Chinese Journal of Chemistry, 2009, 27, 433—436 Note

* E-mail: wlxioc@cioc.ac.cn; Tel./Fax: 0086-028-85255208 Received May 6, 2008; revised August 20, 2008; accepted October 30, 2008.

© 2009 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Improved Preparation of Tyramine by Curtius Rearrangement

LI, Yuna(李云) YANG, Fana(杨帆) XU, Xiaoyingb(徐小英) PAN, Shiyinb(潘士印) WANG, Lixin*,b(王立新) XIA, Chuanqin*,a(夏传琴)

a Department of Chemistry, Sichuan University, Chengdu, Sichuan 610041, China b Key Laboratory of Asymmetric Synthesis & Chirotechnology of Sichuan Province and National Engineering

Research Center of Chiral Drugs, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, Sichuan 610041, China

An improved and facile preparation of tyramine [2-(p-hydroxyphenyl)ethylamine] was described, which starts from phenol and acrylonitrile to form β-(p-hydroxyphenyl) propionic acid via Friedel-Craft’s alkylation and nitrile hydrolysis. After hydrazinolysis and a subsequent Curtius rearrangement, tyramine was obtained in 30.2% total yield.

Keywords preparation, tyramine, β-(p-hydroxyphenyl)propionic acid, curtius rearrangement

Introduction

Tyramine [2-(p-hydroxyphenyl)ethylamine], has been extensively used as a catecholamine drug, which can inhibit the toxic effects of neurotoxins, treat and diagnose neurodegenerative diseases and disorders.1 Moreover, it is also an important intermediate for or-ganic and pharmaceutical synthesis, such as that of bezafibrate2 (Scheme 1).

Scheme 1 Tyramine as the key intermediate of bezafibrate

Tyramine was first separated from ergotine and rot-ted animals’ bodies3 and originally prepared by decar-boxylation of tyrosine.4 Other chemical preparations were also widely published. For example, Barger and Walpole5 used phenylacetonitrile as the starting material, and after nitration, stannum reduction and hydrogena-tion of the diazotizated p-hydroxyphenylethylcyanide, finally synthesized tyramine. Reduction of 2-(4-hy- droxyphenyl)-2-oxoacetaldehyde oxime catalyzed by palladium also gave tyramine in a good yield.6 Another method7 starting from p-methoxybenzaldehyde, through multistep reactions and a key Hoffmann step in a high yield was also reported. But this process involved so-dium azide, which was highly toxic and explosive. Re-cent preparation starting from phenyl methyl ether to prepare tyramine with Hoffmann degradation in a high yield was reported in a Chinese patent.8 Tafesh and

Wood reported two processes via hydrogenation of 4-hydroxy-α-halo-α-oximinoacetophenones9 and reduc-tion of isonitrosoalkanone.10 Wang11 also reported a method via reduction of 4-hydroxy-β-nitrostyrene. However it was found that the selectivities of these re-ductions were poor and the products were difficult to be separated.

The Curtius rearrangement is one of the most widely used methods to manufacture amine derivatives and a number of these methods have been developed to obtain acyl azides from carboxylic acid derivatives, such as hydrazides,12 acyl chlorides,13 and mixed anhydrides.14

Herein we devise and report an improved and facile preparation of tyramine, which starts from phenol and acrylonitrile to form β-(p-hydroxyphenyl)propionic acid via Friedel-Craft’s alkylation and nitrile hydrohysis. After hydrazinolysis and a subsequent Curtius rear-rangement, Tyramine was obtained in a 30.2% total yield (Scheme 2).

Results and discussion

Phenol was satisfactorily 2-cyanoethylized with acrylonitrile in a 71% yield via Friedel-Craft’s alkyla-tion catalyzed by aluminum chloride.15 Phenol, byprod-ucts and β-(p-hydroxyphenyl)propionyl nitrile were eas-ily separated and purified by vacuum rectification. The obtained nitrile 1 was hydrolyzed in alkaline condition t o f o r m a c i d 2 ( a l s o c a l l e d h y d r o g e n a t e d p-hydroxycinnamic acid). This method also provides a new and economical approach to the preparation of β-(p-hydroxyphenyl)propionic acid, which is a key in- termediate for Esmolol, an ultra-short-acting β-antagonist16,17

and generally prepared by hydrogena-tion of p-hydroxycinnamic acid.

