013; Published date: April 29, 2013

Citation: Venkateswara Rao P, Ravindhranath K, Ravi Kumar K (2013) Synthesis of 9-Substituted Derivatives of tert-Butyl 6-(9h-Purin-6-Ylthio) Hexylcarbamate. Med chem 3:188-191. doi:10.4172/2161-0444.1000137

Copyright: © 2013 Venkateswara Rao P, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

We report herein the synthesis of series of 9-substituted derivatives of tert-butyl 6-(9H-purin-6-ylthio) hexylcarbamate by the reaction of tert-butyl 6-(9H-purin-6-ylthio) hexylcarbamate with different acid chlorides using triethylamine in Dichloromethane solvent.

Keywords

6-mercaptopurine; Tert-butyl 6-(9H-purin-6-ylthio) hexylcarbamate; Acylation; Dichloromethane; Boc-deprotection

Introduction

The purine ring system possesses undisputed biological importance and it is considered to be one of the most important heterocyclic rings in nature [1]. Cells obtain purine nucleotides through two separate metabolic pathways, de novo purine synthesis and salvage of extracellular purine bases and nucleotides [2]. Therefore, de novo purine synthesis and several enzymes involved in the purine metabolism pathway are important targets for antimetabolites [2]. Purine antimetabolites have been used in the development of many potent medicinal agents, which exhibited antineoplastic, antileukemic, antiviral, antibacterial, and antifungal activities [1-4]. The purine nucleoside analogs are also used in the treatment of autoimmune diseases [5]. 6-mercapto purine is used therapeutically as an immunosuppressive agent [6] and inhibits the growth of bacterial and mammalian cells [7]. Other 6-mercapto purine, mercapto pyridine and mercapto pyrimidine derivatives also exhibit antibacterial activity, and have been studied as agents for targeting melanoma [8], reducing cholesterol and as vasodilators [9]. As part of our present research work we are preparing acylated derivatives of tertbutyl 6-(9H-purin-6-ylthio) hexylcarbamate. According the Neiman and Bergmann [10] work we confirmed that acylation at the 9- position.

Materials and Methods

All 1H NMR spectra were recorded on 400 MHz Varian FT-NMR spectrometers. All chemical shifts are given as δ value with reference to Tetra methyl silane (TMS) as an internal standard. Melting points were taken in open capillaries. The IR spectra were recorded on a PerkinElmer 257 spectrometer using KBr discs. Products were purified by flash chromatography on 100-200 mesh silica gel. The chemicals and solvents were purchased from commercial suppliers either from Aldrich, Spectrochem and they were used without purification prior to use.

Scheme of synthesis

The synthesis of the title compounds (8a-8i) were prepared by the acylation of compound 6 by using different acid chlorides. The main intermediate compound 6 was prepared from 6- mercaptopurine.

Experimental

Synthesis of tert-butyl 6-hydroxyhexylcarbamate (2)

To a stirred solution of compound 1 (5 gm, 42.73 mmol) in THF (50 ml) was added (Boc)2O (9.8 mL, 42.73 mmol) at 0°C for 30 min and at rt for over 1 h. The reaction mixture was evaporated in vacuum until dryness. The obtained crude reaction product 2 (8 gm) was used to next step without any further purification.

Synthesis of 6-(tert-butoxycarbonylamino) hexyl methanesulfonate (3)

To a stirred solution of compound 2 (8 gm, 36.86 mmol) in THF (50 ml) was added DIPEA (20.3 mL, 110.5 mmol), methane sufonyl chloride (4.5 mL, 55.29 mmol) at 0°C for 30 min and at rt for over 2 h. Reaction was monitored by TLC. When reaction was completed the mixture was diluted with ethyl acetate and washed with H2O, brine solution. Organic layer was dried over Na2SO4, concentrated under reduced pressure. Crude compound was purified by column chromatography to obtained compound 3 (9 g, 71%) as a light yellowish gummy solid. 1H NMR (DMSO-d6): δ 6.76 (m,1H), 4.17 (t, J=8.4 Hz, 2H), 3.15 (s, 3H), 2.89 (q, J=8.4 Hz, 2H), 1.66-1.59 (m, 2H), 1.36 (s, 9H), 1.33-1.25 (m, 6H); (LC-MS) m/z: 196.1 [M-100(Boc)]+.

