Synthesis and biological activity of allosteric modulators of GABA B receptors part 3. 3-(2,6-bis-iso-propyl-4-hydroxyphenyl)propanols

ARTICLE

Synthesis and biological activity of allosteric modulators of GABA_B receptors part 3. 3-(2,6-bis-iso-propyl-4-hydroxyphenyl)propanols

David I. B. KerrI, ^†; Jabbar KhalafyII, ^*; Jennifer Ong^I; Rolf H. Prager^III; Mehdi Rimaz^II

^IDepartment of Anaesthesia and Intensive Care, University of Adelaide, Adelaide, Australia 5005

^IIChemistry Department, Urmia University, Urmia 57154, Iran

^IIISchool of Chemistry, Physics and Earth Sciences, Flinders University, G.P.O. Box 2100, Adelaide, Australia 5001

ABSTRACT

A series of six 2,2-disubstituted 3-[3,5-di-iso-propyl-4-hydroxyphenyl]propan-1-ol derivatives have been prepared for evaluation as allosteric modulators of GABA_B receptors. The activity (EC₅₀ 30 µM) was greatest for the dimethyl analogue, but the isopropylphenyl compounds were generally weaker than the corresponding t-butyl compounds. Methylation of the phenolic group led to loss of activity.

Keywords: propofol analogue, allosteric positive modulation, GABA_B

RESUMO

Uma série de seis derivados do propan-1-ol 2,2-disubistituído 3-[3,5-di-iso-propil-4-hydroxifenil] foi preparada para avaliação como moduladores alostéricos de receptores GABA_B. A maior atividade (EC₅₀ 30 µM) encontrada na série foi para os análogos do dimetil, mas os compostos isopropilfenil foram, de maneira geral, mais fracos que os compostos t-butílicos. A metilação do grupo fenólico levou à uma perda de atividade.

Introduction

Following a random mass screening, Urwyler et al.¹ recently reported that 2,6-di-tert-butyl-4-(3-hydroxyphenyl)-2,2-dimethylpropionaldehyde, CGP 13501, (1) acted as a positive allosteric modulator for GABA_B receptors,^2,3 and its reduction product, the corresponding alcohol CGP 7930 (2) was found to be even more potent. Because of our interest in such modulators,^2,4,5 we speculated that the latter could be regarded as a hybrid of propofol (3) and hydroxybutyric acid (GHB, 4). Propofol^6,7 is a short-acting hypnotic agent (GABA_A modulator), effective for induction and maintenance of anaesthesia when administered intravenously either as repeated bolus injections or by continuous infusion. GHB is best known as a drug of abuse,⁸ and is a GABA analogue. Accordingly, we have recently synthesized a series of compounds modifying the structure 2, all of which acted as positive modulators at GABA_B receptors.⁹ The most active was the cyclohexyl analogue (5), which was 2 to 3 times as active as the lead compound (2). Our working hypothesis for the lead compound (2) is that it acts through the 3-hydroxyphenylpropyl moiety, with the hydroxyphenyl group corresponding to the carboxyl group of GHB, in addition to providing hydrophobic properties that would facilitate transport across cell membranes.

Since our previous work⁹ was concerned mainly with an examination of the effect of changing the hydrophobicity and steric bulk near the hydroxyl end of the molecule, we now report the preparation of some variants at the phenolic portion of the molecule; at this stage little is known of the pharmacokinetics of these compounds, and their therapeutic potential is uncertain. The basic synthetic approach continues to be basically that of Urweyler et al.¹

Discussion

Chemical synthesis

2,6-Di-isopropyl-4-methoxymethylphenol (6) reacted with carbonyl compounds in methanol more slowly than the t-butyl analogue.⁹ The resulting carbonyl compounds (7a-d) were either reduced with sodium borohydride to the alcohols (8a, 8b, 9a, 9c), or reacted with alkyllithium reagents to give a mixture of diastereoisomers of alcohol (9b) (Scheme 1).

Since we suspected that these compounds were GABA mimics, it was desirable to synthesise at least one example of a primary amine, and the reductive amination method of Borch et al.¹⁰ was chosen.