434 Chin. J. Chem., 2009, Vol. 27, No. 2 LI et al.

© 2009 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Scheme 2 Preparation of tyramine by Curtius rearrangement

In the process of hydrazinolysis, the acid 2 was di-rectly converted to 3 with 80% aqueous hydrazine hy-drate in toluene by an azeotropic process quantitatively. The excess aqueous hydrazine hydrate was removed just by simple filtration after water was completely removed and the separated aqueous solution could be reused. This procedure is soundly convenient and practical in larger scale preparation. Hydrazides are generally pre-pared by hydrazinolysis of ester.18 In contrast, our pro-cedures directly using aqueous hydrazine and hydro-genated p-hydroxycinnamic acid are lower cost and more atom economical. Diazotization of hydrazide 3 gave active azidocarbonyl intermediate 4 under the di-azotizing condition in 1,2-dichloroethane (DCE) below 5 . The DCE solution of ℃ β-(p-hydroxyphenyl)pro- pionyl azide which is quite safe and stable under cool-ing conditions (generally below 5 ) was used directly ℃

in the next step without storage. The key Curtius rearrangement step was carried out

by one-pot or separated procedures. The azidocarbonyl intermediate 4 was heated to 75—80 ℃ in DCE and isocyanate 5 was formed with a little carbamide by-product (solid) if drying was insufficient and a hint of water existed. Hydrochloric acid was added in the newly formed isocyanate 5 solution and the reaction took place immediately to form tyramine hydrochloride.

This process may also take place in one pot in a lower yield and selectivity. The azidocarbonyl interme-diate 4 and concentrated hydrochloric acid may be added in DCE together and heated to 75—80 ℃. The in situ formed isocyanate solution reacted with hydrochlo-ric acid directly and tyramine hydrochloride formed immediately. For safety, this one pot preparation proc-ess was not recommended.

During the process of Curtius rearrangement, the

temperature must be controlled strictly. Generally, the reaction did not work until the temperature reached 75 ℃. At lower temperature, it was very dangerous if ac-tive intermediate 4 accumulated. Once the rearrange-ment started, it took place fiercely and nitrogen gas evolved at the same time. The rearrangement of the azide was completed when nitrogen evolution ceased. The solid carbamide by-product would be detected if a hint of water existed in the azidocarbonyl intermediate solution especially in the one-pot process. After filtra-tion, the filtrate could be used in the next batch. Carbon dioxide was copiously evolved when the isocyanate so-lution was added gradually and cautiously to the con-centrated hydrochloric acid. It might cause the solution to foam over if the isocyanate solution was added too speedily.

Experimental

Materials and apparatus

All solvents and reagents were obtained from com-mercial sources and used without further purification. NMR spectra were recorded in CDCl3, DMSO-d6, D2O or CD3OD solution at room temperature on a Bruker DPX 300-MHz spectromter. MS data were recorded on a Bio TOF Q instrument of Bruker Daltonics Int. IR spectra were performed on a nicolet MX-1E FT-IR in-strument.

Synthesis of β-(p-hydroxyphenyl)propionitrile (1)15

A three necked flask, equipped with a mechanical stirrer and a thermometer, was charged with phenol (313 g, 3.33 mol), acrylonitrile (215 g, 4.05 mol), and aluminium chloride (222 g, 1.66 mol) in portions over 30 min at 30 ℃. The mixture was stirred for 3 addi-tional hours at this temperature, reacted for 6 additional hours at 105 ℃, then cooled to 70 ℃, and poured into 2000 mL of cold water. The solution was stirred for an-other 30 min at 70 ℃ and separated. The organic solu-tion was washed to neutral with 70 ℃ hot water. The organic layer was rectified on a 15 cm high coloum with a diameter of 12.5 mm, filled with glass helices (2.5 mm, single turn) to give 1 (348 g, 71%), at 190—170 ℃ (9.8—9.6 KPa).

Synthesis of β-(p-hydroxyphenyl)propionic acid (2)

To a three necked flask, 320 mL of water, β-(p-hydroxyphenyl) propionitrile (250 g, 1.70 mol) and sodium hydroxide (160 g) were added in portions for 30 min and the mixture was refluxed for 6 h. After acidifi-cation of pH to 1 with concentrated hydrochloric acid at 10 ℃, the mixture was filtered, and the filter cake was dried to give 2 (259 g, 92%).19 1H NMR (CD3OD, 300 MHz) δ: 7.02 (d, J＝8.4 Hz, 2H), 6.94 (d, J＝8.4 Hz, 2H), 2.80 (t, J＝7.5 Hz, 2H), 2.53 (t, J＝7.8 Hz, 2H); 13C NMR (CD3OD, 75 MHz) δ: 177.1, 156.3, 132.9, 130.2, 116.1, 37.0, 31.0.

