DE102006045603A1 - New phenyl-carboxyl compounds useful in the preparation of 6-halo-3,4-dihydroxy-L-phenylalanine - Google Patents

Abstract

Phenyl-carboxyl compounds (I), are new. Phenyl-carboxyl compounds of formula (I), are new. R1>optionally substituted 3-6C alkyl (preferably tert-butyl); R2>alkyloxycarbonyl, formyl, alkylcarbonyl, optionally substituted trityl, phenyl or diphenylene, where the alkyl group is optionally substituted by 1-6C alkyl, preferably tert-butyloxycarbonyl; R3>, R4>alkyloxycarbonyl, alkyloxymethyl or alkyloxyethyl, where the alkyl group is optionally substituted by 1-6C alkyl, optionally substituted 3-8C cycloalkyl, optionally substituted 3-8C cycloalkenyl, tetrahydrofuranyl or tetrahydropyranyl, preferably tert-butyloxycarbonyl; and R5>optionally substituted 1-6C alkyl, preferably butyl. Independent claims are included for: (1) the preparation of (I); and (2) use of (I) for the preparation of a phenyl-halogen compound of formula (IIa), by reacting (I) with X-containing compound and subsequently with an optionally substituted 1-6C alkylcarboxylic acid or a mixture containing an unsubstituted 1-6C alkylcarboxylic acid. X : F, 1>8>F, I, I-123, I-125 or I-131. [Image] [Image].

Description

The This invention relates to compounds useful in the preparation of 6-halo-L-DOPA, in particular of 6-radiohalo-L-DOPA, can be used Process for the preparation of the compounds and their use for the preparation of 6-halo-L-DOPA.

Dopamine plays an important role as a neurotransmitter in stimulation in the organism. At the nerve endings, it is made from 3,4-dihydroxy-L-phenylalanine (L-DOPA), a common blood-brain barrier precursor, by decarboxylation. L-DOPA can either be synthesized in the body from L-tyrosine by hydroxylation or externally supplied. For some diseases, such. Parkinson's disease, Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia and depression, the production, transport and / or degradation of L-DOPA at the nerve endings are disrupted. These processes can be visualized by an imaging technique such as positron emission tomography (PET) and examined for pathological deviations. For such PET scans 6- ¹⁸ F-DOPA is used that similar to the DOPA is metabolized. The resulting ¹⁸ F-dopamine is mainly taken up by certain brain regions (striatum) and provides insight into the presynaptic dopaminergic functions of a patient in vivo. 6- ¹⁸ F-DOPA synthesized by radiochemical labeling of a precursor with ¹⁸ F _2, ¹⁸ F-fluoride, and subsequent removal of the protecting groups.

At present, only for O- (2- [ ¹⁸ F] fluoroethyl) -L-tyrosine (FET) is there a nucleophilic synthesis method (with ¹⁸ F-fluoride) which is also suitable for routine production. Production method of ^[18 F] -kernfluorierte aromatic amino acids such as ^6-18 F-DOPA with a nucleophilic fluorination require a multi-step synthesis with sensitive intermediates. This process has not been successful in routine production. Thus, there is a need to improve the path with electrophilic fluorination by using new precursors.

A process is known for the preparation of N-formyl-3,4-di-O-tert-butoxycarbonyl-6-trimethylstannyl-L-DOPA-ethyl ester as precursor for radiolabelling with the nuclide ¹⁸ F (Satyamurthy, N .; Barrio, JR; Bishop, AJ; Namavari, M. WO 94/00460 A1 ). Disadvantages of this method are that (1) in the meantime methyl groups are introduced in the synthesis, which must be split off again, and that (2) drastic reaction conditions are necessary to cleave the protecting groups after the radiosynthesis. The first point leads to a longer synthesis sequence, the second disadvantage to the formation of impurities in the product.