Reaction of the aldehyde 7b with ammonium acetate and sodium cyanoborohydride,¹⁰ gave a good yield, not of the desired primary amine 10, but of the secondary amine 11. We suspect that the initially formed 10 reacted with 7b faster than with ammonium acetate, leading to the new intermediate 13, reduction of which gave the observed product 11, as shown in Scheme 2.

The subtle difference in the decreased activating effect of isopropyl groups compared to tert-butyl groups was noted when the reaction of ether 6 with 3-methylbutan-2-one failed to occur to any significant extent under basic conditions. However, the use of trifluoroacetic acid in refluxing dichloromethane allowed efficient reaction of the ether with ketones, and indeed also gave cleaner reaction products with aldehydes, leading to products 7a-7c.

The requirement for an acidic or hydrogen-bonding centre on the phenyl group was probed by methylation of 8a in this series to give 14, but attempt to synthesize methyl ethers from tertiary butyl derivatives failed.

In order to further examine the suspected importance of the bulkiness of the aryl substituents in these compounds, the synthesis of methyl analogues was investigated. However, as reported in the literature,¹¹ the base catalysed condensation of 2,6-dimethylphenol with formaldehyde in basic methanol gave 4,4'-dihydroxy-3,5,3',5'-tetramethylphenylmethane 15 instead of the desired 2,6-dimethyl-4-methoxymethylphenol 16, and this area was not pursued further.

Biological evaluation

As described previously,^4,12,13 the compounds prepared above were examined for their pharmacological effects in enhancing baclofen-induced hyperpolarizing responses at GABA_B post-synaptic receptors, and as potentiators of baclofen actions in reducing electrically-evoked release of [³H]-GABA or [³H]-glutamate at presynaptic receptors, mediated via GABA_B auto or heteroreceptors, respectively, in rat neocortical slice preparations.^14,15 Baclofen is a classical selective agonist at GABA_B receptor sites,^16,17 and is commonly used in rat brain preparations to stimulate these receptors to induce a neuronal response. Herein (Table 1) we summarise the results of the effects of the test compounds in modulating baclofen mediated function using grease gap recording in rat neocortical slices.^12,13 The responses induced by baclofen are dose-dependent, with baclofen generating an EC₅₀ value of approximately 10 µM.¹² The EC₅₀ value for the agonist baclofen is calculated as the concentration of baclofen inducing 50% of the maximum hyperpolarizing response. Using this fixed concentration of baclofen at 10 µM, the concentration-response curves of differing concentrations of the test compounds are subsequently constructed. From these curves, the EC₅₀ values of the test compounds in potentiating the baclofen response are measured, the values representing the concentration of the compound needed to induce 50% of the maximal potentiated responses.

All the new 3-(hydroxyphenyl)propanol derivatives had relatively low activity with EC₅₀ typically around 30-100 µM. As with the t-butyl compounds reported earlier,⁹ this may be a reflection of their extremely low solubility even in DMSO/water mixtures, leading to partial precipitation during the testing procedure: real activities possibly may be somewhat greater. The methyl ethers were of very low activity, and their solubility was even lower. The tert-butyl derivatives reported previously⁹ appeared to be two to three times more active than the isopropyl series, but still several orders of magnitude lower than that of the N-(phenylpropyl)-1-arylethylamines. ²

Conclusion

Generally, it can be concluded that 3-(4-hydroxy-3,5-dialkylphenyl)propanols represent a new distinct classes of GABA_B receptor modulators, limited at this stage by very poor solubility. The 3,5-di i-propyl analogues are less active than the corresponding t-butyl compounds. However, these GABA_B modulators may still represent a novel therapeutic strategy for the treatment of various neurological and pathological diseases mentioned previously, without the side effects of full GABA_B receptor agonists.

