Process for the preparation of 2- (aryloxymethyl)-2, 5, 7, 8- tetramethylchroman-6-ols The present invention relates to a process for the preparation of 2- (aryloxymethyl)-2,5,7,8-tetra- methylchroman-6-ols of the general formula in which Ru, R I R R and R independently of one another are each hydrogen, C1_4-alkyl, C14-alkoxy, 1-di (C1_4-alkoxy)-Cl4-alkyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 2-(C13-alkyl)-1,3-dioxolan-2-yl, 2-(C13-alkyl)-1,(C13-alkyl)-1, 3-dioxan-2-yl, halogen or amino, or are a C14-alkyl group substituted by an aromatic or nonaromatic isocyclic or heterocyclic ring system.

In particular, C14-alkyl is here and below taken to mean methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

Correspondingly, C14-alkoxy is taken to mean the groups composed of C14-alkyl and oxygen.

1-Di (C14-alkoxy)-Cl-4-alkyl means the acetals or ketals of C14-acyl groups obtainable by acetylation with C14-alkanols. Correspondingly, 1,3-dioxolan-2-yl and 2- (C1_3-alkyl)-1, 3-dioxolan-2-yl, and 1,3-dioxan-2- yl and 2- (C13-alkyl)-1, 3-dioxan-2-yl mean the cyclic acetals or ketals of C14-acyl groups obtainable by acetylation with ethanediol or 1,3-propanediol, or ketals of C14-aycl groups. C14-Acyl groups are, in particular, formyl, acetyl, propionyl, butyryl and isobutyryl.

Halogen here means fluorine, chlorine, bromine or iodine, in particular fluorine.

Aromatic isocyclic ring systems are taken to mean, for example, phenyl, naphthyl, anthracenyl or phenanthrenyl, and nonaromatic isocyclic ring systems are in particular taken to mean C3-8-cycloalkyl or bicyclic hydrocarbon radicals such as, for example, norbornyl.

Aromatic heterocyclic ring systems are, for example, taken to mean pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, thiophenyl, furyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl or indolyl, and nonaromatic heterocyclic ring systems are, for example, taken to mean pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuryl, thiazo- lidinyl or tetrahydropyranyl.

The 2- (aryloxymethyl)-2, 5, 7,8-tetramethyl- chroman-6-ols which can be prepared according to the invention are pharmaceutical active ingredients or intermediates for the preparation of pharmaceutical active ingredients, for example hypolipidemics (J. Med.

Chem. 1989,32,421).

It is known that compounds of the formula I, in particular those in which Ru, R2, R4 and R5 are hydrogen and R3 is amino, can be prepared in two or more stages from the corresponding 6-hydroxy-2,5,7,8-tetramethyl- chroman-2-carboxylic acids or from 2,5-dihydroxy-3,4,6- trimethylacetophenone (EP-A-0 139 421). It is further known to prepare such compounds from the corresponding 2-(aryloxymethyl)-2, 5, 7, 8-tetramethylchroman-6-ol-4- ones (EP-A-0 556 830).

The object of the present invention was to provide an alternative process for the preparation of 2- (aryloxymethyl)-2,5,7,8-tetramethylchroman-6-ols which requires only readily available starting materials and which is suitable for implementation on an industrial scale.

According to the invention, this object is achieved by the process according to Claim 1. It has been found that the phenethyloxiranes known from the synthesis of vitamin E (EP-A-0 129 252) and of the general formula

in which R is a protective group which can be cleaved off hydrogenolytically, are reacted with a phenol of the general formula

in hi h R1 R2 R3 R4 and R5 are each as defined above for R1, R2, R3, R4 and R5, or can be converted into one of these groups by hydrogenation or hydrogenolysis, in a first stage to give 2-methyl-1-phenoxy- 4-phenylbutan-2-ols of the general formula

in which R and R1 to R5 are as defined above, and the latter can be converted into the target compound in a second and third stage by catalytic hydrogenolysis and optional hydrogenation and subsequent acid-catalysed cyclization.

Groups R1 to R5 which can be converted by hydrogenation into one of the groups R1 to R5 are, for example, nitro (convertible into amino) and 1-hydroxy- C14-alkyl or C14-acyl (each convertible into C1_4-alkyl).

Preference is given to using those phenethyloxiranes (II) in which R is optionally substituted benzyl.

Suitable substituents here are, in particular, C1_4-alkyl groups and/or C14-alkoxy groups.