To solve the second disadvantage DOPA esters, z. As DOPA tert-butyl ester, which can be cleaved under mild acid conditions. The Known Process for the Preparation of Amino Acid Tertiary Butyl Esters by Roeske ( J. Org. Chem. 1963, 28 1251. ), which can also be used on a larger scale, did not succeed for L-DOPA. In contrast, it provides for L-tyrosine the corresponding tert-butyl ester in an acceptable yield.

• 1. a) Bretschneider, H., Hohenlohe-Oehringen, K., Kaiser, A., Wölcke, U. Eine neue Synthese des 3-[3,4-Dihydroxyphenyl]-L-alanins (L-DOPA) aus L-Tyrosin, Helv. Chim. Acta 1973, 56, 2857-2860 .
• b) Kaiser, A., Koch, W. Process for the Production of DOPA CA944772 .
• c) Hausermann, W., Leo, M. Process for Manufacturing L-3-(3,4-Dihydroxyphenyl)alanine CA871150 .
• d) Kaiser, A., Scheer, M. Process for the Preparation of L-DOPA DE1964420 .
• e) Farmaceutici Italia, Preparation of L-DOPA GB1287070 .
• 2. Vorbrüggen, H., Krolikiewicz, K. Eine neue Synthese des 3-[3,4-Dihydroxyphenyl]-L-alanins (L-DOPA) Chem. Ber. 1972, 105, 1168-1173 .
• 3. a) Chen, C., Zhu, Y.-F., Wilcoxen, K. An improved Synthesis of Selectively Protected L-DOPA Derivatives from L-Tyrosine, J. Org. Chem. 2000, 65, 2574-2576 .
• b) Jung, M.E., Lazarova, T.I. Efficient Synthesis of Selectively Protected L-DOPA Derivatives from L-Tyrosine via Reimer-Tiemann and Dakin Reactions, J. Org. Chem. 1997, 62, 1533-1555 .
• c) Boger, D.L., Yohannes, D. Selectively Protected L-DOPA Derivatives: Application of the Benzylic Hydroperoxide Rearrangement, J. Org. Chem. 1987, 52, 5283-5286 .
• 4. a) Luying, X. Young, L.J. Method for making L-dopa from L-tyrosine US5837504 .
• b) Chattopadhyay, S., Das, A. Production of L-DOPA by Aspergillus terreus FEMS Microbiology Letters 1990, 72(1-2), 195 .
• c) Sih, C.J., Foss, P., Rosazza, J., Lemberger, M. J. Am. Chem. Soc. 1969, 91, 6204 .

The following processes are known from the prior art for the preparation of L-DOPA and derivatives of L-tyrosine:

• 1. a) Bretschneider, H., Hohenlohe-Oehringen, K., Kaiser, A., Wölcke, U. A new synthesis of 3- [3,4-dihydroxyphenyl] -L-alanine (L-DOPA) from L-tyrosine, Helv. Chim. Acta 1973, 56, 2857-2860 ,
• b) Kaiser, A., Koch, W. Process for the Production of DOPA CA944772 ,
• c) Hausermann, W., Leo, M. Process for Manufacturing L-3- (3,4-dihydroxyphenyl) alanine CA871150 ,
• d) Kaiser, A., Scheer, M. Process for the Preparation of L-DOPA DE1964420 ,
• e) Farmaceutici Italia, Preparation of L-DOPA GB1287070 ,
• Second Vorbrüggen, H., Krolikiewicz, K. A new synthesis of 3- [3,4-dihydroxyphenyl] -L-alanine (L-DOPA) Chem. Ber. 1972, 105, 1168-1173 ,
• 3. a) Chen, C., Zhu, Y.-F., Wilcoxen, K. An improved Synthesis of Selectively Protected L-DOPA Derivatives from L-Tyrosine, J. Org. Chem. 2000, 65, 2574-2576 ,
• b) Jung, ME, Lazarova, TI Efficient Synthesis of Selectively Protected L-DOPA Derivatives from L-Tyrosine via Reimer-Tiemann and Dakin Reactions, J. Org. Chem. 1997, 62, 1533-1555 ,
• c) Boger, DL, Yohannes, D. Selectively Protected L-DOPA Derivatives: Application of the Benzylic Hydroperoxide Rearrangement, J. Org. Chem. 1987, 52, 5283-5286 ,
• 4. a) Luying, X. Young, LJ Method for making L-dopa from L-tyrosine US5837504 ,
• b) Chattopadhyay, S., Das, A. Production of L-DOPA by Aspergillus terreus FEMS Microbiology Letters 1990, 72 (1-2), 195 ,
• c) Sih, CJ, Foss, P., Rosazza, J., Lemberger, MJ Am. Chem. Soc. 1969, 91, 6204 ,