Experimental

All solvents used were freshly distilled and dried according to the methods of Perrin and Armarego.¹⁸ Melting points were determined on a Reichert hot stage microscope and are uncorrected. ¹H (300 MHz) and ¹³C (75.5 MHz) NMR spectra were recorded on a Gemini Varian 300 spectrometer in deuteriochloroform with tetramethylsilane as internal standard, unless otherwise stated. Infrared spectra were recorded on a Thermonicolet (Nexus 670) FT-infrared spectrophotometer, measured as films or KBr disks. Mass spectra and high resolution mass spectra were recorded on a Kratos MS25RF spectrometer.

3-[4-Hydroxy-3,5-bis(1-methylethyl)phenyl]-2,2 -dimethylpropanal (7a)

2,6-Diisopropyl-4-methoxymethylphenol (6)¹⁹ (0.5 g), potassium hydroxide (0.10 g) and isobutyraldehyde (0.5 g) were heated under N₂ at 100 ºC for 2h. The reaction mixture was poured into 1% acetic acid (20 mL), and extracted with dichloromethane. The extracts were washed with water, dried and evaporated, and the product recrystallised from hexane as white needles (0.39 g, 65%), mp 67-68 ºC. Found (M+H-H₂O)⁺ 245.1895. C₁₇H₂₅O requires 245.1900. ¹H NMR d 1.06 (s, 6H), 1.24 (d, J 6.8 Hz, 12H), 2.71 (s, 2H), 3.12 (sep, J 6.8 Hz, 2H), 4.62 (bs, 1H), 6.75 (s, 2H), 9.59 (s, 1H). ¹³C NMR d 21.3, 22.7, 27.0, 43.1, 46.9, 125.2, 128.5, 133.3, 148.5, 206.5. FT-IR (KBr) n_max/ cm^-1: 3518, 2960, 2869, 1716, 1470, 1199, 1154, 884.

3-[4-Hydroxy-3,5-bis(1-methylethyl)phenyl]-2,2 -dimethylpropanol (8a)

A mixture of 7a (131 mg) and sodium borohydride (48 mg) in dry ethanol (4 mL) was refluxed overnight. Water (10 mL) was added, the mixture extracted with dichloromethane, and the combined extracts washed with water, dried, and evaporated to give 8a, which was recrystallised from hexane as colourless crystals (121 mg, 91%), mp 96-97 ºC. Found (M+H)⁺ 265.2158. C₁₇H₂₉O₂ requires 265.2168. ¹H NMR d 0.87 (s, 6H), 1.26 (d, J 6.8 Hz, 12H), 2.50 (s, 2H), 2.93 (bs, 2H), 3.15 ( sept, J 6.8 Hz, 2H), 3.33 (s, 2H), 6.82 (s, 2H). ¹³C NMR d 22.8, 23.9, 27.0, 36.3, 44.6, 71.4, 125.3, 130.4, 133.0, 148.1. FT-IR (KBr) n_max/ cm^-1: 3417, 3241, 2961, 2866, 1462, 1359, 1203, 1167, 1034.

1-[4-Hydroxy-3,5-bis(1-methylethyl)phenylmethyl] cyclohexanecarboxaldehyde (7b)

Method 1

2,6-Diisopropyl-4-methoxymethylphenol (6)¹⁹ (1.0 g), potassium hydroxide (0.10 g) and cyclohexanecarboxaldehyde (1.5 g) were heated under N₂ at 110 °C for 3h. The reaction mixture was poured into 1% acetic acid (20 mL), and extracted with dichloromethane. The extracts were washed with water, dried and evaporated, and the product chromatographed on silica (dichloromethane:hexane, 1:1) to yield colourless crystals (0.98 g, 72%), mp 67-68 ºC. Found (M+H-H₂O)⁺ 285.2216. C₂₀H₂₉O requires 285.2218. ¹H NMR d 1.23 (d, J 6.8 Hz, 12H), 1.20-1.36 (m, 4H), 1.48-1.72 (m, 4H), 1.83-1.94 (m, 4H), 2.65 (s, 2H), 3.10 (sep, J 6.8 Hz, 2H), 4.68 (bs, 1H), 6.70 (s, 2H), 9.50 (s, 1H). ¹³C NMR d 22.7, 25.6, 27.0, 31.1, 43.5, 50.6, 125.2, 127.9, 133.2, 148.5, 207.8. FT-IR (KBr) n_max/ cm^-1: 3520, 2960, 2866, 2712, 1716, 1596, 1383, 1362, 1343, 1306, 1284, 1263, 1125, 1107, 1071, 1033, 959, 938, 882, 863, 847, 831, 812. Mass spectrum m/z 302 (M), 192, 191, 175, 161, 105, 91, 55.

