NO126573B - - Google Patents

Description

Tyrosine derivatives and method for their preparation.

The present invention relates to tyrosine derivatives and a method for the preparation of compounds with the general formula I, particularly in L- or D,L-form

where R x means hydrogen, lower alkyl or halogen,

1*2 hydrogen or lower alkyl,

R 4 hydrogen, lower alkyl or lower alkanoyl, and one of the residues R & and R^ hydroxy and the other lower

alkanoyl,

as well as salts of these derivatives.

The aforementioned alkyl residues can preferably contain up to 6 carbon atoms, which e.g. methyl, ethyl, isopropyl or hexyl.

Of the halogens fluorine, chlorine, bromine and iodine, chlorine is preferred.

The amino group in the amino acid can also be monosubstituted with lower alkyl or substituted with lower alkanoyl with up to 6 carbon atoms, e.g. with formyl or acetyl.

The method according to the invention is characterized

by reacting a compound present particularly in L, or D,L form with the general formula

where R1, R2 and R4 are as stated above and one of the residues R'g and R'^ means hydrogen and the other hydroxy,

or a salt of such a compound with a functional derivative of a lower alkanecarboxylic acid in the presence of a Friedel-Crafts reagent and, if desired, in any order hydrolyzes the reaction product obtained and separates an obtained racemate optionally into the optically active forms and transfers an obtained base, if desired, to a salt.

A strong Lewis acid in particular can be used as a Friedel-Crafts reagent.

Particularly preferred as the Friedel-Crafts reagent is a boron trihalide, e.g. boron trifluoride or boron tribromide, an aluminum trihalide, e.g. aluminum trichloride or aluminum tribromide, a titanium tetrahalide, e.g. titanium tetrachloride, a tin tetrahalide, e.g. tin tetrachloride, an antimony trihalide, e.g. antimony trichloride, an antimony pentahalide, e.g. antimony pentachloride, or an iron trihalide, e.g. iron trichloride or iron tribromide is used.

The reaction is suitably carried out in the presence of a heat-removing agent.

As a heat-removing agent (diluent) can e.g. an aprotic solvent inert to the Friedel-Crafts reagents is used.

As an inert solvent, you can e.g. use an inert organic solvent, e.g. nitrobenzene, halogenated benzene, e.g. chlorobenzene, a halogenated aliphatic hydrocarbon, e.g. carbon tetrachloride or tetrachloroethane or carbon disulphide.

As a functional derivative of a lower alkane carboxylic acid, in particular a halide of such an acid, e.g. acetyl chloride or an anhydride of such an acid, e.g. acetic anhydride, speaking.

The reaction is conveniently carried out at a temperature between approx. 0 and 200°C, preferably at a temperature between approx. 0 and 180°C.

When using tyrosine derivatives with formula II as starting material and when using aluminum chloride as a Friedel-Crafts reagent, of nitrobenzene as a solvent and of acetyl chloride as a functional acid derivative, it has e.g. proved to be appropriate to heat the reaction mixture for approx. 2 hours to approx. 100°C.

As starting materials with formula II, those are preferably used, where R 1 , R 1 , R 4 , R 1 and R 7 mean hydrogen and R 1 is a hydroxy group.

Additional preferred starting materials of formula II are

such, where R 1 , R 2 , R 1 , and R 1 are hydrogen, R 1 lower alkanoyl or aroyl and R 1 hydroxy.

Particularly preferred is the use of starting materials with formula II, which are in L-form and especially of such,

which leads to 3-acetyl-L-tyrosine, 3-propionyl-L-tyrosine, N,3-diacetyl-L-tyrosine and 3-acetyl-5-chloro-L-tyrosine respectively. salts of these.

The process products are new compounds, which should

are used as starting materials for the production of pharmacodynamically active compounds with formula

as well as salts thereof.

The process products (compounds of formula I and their salts) can be transferred to the compounds of formula III by subjecting them to an oxidative rearrangement and saponifying the obtained carboxylic acid esters, and by hydrolyzing the obtained compound in any order, separating a obtained racemate in the optically active forms and transfers an obtained base, if desired, to a salt.The oxidative rearrangement can then take place with hydrogen peroxide in an alkaline medium.

As a particularly important representative of the connection with formula

III is to mention L-Dopa.

The starting materials for the method according to the invention (compounds of formula II and their salts) are obtainable by methods known per se.

The facultative hydrolysis of the reaction products in the method according to the invention takes place in an acidic medium, e.g. in aqueous mineral acid, such as hydrochloric or sulfuric acid.

The racemate cleavage can take place according to usual methods, e.g. with

an optically active acid, such as tartaric acid, or an optically active base, such as quinine or brucine.

Obtained free amino acids of formula I are amphoteric. The carboxyl group can form with bases the corresponding salts. The amino group has the ability to form acid addition salts.

In patent no. (patent application no. 1786/70) a new method for producing compounds of the general formula III from compounds of the general formula I is described.