The Methods 1 to 3a are based on a Baeyer-Villiger reaction of one previously prepared 3-acyl tyrosine with hydrogen peroxide, organic Hydroperoxides and peracids. Method 3b uses a sequence of a Reimer-Tiemann and a Dakin reaction while Method 3c a series of acylation, reduction and subsequent hydroperoxide rearrangement uses. All the chemical processes from 1 to 3 require at least two steps, to introduce in L-tyrosine the second hydroxy group and are - except of the methods under 3 - because of their drastic reaction conditions only conditionally suitable for the synthesis protected DOPA derivatives. Method 4 describes the microbiological (enzymatic) Hydroxylation of L-Tyrosine to L-DOPA.

It So far there is no chemical process for the direct oxidation of Tyrosine derivatives to DOPA derivatives.

Furthermore, it is known that some substituted phenols, but not phenol itself, can be oxidized to ortho-quinones with 2-iodoxybenzoic acid and reduced to catechols with hydrogen ( Pettus et al. Org. Lett. 2002, 4, 285). Reduction with ascorbic acid is also possible (Cavalieri et al., Steroids 2005, 70, 173 ). The applicability of this Re action sequence on the synthesis of DOPA derivatives from tyrosine has not been studied.

task The invention is to the disadvantages of the prior art remove. In particular, compounds should be specified which allow easier production of 6-halo-L-DOPA. Furthermore, a method for producing these compounds as well as uses of these compounds.

These The object is solved by the features of claims 1, 4 and 10. Advantageous embodiments The inventions result from the features of claims 2, 3, 5 to 9 and 11 to 14.

vorgesehen, worin
R¹ unsubstituiertes oder substituiertes C₃-C₆-Alkyl darstellt;
R² Alkyloxycarbonyl, wobei die Alkylgruppe unsubstituiertes oder substituiertes C₁-C₆-Alkyl ist; Formyl; Alkylcarbonyl, wobei die Alkylgruppe unsubstituiertes oder substituiertes C₁-C₆-Alkyl ist; unsubstituiertes oder substituiertes Trityl; Phenyl oder Diphenylen darstellt;
R³ und R⁴ unabhängig voneinander Alkyloxycarbonyl, wobei die Alkylgruppe unsubstituiertes oder substituiertes C₁-C₆-Alkyl ist; Alkyloxymethyl oder Alkyloxyethyl, wobei die Alkylgruppe unsubstituiertes oder substituiertes C₁-C₆-Alkyl ist; unsubstituiertes oder substituiertes C₃-C₈-Cycloalkyl; unsubstituiertes oder substituiertes C₃-C₈-Cycloalkenyl; Tetrahydrofuranyl oder Tetrahydropyranyl darstellen; und
R⁵ unsubstituiertes oder substituiertes C₁-C₆-Alkyl darstellt.According to the invention are compounds of the formula I.

provided in which
R ^{1 is} unsubstituted or substituted C ₃ -C ₆ alkyl;
R ^{2 is} alkyloxycarbonyl wherein the alkyl group is unsubstituted or substituted C ₁ -C ₆ alkyl; formyl; Alkylcarbonyl wherein the alkyl group is unsubstituted or substituted C ₁ -C ₆ alkyl; unsubstituted or substituted trityl; Phenyl or diphenylene;
R ³ and R ^{4 are} independently alkyloxycarbonyl wherein the alkyl group is unsubstituted or substituted C ₁ -C ₆ alkyl; Alkyloxymethyl or alkyloxyethyl wherein the alkyl group is unsubstituted or substituted C ₁ -C ₆ alkyl; unsubstituted or substituted C ₃ -C ₈ cycloalkyl; unsubstituted or substituted C ₃ -C ₈ cycloalkenyl; Tetrahydrofuranyl or tetrahydropyranyl; and
R ^{5 is} unsubstituted or substituted C ₁ -C ₆ alkyl.