Method 2

2,6-Diisopropyl-4-methoxymethylphenol (0.2 g), cyclohexanecarboxaldehyde (0.2 g), and trifluoroacetic acid (0.1 g) were refluxed in dry dichloromethane (5 mL) under N₂ for 3h. The reaction mixture was evaporated, and the product chromatographed on silica (dichloromethane:hexane, 1:1) to yield colourless crystals (0.21 g, 75%), mp 67-68ºC, identical with those obtained above.

3-[4-Hydroxy-3,5-bis(1-methylethyl)phenyl]-2-(1,1 -spirocyclohexyl)propanol (8b)

A mixture of 7b (200 mg) and sodium borohydride (50 mg) in dry ethanol (5 mL) was refluxed overnight. Water (10 mL) was added, the mixture extracted with dichloromethane, and the combined extracts washed with water, dried, and evaporated to give 8b as a pale yellow oil (177 mg, 88%). Found (M+H-H₂O)⁺ 287.2378. C₂₀H₃₁O requires 287.2376. ¹H NMR d 1.26 (d, J 6.8 Hz, 12H), 1.25-1.37 (m, 6H), 1.38-1.62 (m, 4H), 2.58 (s, 2H), 3.13 (sep, J 6.8 Hz, 2H), 3.36 (s, 2H), 4.50 ( bs, 2H), 6.86 (s, 2H). ¹³C NMR d 21.6, 22.8, 26.4, 27.0, 32.3, 38.4, 41.7, 67.6, 125.3, 130.3, 133.1, 148.1. FT-IR (film) n_max/ cm^-1: 3412, 2960, 1595, 1383, 1362, 1264, 1123, 1107, 1073, 974, 940, 926, 883, 812. Mass spectrum m/z 304 (M), 192, 191, 177, 149, 105, 85, 83, 55.

4-[4-Hydroxy-3,5-bis(1-methylethyl)phenyl]-3-(1,1 -spirocyclohexyl)butan-2-ol (9b)

To a solution of aldehyde 7b (75 mg) in dry ether (4 mL) at 0 °C was added dropwise a solution of 1.5 mol L^-1 methyllithium (mL in hexane) under N₂. After 30 min at 0 °C, the mixture was stirred at rt for 15 min, and water (5 mL) added at 0 °C. The mixture was extracted with ether, the extracts washed with water, dried and evaporated to give 9b as colourless crystals (75 mg, 95%), mp 106-107 °C. Found (M+H-H₂O)⁺ 301.2533. C₂₁H₃₃O requires 301.2535. ¹H NMR d 1.19 (d, J 6.6 Hz, 3H), 1.24 (d, J 6.8 Hz, 12H), 1.21-1.63 (m, 10 H), 2.58 (d, J 13.6 Hz, 1H), 2.75 (d, J 13.6 Hz, 1H), 3.13 (sep, J 6.8 Hz, 2H), 3.73 (q, J 6.6 Hz, 1H), 4.70 (bs, 2H), 6.86 (s, 2H). ¹³C NMR d 17.3, 21.4, 21.5, 22.8, 26.3, 27.0, 30.3, 30.8, 37.7, 40.7, 71.0, 125.6, 130.6, 133.1, 148.0. FT-IR (KBr) n_max/ cm^-1: 3417, 2865, 1594, 1382, 1362, 1309, 1282, 1266, 1152, 1098, 1052, 1008, 946, 934, 897, 852 . Mass spectrum m/z 318 (M), 192, 191, 177, 149, 91, 83, 67, 55.