It has previously been described that a phenyl compound can

is acylated in the presence of a Lewis acid by means of a reagent, e.g. an alkanecarboxylic acid deriv. In the present case, however, the starting material with formula II used is not a phenyl compound, but a hydroxyphenyl compound, and it would then have been expected that the corresponding ester would be obtained by acylation of such a hydroxyphenyl compound.

o

bond. In contrast to this, however, the expected ester is not obtained, but an acylated compound of formula I in the ortho position to the hydroxy group.

The following examples illustrate the invention. The temperature is indicated in degrees Celsius.

EXAMPLE 1

Into a solution of 21.2 g of aluminum chloride in 80 ml of nitrobenzene, 7.24 g of L-tyrosine is introduced at room temperature, which dissolves after some time with stirring. After adding 3.45 ml of acetyl chloride, the mixture is heated for 6 hours to 100°, whereby the solution gradually becomes viscous and then solidifies. After cooling to room temperature, the congealed mass is introduced into 40 ml of concentrated hydrochloric acid and 200 g of ice. The aqueous phase is extracted with 200 ml of acetic acid, once more with 200 ml of acetic acid and finally a third time with 200 ml of acetic acid and the remaining clear aqueous solution is concentrated to a volume of 50 ml. The reaction product is thereby precipitated crystalline. After some rest at 0°, it is filtered off and the crude product is recrystallized from slightly semi-concentrated hydrochloric acid. After drying over potassium hydroxide and phosphorus pentoxide, yield of 3-acetyl-L-tyrosine hydrochloride: 7.2 g = 69%, melting point 227 228°, [cx ]^5 = -3.2° (c = 1, H20) .

EXAMPLE 2

Analogous example 1 is obtained by starting from L-tyrosine 3-propionyl-L-tyrosine hydrochloride with a cleavage point of 223 - 225°C, [a]* 5 = -1.3° (c = 1 in water).

EXAMPLE 3

26 g of anhydrous aluminum chloride, 7.9 g of acetyl chloride and 11.3 g of N-acetyl-L-tyrosine are added in order to 110 ml of nitrobenzene. After approx. 10 minutes everything is resolved. The solution is then heated for 5 hours to 100°C. The viscous, dark brown reaction mixture is split after cooling to 20° with a mixture of 250 g of ice and 25 ml of concentrated hydrochloric acid. The mixture is extracted after adding 60 g of sodium chloride twice each time with 500 ml of acetic acid ethyl ester. The organic extracts are washed twice each time with 100 ml of saturated sodium chloride solution and then extracted three times each time with 50 ml of 2-N soda solution. The soda extracts are brought to pH 1 with concentrated hydrochloric acid. The acidified solution is freed from the remaining organic solvents in vacuum and then cooled for 14 hours to 4°. The separated crystals are filtered off and recrystallized from water while adding activated carbon. 7.1 g (52%) of N,3-diacetyl-L-tyrosine with m.p. 142 - 143°C. [or. = + 22.4°

(c = 1, acetone).

EXAMPLE 4

Analogous to example 1, however, with a reaction time of 20 hours, starting from 5-chloro-L-tyrosine, 3-acetyl-5-chloro-L-tyrosine hydrochloride with a melting point of 231°C (decomposition) is obtained.

EXAMPLE 5

35.35 g of aluminum chloride in powder form are dissolved at room temperature in 133.5 ml of nitrobenzene. 12 g of m-tyrosine and finally 5.75 ml of acetyl chloride are then added. The mixture is heated for 6 hours to 100° and, after cooling, 66.5 ml of concentrated hydrochloric acid is added to 335 ml of ice water. The aqueous phase is separated and washed three times each time with 350 ml of ethyl acetate, concentrated to 100 ml and cooled, after which the crystallized reaction product is filtered off. After recrystallization twice from 5-n hydrochloric acid, 7.7 g of 4-acetyl-D,L-m-tyrosine hydrochloride with a melting point of 217 - 220°C is obtained.

EXAMPLE 6

71.3 g of anhydrous aluminum chloride are added to a suspension of 33.9 g of 3,α-dimethyl-D,L-tyrosine in 340 ml of nitrobenzene. After the total quantity of aluminum chloride has gone into solution (after approx. 10 minutes), 13.6 g of acetyl chloride are added to the solution. The mixture is then heated for 18 hours with stirring to 105°. The tough reaction mixture is then cooled to 50° and poured on

a mixture of 1000 g of ice and 100 ml of concentrated hydrochloric acid. It is then extracted once with 1400 ml of ether and once with 700 ml of ether, and the combined extracts are washed twice each time with 200 ml of 2-N aqueous hydrochloric acid.

The combined aqueous extracts are concentrated at 40°C and under a pressure of 12 mm Hg to a volume of approx. 400 ml and then cooled for 12 hours at 4°C. The separated crystals are filtered off and recrystallized after addition of activated carbon from 5-n aqueous hydrochloric acid, whereby 33.7 g of 3-acetyl-α,5-dimethyl-D,L-tyrosine hydrochloride is obtained in the form of colorless crystals with a melting point of 251 - 255°.