Tyramine Chin. J. Chem., 2009 Vol. 27 No. 2 435

© 2009 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis of β-(p-hydroxyphenyl)propionyl hy-drazide (3)

A 1000-mL three necked flask, equipped with a me-chanical stirrer, a thermometer and a Dean-Stark trap, was charged with toluene (400 mL), β-(p-hydroxy- phenyl)propionic acid (83 g, 0.50 mol) and 80% aque-ous hydrazine hydrate (37 mL). After an azeotropic process by refluxing for about 6 h without obvious wa-ter forming, the mixture was cooled, filtered, and the obtained crude solid was recrystallized from 140 mL of ethanol to give 3 (85.0 g, 94.4%). 1H NMR (DMSO-d6, 300 MHz) δ: 9.14 (s, 1H), 8.93 (s, 1H), 6.97 (d, J＝8.5 Hz, 2H), 6.64 (d, J＝8.9 Hz, 2H), 4.17 (s, 2H), 2.68 (t, J＝7.8 Hz, 2H), 2.24 (t, J＝7.8 Hz, 2H); 13C NMR (DMSO-d6, 75 MHz) δ: 171.1, 155.5, 131.3, 129.1, 115.1, 35.7, 30.3; IR (KBr) v: 3324, 3284, 3202, 1648, 1620, 1595, 1515, 1458, 1259, 1240, 822, 803 cm－1; ESI-MS m/z: 179 (M＋

－1), 181 (M＋

＋1), 203 (M＋

＋

23); HRMS (ESI-MS) calcd for (C9H12N2O2＋Na)＋ 203.0791, found 203.0790.

Synthesis of tyramine hydrochloride (6)

Method 1 (separated process) To a 1000-mL three necked flask equipped with a mechanical stirrer, and a thermometer, filled with 300 mL of water, β-(p- hydroxyphenyl) propionyl hydrazide 3 (72 g, 0.40 mol), 62 mL of concentrated hydrochloric acid and 300 mL of 1,2-dichloroethane at 0 ℃ was added dropwise 131 g of sodium nitrate solution (31 g in 100 mL of water) below 5 ℃. The mixture was allowed to stir for another 20 min and extracted with 1,2-dichloroethane (150 mL×3). The organic phase was washed with water and dried with anhydrous calcium chloride (by constant cooling) below 5 ℃. The dried solution was filtered, and carefully added dropwise (by constant cooling be-low 5 ℃) to a flask with 100 mL of 1,2-dichloroethane in 75—80 ℃. When nitrogen evolution ceased, the mixture was refluxed for additional 1 h, then cooled and left stand-by.

The above 1,2-dichloroethane solution was added dropwise to 350 mL of concentrated hydrochloric acid solution at 0 ℃. The mixture was heated to reflux for about 4 h until carbon dioxide evolution ceased. After being cooled to 5 ℃ and stirred in a hydrogen chloride atmosphere, the mixture was filtered and the filter cake was dried. The crude product 6 (42.0 g) was decolorized in methanol with 0.05 g of EDTA and 4.0 g of active carbon, filtered and crystallized. 32 g of qualified 6 were obtained in a 49.0% yield.20 1H NMR (D2O, 300 MHz) δ: 7.20 (d, J＝7.1 Hz, 2H), 6.89 (d, J＝8.4 Hz, 2H), 3.23 (t, J＝7.2 Hz, 2H), 2.92 (t, J＝7.2 Hz, 2H); 13C NMR (D2O, 75 MHz) δ: 154.1, 129.86, 128.0, 115.4, 40.4, 31.5.

Method 2 (one-pot process, not recommended) The same as the above procedure, except adding the dried solution of 4 directly to 350 mL of concentrated hydrochloric acid solution in 75—80 ℃. After usual work-up 27 g of 6 were obtained in a 41.0% isolated

yield.

Conclusion

In conclusion, we have developed an efficient and improved synthetic pathway for the preparation of tyramine starting from commercially available phenol in four steps in a 30.2% total yield based on the main reac-tion of Curtius rearrangement. This method proves to be as equally economical as other syntheses.

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