1-(4-Chlorophenyl)-3-[4-hydroxy-3,5-bis(1-methylethyl) phenyl]- 2-methylpropan-1-one (7c)

2,6-Diisopropyl-4-methoxymethylphenol (6)¹⁹ (0.7 g), potassium hydroxide (0.12 g) and 4-chloropropiophenone (1.3 g) were heated under N₂ at 110 ºC for 3h. The reaction mixture was poured into 1% acetic acid (20 mL), and extracted with dichloromethane. The extract were washed with water, dried and evaporated, and the product recrystallised from hexane as colourless crystals (0.71 g, 62%), mp 73-76 ºC. Found (M+H)⁺ 359.1765. C₂₂H₂₈ClO₂ requires 359.1778. ¹H NMR d 1.20 (d, J 6.9 Hz, 3H), 1.24 (d, J 6.9 Hz, 12H), 2.69 (dd, J 14.4, 6.9 Hz, 1H), 3.01-3.16 (m, 1H), 3.69 ( dd, J 14.4, 6.9 Hz, 1H), 4.7 (bs, 1H), 6.84 (s, 2H), 7.48 (d, J 8.5Hz, 2H), 7.82 (d, J 8.5Hz, 2H). ¹³C NMR d 17.9, 23.1, 27.5, 40.2, 43.4, 124.3, 129.1, 130.1, 131.8, 134.0, 135.6, 139.5, 148.6, 203.7. FT-IR (KBr) n_max/ cm^-1: 3443, 3068, 2965, 2925, 2866, 1669, 1589, 1569, 1471, 1400, 1376, 1362, 1291, 1255, 1208, 1152, 1176, 1091, 1043, 1012, 977, 953, 910, 876, 863, 840, 816, 747, 684 . Mass spectrum m/z 360 (M+2), 358 (M), 193, 191, 175, 139, 111.

3-(3,5-Bis(1-methylethyl)-4-hydroxyphenyl)-1-(4 -chlorophenyl)-2-methyl-1-propanol (9c)

A mixture of 7c (200 mg) and excess sodium borohydride (53 mg) in dry ethanol (10 mL) was refluxed overnight, water (12 mL) was added and the mixture was extracted with dichloromethane (30 mL). The extract was washed with water, dried and evaporated to give ca. 1:1 mixture of diastereoisomers of 9c as a colourless oil (170 mg, 85%). ¹H NMR d 0.71 (d, J 6.9 Hz, 3H in isomer A), 0.86 (d, J 6.9 Hz, 3H in isomer B), 1.28 (d, J 6.9Hz, 12H), 2.11-2.15 (m, 1H), 2.29-2.41 (m, 1H in two isomers), 2.73 (dd, J 13.5, J 6.3 Hz, 1H in isomer A), 2.94 (dd, J 13.5, 4.2 Hz, 1H in isomer B), 3.16 (sep, J 6.9 Hz, 2H), 4.52 (d, J 6.9 Hz, 1H in isomer A), 4.64 (d, J 4.5 Hz, 1H in isomer B), 4.8 (bs, 1H), 6.84 (s, 2H, in isomer A), 6.85 (s, 2H, in isomer B), 7.27 (d, J 8.7 Hz, 2H), 7.34 (d, J 8.7Hz, 2H). ¹³C NMR d 13.6, 15.4, 22.8, 27.1, 29.7, 38.6, 39.3, 42.2, 42.3, 76.0, 78.1, 123.9, 124.2, 127.5, 128.1, 128.2, 128.3, 132.1, 132.2, 132.7, 133.1, 133.4, 133.5, 141.7, 142.2, 148.0. FT-IR (film) n_max/ cm^-1: 3437, 2962, 2936, 2877, 1597, 1491, 1470, 1383, 1200, 1152, 1091, 1013, 835 . Mass spectrum m/z 362 (M+2), 360 (M), 342, 300, 299, 220, 219, 192, 191, 178, 177, 163, 149, 141, 107, 91, 77.