Synthesis of 9H-purine-6-thiol (5)

To a stirred solution of compound 4 (20 gm, 129.39 mmol) in DMF (200 ml) was added potassium thioacetate (29.5 gm, 258.79 mmol) at room temperature. The reaction mixture was stirred for an additional 6 h at 80°C. Reaction was monitored by TLC. When reaction was completed the mixture was cooled to room temperature and diluted with water (200 mL), ethyl acetate (200 mL) and stirred for 1 h at RT. Reaction mixture was filtered and obtained solid was dried under vacuum to get compound 5 (16 g, 80%) as a brown colour solid. 1H NMR (DMSO-d6): δ 13.78 (s, 1H), 13.66 (s, 1H), 8.41 (s, 1H), 8.20 (s, 1H); (LC-MS) m/z: 153.06 [M+H]+.

Synthesis of tert-butyl 6-(9H-purin-6-ylthio) hexylcarbamate (6)

To a stirred solution of compound 5 (5 gm, 32.89 mmol) in DMF (50 ml) was added potassium carbonate (4.5 gm, 32.89 mmol) and compound 3 (9.7 gm, 32.89 mmol) at room temperature. The reaction mixture was stirred for an additional 16 h at RT. Reaction was monitored by TLC. When reaction was completed the mixture was diluted with ethyl acetate and washed with H2O, brine solution. Organic layer was dried over Na2SO4, concentrated under reduced pressure. Crude compound was purified by column chromatography to obtained compound 6 (6.5 g, 56%) as an off-white solid, compound 7 (600 mg) as a light brown solid. Compound 6-1H NMR (DMSO-d6): δ13.50 (s, 1H), 8.71 (s, 1H), 8.42 (s, 1H), 6.78 (s, 1H), 2.95-2.89 (m, 2H), 1.72-1.68 (m, 2H), 1.38 (s, 9H), 1.36-1.25 (m, 8H); (LC-MS) m/z: 352.2 [M+H]+. Compound 7-1H NMR (DMSO-d6): δ 8.70 (s, 1H), 8.47 (s, 1H), 6.77-6.75 (m, 2H), 4.24-4.21 (m, 2H), 3.60 (br s, 1H), 2.90-2.85 (m, 4H), 1.83-1.68 (m, 5H), 1.36 (s, 18H), 1.36-1.24 (m, 12H); (LC-MS) m/z: 551.4 [M+H]+.

General procedure for compound 8a-8i

To a stirred solution of compound 7 (1 mmol) in Dichloromethane (3 ml) was added TEA (3 mmol), Acid chloride (1.2 mmol) at 0°C for 30 min and at rt for over 4h. Reaction was monitored by TLC. When reaction was completed, the reaction mixture was diluted with DCM and washed with H2O, brine solution. Organic layer was dried over Na2SO4, concentrated under reduced pressure. Crude compound was purified by column chromatography to get compound 8a-8i.

tert-butyl 6-(9-(2-fluorobenzoyl)-9H-purin-6-ylthio) hexylcarbamate 8a: 1H NMR (CDCl3): δ 8.62 (s, 1H), 8.56 (s, 1H), 7.78-7.68 (m, 2H), 7.38 (t, J=7.6 Hz, 1H), 7.21 (t, J=9.2 Hz, 1H), 4.51 (br s, 1H), 3.36 (t, J=7.2 Hz, 2H), 3.12-3.10 (m, 2H), 1.82-1.75 (m, 2H), 1.58-1.37 (m, 6H), 1.43 (s, 9H); IR (KBr, cm-1): 3377, 2934, 1723, 1692, 1577, 1522, 1381, 1167, 899, 748, 633; Anal. Calcd. For C23H28FN5O3S: C, 58.33; H, 5.96; F, 4.01; N, 14.79; O, 10.14; S, 6.77. Found: C, 57.87; H, 5.86; N, 14.59. (LC-MS) m/z: 474.11 [M+H]+.