The reaction of the phenethyloxirane (II) with the phenol (III) is preferably carried out with a strong base in a dipolar aprotic solvent.

Examples of suitable strong bases are alkali metal hydrides, Grignard compounds, alkyllithium compounds, alkali metal hydroxides or optionally also alkali metal carbonates. Particular preference is given to sodium hydride.

Particularly preferred dipolar aprotic solvents are N, N-dimethylacetamide, N-methylpyrrolidine and, in particular, N, N-dimethylformamide.

The catalysts used for the hydrogenolysis/hydrogenation are preferably heterogeneous noble-metal catalysts.

Particular preference is given to palladium on activated carbon.

The second and third stage of the process according to the invention are preferably carried out in a single process step. This can be achieved by carrying out the hydrogenolysis/hydrogenation in the presence of a strong acid. Examples of suitable strong acids are hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulfonic acids such as p-toluene- sulfonic acid or camphorsulfonic acid or activated carboxylic acids such as trifluoroacetic acid.

Particular preference is given to the preparation of 2- (4-aminophenoxymethyl)-2,5,7,8- tetramethylchroman-6-ol (I; R1 = R2 = R4 = Rs = H, R3 = NH2), which starts from 4-nitrophenol (III; R1' = R2' = R4' = R5'= H, R3 = NO2).

The 2- (4-aminophenoxymethyl)-2,5,7,8-tetra- methylchroman-6-ol prepared according to the invention is preferably, for the preparation of 5-{4-(6-hydroxy- 2,5,7,8-tetramethylchroman-2-ylmethyloxy) phenyl]- methylXthiazolidine-2,4-dione of the formula

(=T; R1 = R = R = Rs = H, R3 = 2,4-dioxothiazolidin-5- ylmethyl), diazotized in additional steps and reacted with a C16-alkyl acrylate in the presence of a copper chloride or bromide to give an alkyl 2-halo-3- (4-chromanylmethyloxyphenyl) propionate of the general formula

in which is X is chlorine or bromine, and R6 is C16-alkyl, and this is converted into the target compound using thiourea.

In particularly preferred terms, R6 is butyl and X is preferably bromine.

The examples below illustrate how the process according to the invention is carried out but are not intended to impose any limitation.

Example 1 8-tetramethylchroman-6-ol Trimethylhydroquinone (152.2 g, 1 mol), trimethyl orthoformate (150 ml, 1.37 mol) and methanol (600 ml) were mixed at room temperature and then cooled to 0-3°C. Conc. sulfuric acid (2.5 ml, 2 mmol) was then added and subsequently methyl vinyl ketone (145.3 g, 2.07 mol) was added dropwise over the course of 3 h.

The resulting suspension was stirred at room temperature for 44 h. Diethyl ether (450 ml) and saturated aqueous sodium hydrogencarbonate solution (100 ml) were then added, and the two phases were separated. The organic phase was concentrated by evaporation and the solid residue was dried at 50°C/25 mbar. Yield: 246.7 g of crude product (about 100%).

For purification, 177.7 g of crude product were recrystallized from 1.8 1 of methanol/water (v: v = 2: 1). This gave 154.9 g of pure product. m. p. : 124-125°C, colourless solid 'H NMR (CDC13,400 (s, 1H); 3.20 (s, 2H); 2.77 (m, 1H); 2.55 (m, 1H); 2.20 (s, 6H); 2.12 (s, 3H + m, 1H); 1.80 (m, 1H); 1.57 (s, 3H).

Example 2 2,5,7,8-Tetramethylchroman-2,6-diol 2-Methoxy-2,5,7,8-tetramethylchroman-6-ol (40 g, 169 mmol) was dissolved in acetone (204 ml) and water (163 ml) at room temperature, and then conc. hydrochloric acid (1.62 g, 16 mmol) was added thereto.

The solvent was then distilled off until the head

temperature of the distillation bridge reached 92°C.

The heating source was removed, the solution was cooled to 70°C, and acetone (130 ml) was added. The solution was then further cooled slowly to 0°C, and the product crystallized out. After 1 h, this was filtered off, washed with water (2 x 50 ml) and dried under reduced pressure.

Yield: 30.6 g (81%).

The 1H NMR spectrum showed the presence of a mixture of keto and lactol form.