4-[4-Hydroxy-3,5-bis(1-methylethyl)phenyl]-3,3-dimethyl -2-butanone (7d)

2,6-Diisopropyl-4-methoxymethylphenol (6)¹⁹ (600 mg), potassium hydroxide (100 mg) and 3-methyl-2-butanone (600 mg) were heated under N₂ at 100 °C for 2h. The reaction mixture was poured into 1% acetic acid (10 mL), and extracted with dichloromethane. The extracts were washed with water, dried and evaporated, and the product recrystallised from hexane as a white solid (620 mg, 82%), mp 76-77 ºC. ¹H NMR d 1.1 (s, 2H), 1.24 (d, J 6.8Hz, 12H), 2.09 (s, 3H), 2.73 (s, 2H), 3.13 ( sep, J 6.8Hz, 2H), 4.45 (bs, 1H), 6.75 (s, 2H). ¹³C NMR d 22.77, 24.15, 26.33, 26.95, 45.49, 48.69, 125.14, 129.37, 133.14, 148.39, 214.47. FT-IR (KBr) n_max/ cm^-1: 3488, 2962, 2869, 1696, 1595, 1470, 1363, 1310, 1281, 1202, 1153, 1114. Found (M+H-Me₂CHCOMe)⁺ 191.1436 requires (M+H-Me₂CHCOMe)⁺ 191.1430. Mass spectrum m/z 276 (M), 261, 233, 192, 191, 175, 147, 105, 91, 55.

4-[4-Hydroxy-3,5-bis(1-methylethyl)phenyl]-3,3 -dimethyl-2-butanol (9a)

A mixture of 7d (138 mg) and sodium borohydride (48 mg) in dry ethanol (4 mL) was refluxed for 1h. Water (10 mL) was added, the mixture extracted with dichloromethane, and the combined extracts washed with water, dried, and evaporated to give 9a, which was recrystallised from hexane as a white solid (122 mg, 87%). ¹H NMR d 0.81 (s, 3H), 0.86 (s, 3H), 1.19 (d, J 6.4Hz, 3H), 1.26 (d, J 13.2Hz, 1H), 2.60 (d, J 13.2Hz, 1H), 3.15 (sep, J 6.8Hz, 2H), 3.55 (q, J 6.4Hz, 1H), 4.25 (bs, 2H), 6.84 (s, 2H). ¹³C NMR d 17.89, 21.73, 22.83, 22.99, 26.95, 38.62, 44.31, 74.17, 125.60, 130.50, 132.96, 148.06. FT-IR (KBr) n_max/ cm^-1: 3421, 2963, 2870, 1472, 1383, 1201, 1092. Found (M+H-H₂O)⁺ 261.2219 requires (M+H-H₂O)⁺ 261.2218. Mass spectrum m/z 278(M), 260, 233, 192, 191, 177, 161, 149, 105, 91, 77, 55.

3-(3,5-Bis(1-methylethyl)-4-methoxyphenyl)-2,2 -dimethylpropanal

A mixture of 3-(3,5-bis(1-methylethyl)-4-hydroxyphenyl)-2,2-dimethylpropanal (300 mg) and potassium hydroxide (65 mg) in ethanol (5 mL) was stirred vigorously at room temperature. Then dimethyl sulfate (360 mg, excess) was added to the mixture which was stirred vigorously at 20 °C for 1 h. The mixture was warmed for 30 min at 60-70 °C in order to complete the methylation. After cooling, 10% NaOH (45 mL) was added with vigorous stirring. The product was extracted with dichloromethane (30 mL), washed, and dried over Na₂SO₄. Removal of the solvent gave the title compound as a colourless viscous oil (290 mg, 92%). ¹H NMR d 1.1 (s, 6H), 1.23 (d, J 6.9Hz, 12H), 2.75 (s, 2H), 3.32 (sep, J 6.9Hz, 2H), 3.73 (s, 3H), 6.81 (s, 2H), 9.61 (s, 1H). ¹³C NMR ä 21.33, 24.09, 26.30, 43.27, 46.91, 62.2, 125.92, 132.58, 141.19, 153.12, 206.16. FT-IR (film) n_max/ cm^-1: 2963, 2925, 2828, 2699, 1726, 1471, 1363, 1283, 1214, 1164, 1119, 1016, 884 . Mass spectrum m/z 276 (M), 274, 259, 225, 217, 205, 202, 192, 189, 177, 175, 174, 91, 83, 69, 57, 55, 43, 41.