tert-butyl 6-(9-(2-methylbenzoyl)-9H-purin-6-ylthio) hexylcarbamate 8b: 1H NMR (CDCl3): δ 8.73 (s, 1H), 8.34 (s, 1H), 7.57-7.53 (m, 1H), 7.43-7.31 (m, 3H), 4.51 (br s, 1H), 3.37 (t, J=7.2 Hz, 2H), 3.12-3.09 (m, 2H), 2.46 (s, 3H), 1.83-1.75 (m, 2H), 1.61-1.33 (m, 6H), 1.43 (s, 9H); IR (KBr, cm-1): 3384, 2932, 1708, 1693, 1519, 1378, 1246, 1169, 897, 733, 633; Anal. Calcd. For C24H31N5O3S: C, 61.38; H, 6.65; N, 14.91; O, 10.22; S, 6.83. Found: C, 60.29; H, 6.86; N, 14.89. (LCMS) m/z: 470.21 [M+H]+.

tert-butyl 6-(9-(2-trifluoromethylbenzoyl)-9H-purin-6-ylthio) hexylcarbamate 8c: 1H NMR (CDCl3): δ 8.55 (s, 1H), 8.51 (s, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.79-7.70 (m, 2H), 7.52 (d, J=7.6 Hz, 1H), 4.49 (br s, 1H), 3.35 (t, J=7.2Hz, 2H), 3.11-3.09 (m, 2H), 1.81-1.73 (m, 2H), 1.56- 1.36 (m, 6H), 1.43 (s, 9H); IR (KBr, cm-1): 3392, 2932, 2860, 1719, 1569, 1368, 1316, 1170, 1138, 900, 771, 634; Anal. Calcd. For C24H28F3N5O3S: C, 55.06; H, 5.39; F, 10.89; N, 13.38; O, 9.17; S, 6.12. Found: C, 55.09; H, 5.26; N, 13.21. (LC-MS) m/z: 524.17 [M+H]+.

tert-butyl 6-(9-(2-methoxylbenzoyl)-9H-purin-6-ylthio) hexylcarbamate 8d: 1H NMR (CDCl3): δ 8.68 (s, 1H), 8.39 (s, 1H), 7.65-7.61 (m, 2H), 7.15 (t, J=7.6 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 4.50 (br s, 1H), 3.62 (s, 3H), 3.36 (t, J=7.2 Hz, 2H), 3.12-3.10 (m, 2H), 1.82- 1.79 (m, 2H), 1.54-1.33 (m, 6H), 1.43 (s, 9H); IR (KBr, cm-1): 3380, 2936, 1742, 1689, 1581, 1520, 1387, 1180, 890, 752, 632; Anal. Calcd. For C24H31N5O4S: C, 59.36; H, 6.43; N, 14.42; O, 13.18; S, 6.60. Found: C, 59.21; H, 6.40; N, 14.31. (LC-MS) m/z: 486.26 [M+H]+.

tert-butyl 6-(9-(4-methoxylbenzoyl)-9H-purin-6-ylthio) hexylcarbamate 8e: 1H NMR (CDCl3): δ 8.73 (s, 1H), 8.49 (s, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 4.52 (br s,1H), 3.93 (s, 3H), 3.39 (t, J=7.2 Hz, 2H), 3.13-3.11 (m, 2H), 1.84-1.77 (m, 2H), 1.54-1.38 (m, 6H), 1.44 (s, 9H); IR (KBr, cm-1): 3382, 2928, 1690, 1557, 1514, 1368, 1264, 1172, 899, 762, 634; Anal. Calcd. For C24H31N5O4S: C, 59.36; H, 6.43; N, 14.42; O, 13.18; S, 6.60. Found: C, 59.19; H, 6.42; N, 14.39. (LC-MS) m/z: 486.16 [M+H]+.