Example 3 6-Benzyloxy-2-methoxy-2,5,7,8-tetramethylchroman 2-Methoxy-2,5,7,8-tetramethylchroman-6-ol (40 g, 169 mmol) was dissolved in dimethyl sulfoxide (164 ml) at room temperature, and then potassium carbonate (52 g, 372 mmol) was added, and then benzyl chloride (42.8 g, 336 mmol) was added dropwise. The mixture was stirred for 40 h at room temperature. Water (300 ml) and diethyl ether (300 ml) were then added, and the two phases were separated. The aqueous phase was extracted with diethyl ether (2 x 200 ml), and the combined organic phases were washed with water (3 x 200 ml) and dried over sodium sulfate. Following filtration, the solvent was distilled off on a rotary evaporator (30°C/250->25 mbar).

Yield: 57.75 g (about 100%, crude product). lH NMR (CDC13,400 MHz): 8 = 7.50-7.25 (m, 5H); 4.70 (s, 2H); 3.20 (s, 3H); 2.80-2.70 (m, 1H); 2.60- 2.55 (m, 1H); 2.22 (s, 3H); 2.18 (s, 3H); 2.16 (s, 3H); 2.15-2.10 (m, 1H); 1.85-1.78 (m, 1H); 1.58 (s, 3H).

Example 4 6-Benzyloxy-2,5,7,8-tetramethylchroman-2-ol 6-Benzyloxy-2-methoxy-2,5,7,8-tetramethyl- chroman (50 g, 153 mmol) was dissolved in acetone (300 ml) at room temperature, and hydrochloric acid (0.1 N, 155 ml, 16 mmol) was added thereto. The solvent was then distilled off up to a head temperature of 92°C. The heating source was removed, and the solution was cooled to 70°C, and acetone (150 ml) was added. The mixture was then further concentrated by evaporation until the head temperature reached 97°C. After the residue had been cooled to room temperature, diethyl ether (200 ml) was added, and the two phases were separated. The aqueous phase was extracted with diethyl ether (2 x 100 ml), then the combined organic phases were concentrated by evaporation on a rotary evaporator (20-+40°C/200-+25 mbar).

Yield: 42.6 g of crude product (89%).

The 1H NMR spectrum showed the presence of a mixture of keto and lactol form.

Example 5 4- (2,5-Dibenzyloxy-3,4,6-trimethylphenyl) butan-2-one 6-Benzyloxy-2,5,7,8-tetramethylchroman-2-ol (40 g, 128 mmol) was dissolved in dimethyl sulfoxide (130 ml). Potassium carbonate (21.5 g, 154 mmol), benzyl chloride (16.29 g, 128 mmol) and 5 mol% of potassium iodide (1.06 g, 6.4 mmol) were then added, and the reaction mixture was stirred at room temperature for 22 h. Since the reaction was not complete, the same amount of benzyl chloride was again added, and the reaction mixture was stirred for a further 2 h at room temperature and finally heated at 50°C for 1 h. Water (200 ml) and diethyl ether (150 ml) were then added. The phases were separated, and the aqueous phase was extracted with diethyl ether (2 x 150 ml). The combined organic phases were washed with water (2 x 150 ml), dried over sodium sulfate and,

after filtration, concentrated by evaporation on a rotary evaporator (30°C/250-+25 mbar).

Yield: 56.85 g of crude product.

The crude product was purified by flash chromatography over silica gel (eluent: hexane/diethyl ether, v: v = 4: 1, yield 77%). Further purification was possible by recrystallization from hexane (yield: 64%).

IR (KBr): v = 3448m, 3032s, 2879m, 1706s, 1453s, 1414m, 1366s, 1243s, 1167m, 1085s, 1023m, 1001m, 747m, 696s.

'H NMR (CDC13,400 MHz): 8 = 7.50-7.35 (m, 10H) ; 4.77 (s, 2H); 4.73 (s, 2H); 2.97-2.92 (m, 2H); 2.62- 2.58 (m, 2H); 2.22 (s, 9H); 2.07 (s, 3H).

Example 6 4- (2, 5-Dibenzyloxy-3,4,6-trimethylphenyl) butan-2-one was reacted with benzyl chloride/potassium carbonate in dimethyl sulfoxide as in Example 5. The reaction time was 19 h.

Flash chromatography gave a yield of 20%.