The Compounds of the formula I can be used for the preparation of 6-halo-DOPA, wherein the halogen atom can represent a radioactive isotope.

The compounds of formula I can be obtained under mild conditions with a small number of synthetic steps compared to the prior art by direct oxidation of L-tyrosine derivatives. The preparation of 6-halo-DORA is simplified because the protecting groups R ¹ , R ² , R ³ and R ⁴ can be removed without formation of decomposition products.

The radical R ¹ in formula I is preferably unsubstituted or substituted C ₃ -C ₆ -alkyl, more preferably unsubstituted C ₃ -C ₆ -alkyl and particularly preferably isopropyl, tert-butyl and neopentyl.

The radical R ² in formula I is preferably selected from the group consisting of tert-butyloxycarbonyl, formyl and alkylcarbonyl such as acetyl, trifluoroacetyl, trichloroacetyl; Trityl, phenyl and diphenylene.

The radicals R ³ and R ⁴ can be independently selected from the group comprising tert-butyloxycarbonyl, methyloxymethyl, ethyloxymethyl, ethyloxyethyl, cyclopentyl, cyclohexenyl, and tetrahydrofuranyl. Preferably, the radicals R ³ and R ^{4 are the} same.

The radical R ⁵ is preferably methyl or butyl.

A preferred compound of formula I is the following compound of formula Ia

unter Erhalt einer Verbindung der Formel VIa

According to the invention, a process for the preparation of compounds of formula I is further provided. The process comprises introducing a second phenolic hydroxy group (see formula VIa) in the 3-position by direct oxidation of a compound of formula IVa

to obtain a compound of formula VIa

The direct oxidation of a compound of formula IVa to a compound of formula VIa is preferably prepared by reacting with 2-iodoxybenzoic acid and subsequently with ascorbic acid carried out. The reaction may be carried out in a chlorinated solvent such as dichloromethane carried out become. Preferably, the reaction is carried out at room temperature.

The compound of the formula IVa can be prepared by a known method (see, for example Roeske J. Org. Chem. 1963, 28, 1251 ) are prepared from L-tyrosine by protecting the carboxyl group with a protecting group.

kann nach Schützen der beiden phenolischen Hydroxygruppen (in 3- und 4-Stellung) zur Verbindung der Formel IIa

umgesetzt werden, wobei X Br oder I darstellt. Dabei wird in 6-Stellung eine Halogengruppe eingeführt.The compound of the formula VIa

can after protecting the two phenolic hydroxy groups (in 3- and 4-position) to the compound of formula IIa

where X is Br or I. In this case, a halogen group is introduced in the 6-position.

provides X is iodine, the halogenation is preferably with [bis (trifluoroectoxy) iodo] benzene and iodine performed.

mit einer zinnorganischen Verbindung zu einer Verbindung der Formel I umgesetzt.In a preferred embodiment, the compound of formula IIa

reacted with an organotin compound to give a compound of formula I.

According to the invention, the use of the compounds of formula I as precursor (precursor) for the preparation of 6-halo-3,4-dihydroxy-L-phenylalanine (6-halo-L-DOPA), wherein the halogen atom is preferably a radioactive Isotope is provided. The halogen is preferably selected from the group comprising F, ¹⁸ F, I, I-123, I-125 and I-131.