tert-butyl 6-(9-(3-chlorobenzoyl)-9H-purin-6-ylthio) hexylcarbamate 8f: 1H NMR (CDCl3): δ 8.70 (s, 1H), 8.51 (s, 1H), 7.85 (s, 1H), 7.71 (t, J=7.6 Hz, 1H), 7.53-7.49 (m, 2H), 4.51 (br s, 1H), 3.38 (t, J=7.2 Hz, 2H), 3.12-3.10 (m, 2H), 1.82-1.78 (m, 2H), 1.55-1.37 (m, 6H), 1.43 (s, 9H); IR (KBr, cm-1): 3381, 2942, 2868, 1714, 1570, 1342, 1310, 1178, 1136, 910, 774, 631; Anal. Calcd. For C23H28ClN5O3S: C, 56.37; H, 5.76; Cl, 7.24; N, 14.29; O, 9.80; S, 6.54. Found: C, 56.30; H, 5.69; N, 14.18. (LC-MS) m/z: 490.12, 492.14 [M+H]+.

tert-butyl 6-(9-(1-naphthoyl)-9H-purin-6-ylthio) hexylcarbamate 8g: 1H NMR (CDCl3): δ 8.70 (s, 1H), 8.55 (s, 1H), 8.40 (s, 1H), 8.02-7.91 (m, 4H), 7.72-7.62 (m, 2H), 4.51 (br s, 1H), 3.40 (t, J=7.2 Hz, 2H), 3.13-3.11 (m, 2H), 1.84-1.80 (m, 2H), 1.56-1.38 (m, 6H), 1.44 (s, 9H); IR (KBr, cm-1): 3293, 2929, 1689, 1558, 1369, 1283, 1190, 911, 806, 756, 633; Anal. Calcd. For C27H31N5O3S: C, 64.14; H, 6.18; N, 13.85; O, 9.49; S, 6.34. Found: C, 64.02; H, 6.21; N, 13.59. (LC-MS) m/z: 506.16 [M+H]+.

tert-butyl 6-(9-propionoyl-9H-purin-6-ylthio)hexylcarbamate 8h: 1H NMR (CDCl3): δ 8.77 (s, 1H), 8.69 (s, 1H), 4.51 (br s, 1H), 3.47 (q, J=7.2 Hz, 2H), 3.37 (t, J=7.6 Hz, 2H), 3.12-3.10 (m, 2H), 1.83-1.79 (m, 2H), 1.56-1.34 (m, 9H), 1.44 (s, 9H); IR (KBr, cm-1): 3371, 2921, 1748, 1675, 1563, 1516, 1366, 1240, 1183, 909, 729, 602; Anal. Calcd. For C19H29N5O3S: C, 56.00; H, 7.17; N, 17.18; O, 11.78; S, 7.87. Found: C, 56.09; H, 7.11; N, 17.02. (LC-MS) m/z: 408.09 [M+H]+.

tert-butyl 6-(9-(3-methylbutanoyl)-9H-purin-6-ylthio) hexylcarbamate 8i: 1H NMR (CDCl3): δ 8.77 (s, 1H), 8.67 (s, 1H), 4.51 (br s, 1H), 3.39-3.33 (m, 4H), 3.12-3.10 (m, 2H), 2.35-2.32 (m, 1H), 1.81-1.75 (m, 2H), 1.54-1.37 (m, 6H), 1.44 (s, 9H), 1.09 (d, J=6.8 Hz, 6H); IR (KBr, cm-1): 3379, 2934, 1732, 1689, 1527, 1198, 1170, 916, 639; Anal. Calcd. For C21H33N5O3S: C, 57.91; H, 7.64; N, 16.08; O, 11.02; S, 7.36. Found: C, 57.89; H, 7.56; N, 16.11. (LC-MS) m/z: 436.25 [M+H]+.