Example 7 2- 2- (2, 5-Dibenzyloxy-3,4,6-trimethylphenyl) ethyl]-2- methyloxirane Trimethylsulfoxonium iodide (8.74 g, 38.51 mmol) was dissolved in dimethyl sulfoxide (80 ml). Then, 4- (2,5-dibenzyloxy-3,4,6-trimethyl- phenyl) butan-2-one (10.0 g, 24.84 mmol) was added, and finally a solution of potassium tert-butoxide (4.45 g, 38.51 mmol) in dimethyl sulfoxide (60 ml) was added at room temperature over the course of 10 min. The reaction mixture was stirred at room temperature for 16 h. Water (160 ml) was then added (exothermic reaction), and the mixture was extracted with

dichloromethane (3 x 100 ml). The combined organic phases were washed with water (2 x 60 ml). The solvent was distilled off and the solid residue was dried.

Yield: 11.27 g (about 100%).

IR (NaCl): v = 2923m, 1497s, 1454s, 1415s, 1367s, 1262w, 1244s, 1083s, 1003m, 735s, 697s.

1H NMR (CDC13,400 MHz): 8 = 7.50-7.30 (m, 10H); 4.77 (s, 2H); 4.73 (s, 2H); 2.78-2.70 (m, 2H); 2.60- 2.56 (m, 1H); 2.22 (s, 9H); 1.80-1.63 (m, 2H); 1.35 (s, 3H).

3C NMR (CDCl3,100 MHz): 6 = 152.03; 137.78; 137.54; 131.62; 128.75 ; 128.53; 128.50; 128.30 ; 127.91; 127.89; 127.69 ; 127.55; 127.48; 75.22 ; 74.42; 56.93; 53.77 ; 37.05; 23.27; 20.86 ; 13.22; 13.09; 12.33.

MS (m/e): 175,91,65.

Example 8 4- (2,5-Dibenzyloxy-3,4,6-trimethylphenyl)-2-methyl-1- (4-methoxyphenoxy) butan-2-ol Sodium hydride (0.29 g, 9.6 mmol) was washed with petroleum ether, and then N, N-dimethylformamide (10 ml) was added thereto. 4-Methoxyphenol (1.22 g, 9.6 mmol) and 2- 2- (2,5-dibenzyloxy-3,4,6-trimethyl- phenyl) ethyl-2-methyloxirane (2 g, 4.8 mmol) were added to this mixture at room temperature. The reaction mixture was heated at 150°C for 3 h and then cooled to room temperature. Water (5 ml) and ethyl acetate

(20 ml) were added, then the phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 10 ml). The combined organic phases were washed with saturated sodium chloride solution (2 x 10 ml), dried over sodium sulfate and evaporated to dryness under reduced pressure (45°C/25 mbar).

Yield: 2.43 g of crude product (about 82% according to 'H NMR).

'H NMR (CDC13,400 MHz) 7.50-7.30 (m, 10H); 6.80- 6.62 (m, 4H); 4.80 (s, 2H); 4.70 (s, 2H); 3.77 (s, 3H); 3.70 (d, J = 8 Hz, 2H); 2.82-2.77 (m, 2H); 2.42 (s, 1H); 2.24 (s, 3H); 2.22 (s, 3H); 2.20 (s, 3H); 1.85-1.77 (m, 2H); 1.30 (s, 3H).

3C NMR (CDC13,100 MHz): 6 = 154.06; ; 152.13; 151.69; 149.88 ; 137.77; ; 128.68; ; 128.25; ; 127.73; ; 115.62; ; 75.36; 75.32; 74.40 ; 72.19; 55.79; 55.76 ; 38.96; 23.81; 21.84 ; 13.24; 13.07; 12.33.

Example 9 4- 2-Hydroxy-2-methyl-4- (2,5-dibenzyloxy-3,4,6-tri- methylphenylbutoxy benzaldehyde Sodium hydroxide (0.14 g, 4.8 mmol) was washed with petroleum ether, and then N, N-dimethylformamide (6 ml) was added thereto. A solution of 4-hydroxy- benzaldehyde (0.6 g, 4.8 mmol) in N, N-dimethylformamide (9 ml) was added to this mixture at room temperature,

and then a solution of 2- 2- (2, 5-dibenzyloxy-3, 4, 6- trimethylphenyl) ethyl]-2-methyloxirane (1 g, 2.4 mmol) in N, N-dimethylformamide (9 ml) was added dropwise. The reaction mixture was heated at 150°C for 7 h, then cooled to room temperature, and water (15 ml) and ethyl acetate (15 ml) were added. The phases were separated, and the aqueous phase was extracted with ethyl acetate (2 x 15 ml). The combined organic phases were washed with saturated sodium chloride solution (2 x 30 ml), dried over sodium sulfate and evaporated to dryness.