3-(3,5-Bis(1-methylethyl)-4-methoxyphenyl)-2,2 -dimethylpropanol (14)

A mixture of 3-(3,5-bis(1-methylethyl)-4-methoxyphenyl)-2,2-dimethylpropanal (290 mg) and sodium borohydride (100 mg, excess) in dry ethanol (5 mL) was refluxed overnight. Water was added to the mixture, which was then extracted with dichloromethane (30 mL), and the extract washed with water and dried over Na₂SO₄. Removal of the solvent gave a colourless solid which was recrystallised from n-hexane mp 66-68 °C (260 mg, 89%). ¹H NMR d 0.87 (s, 6H), 1.22 (d, J 7Hz, 12H), 2.52 (s, 2H), 3.28-3.34 (m, 4H), 3.71 (s, 3H), 6.85 (s, 2H). ¹³C NMR d 23.33, 24.79, 25.50, 27.10, 36.30, 61.02, 63.15, 125.18, 127.02, 134.46, 140.81. FT-IR (KBr) n_max/ cm^-1: 3497, 3016, 2965, 2920, 2871, 1472, 1362, 1283, 1211, 1163, 1116, 1055, 1013, 881, 795. Mass spectrum m/z 278 (M), 206, 205, 189, 175, 163, 91.

Reaction of 2,6-dimethylphenol with formaldehyde

A solution of potassium hydroxide (3.2 g in 3.2 mL water) was added under nitrogen to a solution of 2,6-dimethylphenol (5.0 g, 0.04 mol) and 36 % formaldehyde (8 mL) in methanol (50 mL). The solution was refluxed for 30 min under a current of nitrogen, cooled to room temperature and the precipitated 16 was collected and washed with cold water as pale yellow crystals, mp 174-176 ºC (lit.²⁰ mp 172-176ºC). ¹H NMR d 2.24 (s, 12H), 3.72 (s, 2H), 6.80 (s, 4H, ArH). ¹³C NMR d 15.9, 4 ´ CH₃; 40.2, CH₂; 122.9, ArC; 128.8, ArCH; 133.4, ArC; 150.3. FT-IR (KBr) n_max/ cm^-1: 3463, 3008, 2916, 2848, 1608, 1474, 1484, 1437, 1375, 1304, 1186, 1146, 882, 731.

Di-[3-{4-hydroxy-3,5-bis(ethylmethyl)phenyl}-2 -spirocyclohexyl]propylamine (11)

Aldehyde 7b (410 mg), ammonium acetate (1.54 g), and sodium cyanoborohydride (168 mg, 2 equiv.) in methanol (5 mL) were stirred at rt for 48 h. The reaction mixture was evaporated to dryness, and water (10 mL) added. The mixture was extracted with ether (3´10 mL) and the dried extract evaporated. The residue (386 mg) was chromatographed on silica (dichloromethane:methanol 1:1) to give 11 as a white solid (250 mg, 61%), mp 75-80 ºC. Found (M+H)⁺ 590.4941. C₄₀H₆₄NO₂ requires 590.4937. ¹H NMR d 1.24 d, J 6.8 Hz, 24H), 1.25-1.66 (m, 20H), 2.60 (s, 4H), 2.71 (s, 4H), 3.12 (sep, J 6.8 Hz, 4H), 5.65 (bs (exch), 2H), 6.81 (s, 4H). ¹³C NMR d 21.4, 22.7, 25.6, 27.1, 33.1, 37.0, 42.1, 57.7, 125.6, 128.9, 133.6, 148.8. FT-IR (KBr) n_max/ cm^-1: 3362, 3199, 2959, 2930, 2866, 1469, 1383, 1361, 1285, 1202, 1152, 1124, 910.

Acknowledgments

J.K. is grateful for support from Urmia and Flinders Universities for study leave.