Synthesis of 6-(9H-purin-6-ylthio) hexan-1-amine 9: To a stirred solution of compound 8a (200 mg, 0.42 mmol) in Dichloromethane (3 ml) was added TFA (0.034 mL, 0.42 mmol) at 0°C for 30 min. Reaction was monitored by TLC. When reaction was completed, the reaction mixture was concentrated under reduced pressure. Crude compound was purified by column chromatography to get compound 9 as brown colour solid (70 mg, 66%). The same result was obtained from Dioxane- HCl method, and spectral data indicates absence of compound 9a. 1H NMR (DMSO-d6): δ 8.68 (s, 1H), 8.44 (s, 1H), 4.2 (br s, 2H), 3.35 (t, J=6.8 Hz, 2H), 2.79-2.75 (m, 2H), 1.75-1.68 (m, 2H), 1.59-1.36 (m, 6H); (LC-MS) m/z: 252.21 [M+H]+.

Results and Discussions

The synthesis of 9-substituted derivatives of tert-butyl 6-(9H-purin- 6-ylthio) hexylcarbamate (8a-8i) is described in scheme 1. Compound 3 was prepared by the Boc protection of 6-amino- hexanol and then followed by mesylation [11] in THF as a solvent (Scheme 2). 6-chloro purine was reacted with potassium thioacetate in DMF at 80°C for 6 h to get 6-mercaptopurine [12]. The obtained 6-mercaptopurine was reacted with compound 3; the reaction was carried out in anhydrous DMF in the presence of one equivalent of anhydrous potassium carbonate at room temperature for 16 h to get mixture of only mono alkylated as major, di-alkylated derivative as minor amounts 6 and 7. Another one more reaction was tried in two equivalent of anhydrous potassium carbonate to get 1: 1 ratio of mono and di-alkylated compounds. Compound 6 was reacted with different acid chlorides in presence of Triethylamine and DCM to afford the titled compounds of 9-substituted derivatives of tert-butyl 6-(9H-purin-6-ylthio) hexylcarbamate (8a-8i) in good yields. The purity of compounds 8a-8i was confirmed by using TLC, LCMS purity and their NMR spectral data. In other side we are tried for the deprotection of Boc group of compound 8a by using different conditions like Trifluoroacetic acid in Dichloromethane, Dioxane-HCl at cold condition causes deprotection not only of the Boc group but also fission of acylated derivative to give the 6-(9H-purin-6-ylthio)hexan-1-amine 9. The compound 9 was confirmed by 1H NMR and Mass spectral data. The obtained result indicates that the derivatives of 9-substituted tert-butyl 6-(9H-purin- 6-ylthio) hexylcarbamate are acid sensitive (Table 1).

compound Molecular formula Molecular weight Melting range
°C
Yield (%)
8a C23H28FN5O3S 473.56 79-81 56
8b C24H31N5O3S 469.60 98-101 58
8c C24H28F3N5O3S 523.57 52-54 54
8d C24H31N5O4S 485.60 84-86 62
8e C24H31N5O4S 485.60 78-80 64
8f C23H28ClN5O3S 490.02 100-102 53
8g C27H31N5O3S 505.63 115-118 61
8h C19H29N5O3S 407.53 97-99 51
8i C21H33N5O3S 435.58 92-94 62

Table 1: Physical data of the newly synthesized 9-substituted derivatives of tert-butyl 6-(9H-purin-6-ylthio) hexylcarbamate (8a-8i).

medicinal-chemistry-hexylcarbamate-derivatives

Scheme 1: Synthesis of 9-substituted tert-butyl 6-(9H-purin-6-ylthio) hexylcarbamate derivatives.

medicinal-chemistry-Boc-deprotection

Scheme 2: Boc deprotection of 9-substituted tert-butyl 6-(9H-purin-6-ylthio) hexylcarbamate derivative.

Conclusion

In conclusion, we have synthesized 9-substituted derivatives of tert-butyl 6-(9H-purin-6-ylthio) hexylcarbamate in good yields and characterized by 1H NMR, IR and LCMS spectral data.

Acknowledgements

The authors are very much grateful to the management of R.V.R & J.C College of Engineering, Guntur, A.P, India, for providing moral support in carrying out this work.

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