EXAMPLE 7

80 g of aluminum chloride and 39 g of 3-bromo-L-tyrosine are added in sequence to 300 ml of nitrobenzene. After dissolution, 13.1 g of acetyl chloride are added, and the reaction mixture is stirred for 18 hours at 120°C (bath temperature).

The mixture is then poured onto a mixture of 300 g of ice and 150 ml of concentrated aqueous hydrochloric acid and then extracted twice each time with 200 ml of ethyl acetate. The organic phase is washed twice each time with 200 ml of 2-N hydrochloric acid. The combined aqueous extracts are concentrated at 40° and a pressure of 11 mm Hg to approx. 100 ml and then cooled for 14 hours at 4°. The separated crystals are filtered off and recrystallized from 20% hydrochloric acid, whereby 38 g of 3-acetyl-5-bromo-L-tyrosine hydrochloride is obtained, melting point 223 - 224° (under decomposition), [or ]^~* = +3.9°

(c = 1% in methanol).

EXAMPLE 8

A suspension of 21.3 g of aluminum chloride in 80 ml of nitrobenzene is added to 7.95 g of 3-fluoro-D,L-tyrosine. 3.5 ml of acetyl chloride is added to the solution obtained, after which the reaction mixture is stirred for 15 hours at 105°. The dark, tough reaction product is then poured onto a mixture of 200 g of ice and 40 ml of concentrated hydrochloric acid. It is then extracted twice each time with 200 ml of ethyl acetate. The combined organic extracts are extracted twice each time with 100 ml of 2-N aqueous hydrochloric acid. The combined aqueous extracts are concentrated to approx. 50 ml and cooled for 14 hours at 4°. The separated crystals are filtered off and recrystallized from 20% hydrochloric acid. 10.1 g of 3-acetyl-5-fluoro-D,L-tyrosine hydrochloride is obtained in the form of slightly brown colored crystals with a melting point of 238°.

EXAMPLE 9

A suspension of 30 g of α-methyl-L-tyrosine in 450 ml of nitrobenzene is added to 53 g of anhydrous aluminum chloride. After subsequent reheating (after approx. 10 minutes), 27 g of acetyl chloride are added, and the reaction mixture is stirred for 14 hours at 100°. The obtained viscous reaction mixture is cooled to 50° and poured onto a mixture of 900 g of ice and 90 ml of concentrated aqueous hydrochloric acid. Then extract twice each time with 1500 ml of ether. The ether extract is added twice each time with 300 ml of aqueous 2-N hydrochloric acid. The combined aqueous extracts are evaporated at 40° and 12 mm Hg. The residue is heated in 1000 ml of ethyl acetate for 10 minutes to boiling and then kept for 20 hours at room temperature, whereby the largest part of the aluminum chloride crystallizes out. The separated crystals are filtered off, the filtrate is evaporated at 40° and 11 mm Hg, and the evaporation residue is recrystallized from ethyl acetate, whereby 3-acetyl-α-methyl-L-tyrosine hydrochloride is obtained in the form of colorless crystals, melting point 233° (under decomposition ) , [cr]^5 = + 2.9° (c = 1% in water) .

EXAMPLE 10

The N,3-diacetyl-L-tyrosine obtained according to example 3 can be transferred by hydrolysis as follows to 3-acetyl-L-tyrosine hydrochloride: 100 ml of semi-concentrated hydrochloric acid is heated to boiling under gassing with argon for approx. 15 minutes during the return run. 8.8 g of N,3-diacetyl-L-tyrosine is then added to the hydrochloric acid and boiled for a further 40 minutes under gassing with argon. The precipitate formed by cooling the solution is sucked off, and the filtrate is evaporated under reduced pressure to dryness. After drying over phosphorus pentoxide/potassium hydroxide, 3-acetyl-L-tyrosine hydrochloride is obtained, melting point 217°,

[a]^° = + 3.9° (c = 10 56 in water).

Claims (4)

1. Tyrosine derivatives for use as starting material in the preparation of compounds of the general formula and salts thereof, which compounds and salts in particular exist in L or D,L form, characterized in that they have the general formula where means hydrogen, lower alkyl or halogen, R2 hydrogen or lower alkyl, R4 hydrogen, lower alkyl, lower alkanoyl, and one of the residues R^ and R^ hydroxy and the other lower alkanoyl, as well as salts of these derivatives. 2. Process for the preparation of compounds of formula I according to claim 1, which are particularly present in L- or D,L-form, characterized by reacting a particular in L or D,L form present compound with the general formula where , R2 and R^ have the above meaning and where one of the residues R'g and R<1>^ means hydrogen and the other hydroxy, or a salt of such a compound with a functional derivative of a lower alkanecarboxylic acid in the presence of a Friedel-Crafts reagent and, if desired, in any order hydrolyzes the reaction product obtained and separates an obtained racemate optionally in the optically active forms and transfers a obtained base, if desired, to a salt. 3. Method according to claim 2, characterized in that the turnover is carried out in the presence of a heat-removing agent. 4. Method according to claim 2 or 3, respectively, characterized in that the reaction is carried out at a temperature between 0 and 200°C, preferably at a temperature between 0 and 180°C.