References

1. Urwyler, S.; Lingerhoehl, K.; Mosbacher, J.; Heid, J.; Hofstetter, K.; Froestl, W.; Bettler, B.;. Kaupmann, K; Mol. Pharmacol. 2001, 60, 963.

2. Kerr, D.I.B.; Ong, J.; Perkins, M.V.; Prager, R.H.; Puspawati, N.M.; Aust. J. Chem. 2006, 59, 445; see Part 2: Kerr, D.I.B.; Khalafy, J.; Ong, J.; Perkins, M.V.; Prager, R.H.; Puspawati, N.M.; Rimaz, M.; Aust. J. Chem. 2006, 59, 457.

3. Christopoulos, A.; Nature Rev. Drug Discovery 2002, 1, 198.

4. Kerr, D.I.B.; Ong, J.; Puspawati, N.M.; Prager, R.H.; Eur. J. Phamacol. 2002, 451, 69.

5. Kerr, D.I.B.; Ong, J.; In Allosteric Receptor Modulation in Drug Targeting; (Bowery, N.G.) ed., Marcel Dekker Inc: New York, 2006.

6. Trapani, G.; Latrofa, A.; Franco, M.; Altomare, C.; Sanna, E.; Usala, M.; Biggio, G.; Liso, G.; J. Med. Chem. 1998, 41, 1846.

7. Bennet, D.J.; Anderson, A.; Buchanan, K.; Byford, A.; Cooke, A.; Gemmel, D.K.; Hamilton, N.M.; Maidment, M.S.; McPhail, P.; Stevenson, D.F.M.; Sundaram, H.; Vijn, P.; Bioorg. Med. Chem. Lett. 2003, 13, 1971.

8. Guing Ting, W.C.; Chan, K.F.Y.; Gibson, K.M.; Snead, O.C.; Toxicol. Rev. 2004, 23, 3.

9. Kerr, D.I.B.; Khalafy, J.; Ong, J.; Perkins, M.V.; Prager, R.H.; Puspawati, N.M.; Rimaz, M.; Aust. J. Chem. 2006, 59, 457 .

10. Borch, R.F.; Bernstein, M.D.; Durst, H.D.; J.Am. Chem. Soc. 1971, 93, 2897.

11. Kharasch, M.S.; Joshi, B.S.; J. Org. Chem. 1957, 22, 1435.

12. Ong, J.; Parker, D.A.S.; Marino, V.; Kerr, D.I.B.; Puspawati, N.M.; Prager, R.H.; Eur. J. Pharmacol. 2005, 507, 35.

13. Horne, A.L.; Harrison, N.L.; Turner, J.P.; Simmond, M.A.; Eur. J. Phamacol. 1986, 122, 231.

14. Bowery, N.G.; Bettler, B.; Froestl, W.; Gallagher, J.P.; Marshall, F.; Raterri, M.; Bonner, T.I.; Enna, S.J.; Pharmacol. Rev. 2002, 54, 247.

15. Kerr, D.I.B.; Ong, J.; Curr. Med.Chem.-CNS Agents 2001, 1, 27.

16. Bowery, N.G.; Hill, D.R.; Hudson, A.L.; Br. J. Pharmacol. 1983, 78, 191.

17. Bowery, N.G.; Doble, A.; Hill, D.R.; Hudson, A.L.; Shaw, J.S.; Turnbull, M.J.; Warrington, R.; Eur. J. Pharmacol. 1981, 71, 53.

18. Perrin, D.D.; Amarego, W.L.F.; Purification of Laboratory Chemicals, 3^rd ed., Pergamon Press: Oxford, 1988.

19. Shin, K.H.; U.S. Patent 1987 4692555 A19870908. [Chem. Abstr., 1987, 108, 150045].

20. Bamberger, E.; Chem. Ber. 1903, 36, 2028.

Received: September 13, 2006

Web Release Date: June 19, 2007

†

Deceased, July 2005

Publication Dates

• Publication in this collection
  18 Sept 2007
• Date of issue
  2007

History

• Accepted
  06 June 2007
• Received
  13 Sept 2006