Yield: 1.16 g of crude product (according to 1H NMR about 68%).

'H NMR (CDC13,400 MHz): 8 = 9. 87 (s, 1H); 7.80 (d, J = 7Hz, 2H); 7.58-7.30 (m, 10H); 6.85 (d, J = 7Hz, 2H); 4.80 (s, 2H); 4.65 (s, 2H); 3.80 (d, J = 8Hz, 2H); 2.80-2.75 (m, 2H); 2.26 (s, 3H); 2.24 (s, 3H); 2.22 (s, 3H); 1.85- 1.80 (m, 2H); 1.30 (s, 3H).

3C NMR (CDC13,100 MHz): 6 = 191.40; 164.39; 152.86 ; 35 ; 92 ; 20 ; 59 ; 18 ; 44 ; 39.51 ; 24.70; 22.42; 13.90 ; 13.74; 13.02.

Example 10 4- (2,5-Dibenzyloxy-3,4,6-trimethylphenyl)-2-methyl-1- (4-nitrophenoxy) butan-2-ol Sodium hydride (43 mg, 1.44 mmol) was washed with petroleum ether, and then N, N-dimethylformamide (3 ml) was added thereto. A solution of 4-nitrophenol (0.2 g, 1.44 mmol) in N, N-dimethylformamide (2 ml) was added to this mixture at room temperature, and then a solution of 2- 2- (2,5-dibenzyloxy-3,4,6-trimethyl- phenyl) ethyl-2-methyloxirane (0.3 g, 0.72 mmol) was added dropwise. The reaction mixture was heated at 150°C for 3 h, then cooled to room temperature, water (10 ml) was added and then the mixture was extracted with ethyl acetate (2 x 10 ml). The combined organic phases were washed with saturated sodium chloride solution (2 x 10 ml) and evaporated to dryness.

Yield: 0.3 g of crude product (according to 1H NMR about 75%).

H NMR (CDC13,400 (d, J = 6Hz, 2H); 7.55-7.30 (m, 10H); 6.82 (d, J = 6Hz, 2H); 4.80 (s, 2H); 4.70 (s, 2H); 3.82 (d, J = 8Hz, 2H); 2.80-2.75 (m, 2H); 2.24 (s, 3H); 2.23 (s, 3H); 2.21 (s, 3H); 1.85-1.80 (m, 2H); 1.30 (s, 3H).

Example 11 2- (4-Methoxyphenoxymethyl)-2,5,7,8-tetramethylchroman- 6-ol Palladium/activated carbon (10% Pd, 43% water content, 0.35 g) was added to a solution of 4- (2,5- dibenzyloxy-3,4,6-trimethylphenyl)-2-methyl-l- (4-meth- oxyphenoxy) butan-2-ol (0.3 g, 0.49 mmol) in methanol (8 ml), and the mixture was stirred at atmospheric pressure under nitrogen at room temperature for 19 h.

The catalyst was then filtered off over Celte@, and

the solvent was distilled off on a rotary evaporator. The resulting intermediate (0.19 g) was dissolved in toluene (5 ml), and p-toluenesulfonic acid (21 mg, 0.11 mmol) was added. The mixture was heated at 80°C for 5 h, then the same amount of p-toluenesulfonic acid was added again and the mixture was heated at 80°C for a further 4 h. After the mixture had been cooled to room temperature, it was washed with saturated aqueous sodium hydrogencarbonate solution (2 x 10 ml). The aqueous phase was back-extracted with ethyl acetate (2 x 10 ml). The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness.

Yield: 0.12 g of crude product.

A pure product was obtained by preparative layer chromatography.

H NMR (CDC13,400 (d, J = 7Hz, 2H); 6.80 (d, J = 7Hz, 2H); 4.20 (s, 1H); 3.90 (d, J = lOHz, 1H); 3.82 (d, J = lOHz, 1H); 3.78 (s, 3H); 2.60 (m, 2H); 2.18 (s, 3H); 2.10 (s, 6H); 2.08 (m, 1H); 1.90 (m, 1H); 1.20 (s, 3H).

3C NMR (CDC13,100 153.45; 145.18 ; 144.93; 122.68; 121.21 ; 118.51; 117.42; 115.72 ; 114.63; 74.20; 73.45 ; 55.76; 28.75; 22.79 ; 20.35; 12.16; 11.79 ; 11.24.

Example 12 2- (4-Methylphenoxymethyl)-2,5,7,8-tetramethylchroman-6- ol Palladium/activated carbon (10% Pd, 43% water content, 0.14g) was added to a solution of

4- 2-hydroxy-2-methyl-4- (2,5-dibenzyloxy-3,4,6-tri- methylphenyl) butoxy benzaldehyde (0.3 g, 0.56 mmol) in ethyl acetate (6 ml), and the mixture was stirred at atmospheric pressure under hydrogen for 20 h at room temperature. During the reaction, more catalyst (0.21 g) and acetic acid (3 ml) were added. The catalyst was then filtered off over Celte"", and the solvent was distilled off on a rotary evaporator. The resulting intermediate (0.12 g) was dissolved in toluene (5 ml), and p-toluenesulfonic acid (13 mg) was added. The mixture was heated at 80°C for 1.5 h and after it had been cooled to room temperature, was washed with saturated aqueous sodium hydrogencarbonate solution (2 x 10 ml). The aqueous phase was back- extracted with ethyl acetate (2 x 10 ml). The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness.

Yield: 0.12 g of crude product.

'H NMR (CDC13,400 (d, J = 8Hz, 2H); 6.80 (d, J = 8Hz, 2H); 4.20 (s, 1H); 3.97 (d, J = 9Hz, 1H); 3.82 (d, J = 9Hz, 1H); 2.6 (m, 2H); 2.30 (s, 3H); 2.18 (s, 3H); 2.10 (s, 6H); 2.08-2.00 (m, 1H); 1.98-1.91 (m, 1H); 1.40 (s, 3H).

Example 13 2- (4-Aminophenoxymethyl)-2,5,7,8-tetramethylchroman-6- ol (I, R'= R'= R'= R = H, R = NH2) 4- (2,5-Dibenzyloxy-3,4,6-trimethylphenyl)-2- methyl-l- (4-nitrophenoxy) butan-2-ol (20 g, 36 mmol) and hydrobromic acid (48%, 0.31 g, 1.83 mmol) were dissolved in methanol (200 ml) in an autoclave.

Palladium/activated carbon (5% Pd, 50% water content, 40 g) was then added and hydrogen was injected (6 bar).

The reaction mixture was warmed at 50°C for 4 h. The catalyst was then filtered off over Celte*, and the methanol was distilled off. The resulting crude product (9.4 g, 28.8 mmol) was used in the subsequent stage without further purification.

Yield: 80%.

Example 14 5- 4- (6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethyl- oxy)phenyl methylthiazolidine-2,4-dione (I, R1 = R2 = R4 = R5 = H, R3 = 2,4-dioxothiazolidin-5- ylmethyl) 2- (4-Aminophenoxymethyl)-2,5,7,8-tetramethyl- chroman-6-ol (7.2 g, 22 mmol) was dissolved in acetone (20 ml), and the solution was cooled to 5°C.

Hydrobromic acid (48%, 12 g, 71.2 mmol) was then added dropwise at a rate such that the temperature remained below 10°C. Aqueous sodium nitrite solution (28%, 6.2 g, 25.2 mmol) was then added dropwise, and the temperature was maintained below 2°C. Butyl acrylate (30 g, 23.4 mmol) and copper (II) bromide (0.5 g, 2.23 mmol) were then added, and the reaction mixture was warmed to 15°C and maintained at this temperature (exothermic reaction!). After the evolution of nitrogen had subsided, the reaction mixture was extracted with water (4 x 16 ml). Sodium acetate (0.8 g), 4-hydroxy- 2,2,6,6-tetramethylpiperidin-1-oxyl ("OH-TEMPO") (0.06 g) and 4-methoxyphenol ("MEHQ") (0.015 g) were added to the organic phase in order to prevent polymerization of the excess butyl acrylate. The volatile constituents were distilled off at 40°C/65 mbar, and the residue was dissolved in a mixture of methanol and acetone (v: v = 1: 1,45 ml).

Sodium acetate (1.2 g, 14.6 mmol) and thiourea (1.75 g, 23 mmol) were then added, and the reaction mixture was refluxed for 10 h. Hydrochloric acid (2 N, 10 ml, 20 mmol) was then added, and the mixture was refluxed for a further 2 h. The reaction mixture was then cooled

to room temperature, and the product began to crystallize out. This product was filtered off, washed with water (2 x 20 ml) and methanol/acetone (v: v = 1: 1, 2 x 20 ml) and dried.

Yield: 70%.