umgesetzt. Anschließend wird Verbindung IIa mit einer unsubstituierten oder substituierten C₁-C₆-Alkylcarbonsäure oder einem Gemisch, das eine unsubstituierte oder substituierte C₁-C₆-Alkylcarbonsäure enthält, umgesetzt (Schema 2). Die X-enthaltene Verbindung ist im Falle von ¹⁸F [¹⁸F]-F-Gas, im Fall des radioaktiven Iods beispielsweise das entsprechende I₂.For the preparation of 6-halo-L-DOPA, the compound of the formula I is reacted with an X-containing compound

implemented. Subsequently, compound IIa is reacted with an unsubstituted or substituted C ₁ -C ₆ -alkylcarboxylic acid or a mixture containing an unsubstituted or substituted C ₁ -C ₆ -alkylcarboxylic acid (Scheme 2). The X-containing compound is in the case of ¹⁸ F [ ¹⁸ F] -F gas, in the case of radioactive iodine, for example, the corresponding I ₂ .

Scheme 2

To remove the protecting groups R ¹ , R ² , R ³ and R ⁴ , an unsubstituted or substituted C ₁ -C ₆ -alkylcarboxylic acid or a mixture containing an unsubstituted or substituted C ₁ -C ₆ -alkylcarboxylic acid is used. A preferred C ₁ -C ₆ -alkylcarboxylic acid is trifluoroacetic acid. When a mixture containing an unsubstituted or substituted C ₁ -C ₆ alkylcarboxylic acid is used, the mixture preferably further comprises a mineral acid and / or water. The mineral acid is preferably hydrohalic acid, sulfuric acid or phosphoric acid.

The Removal of the protecting groups is preferably at a temperature from room temperature to 100 ° C, stronger preferably from 40 to 100 ° C, more preferably from 40 to 80 ° C. The proposed procedure allows the removal of the protecting groups without the formation of decomposition products, what represents a significant advantage.

The transfer of the Compound IIa in 6-halo-L-DOPA thus takes place under mildly acidic Conditions, which is another significant advantage over the Prior art is.

In order to the compounds of the formula I are particularly preferred as precursors to Radiolabeling for the diagnosis and therapy of tumors suitable, in particular for radiosynthesis of 18F and iodine isotope-labeled 6-halo-L-DOPA.

The inventive method is described below with reference to the drawings and by closer to examples described. Show

1 a reaction scheme for the preparation of compound Ia;

2 a first spectrum of a comparative experiment for the deprotection of compounds of formula I; and

3 A second spectrum of an example according to the invention for the deprotection of compounds of the formula I.

Hereinafter, the preparation of the compound Ia as an exemplary representative of the compound I with reference to 1 described.

L-tyrosine tert-butyl ester (IV) is prepared by a known process ( Roeske J. Org. Chem. 1963, 28, 1251 ) from L-tyrosine (III) and 2-methylpropene. After introduction of a Boc-protecting group at the amino group to compound (V), the aromatic ring in the key step (conversion of V to VI) is selectively oxidized ortho to the phenolic hydroxy group with 2-iodoxybenzoic acid (IBX) and subsequently reduced to catechol VI ascorbic acid. IBX is commercially available but can be easily made from 2-iodobenzoic acid and oxone. Contrary to observations by Pettus et al. ( Org. Lett. 2002, 4, 285 ), a chlorinated solvent (dichloromethane) proved suitable. Further, protecting groups, e.g. B. Boc groups, introduced for the hydroxy groups. The iodination of compound VII is possible with [bis (trifluoroacetoxy) iodo] benzene and iodine in an acceptable yield, followed by stannylation of II (X = I, R ¹ = tert-butyl, R ² , R ³ , R ⁴ = Boc) to compound Ia (with R ¹ = tert-butyl, R ² , R ³ , R ⁴ = Boc, R ⁵ = CH ₃ ).

With a compound of structure II (X = I, R ¹ = tert-butyl, R ² , R ³ , R ⁴ = Boc) were carried out experiments for deprotection, the model character for the deprotection of a labeled precursor after the radiosynthesis. The reaction in pure trifluoroacetic acid at 40 to 80 ° C had been proven. The recorded proton spectrum of the reaction mixture incubated at 20 ° C. (spectrum 1, 2 ) shows an incomplete cleavage of the N-Boc protective group, at 80 ° C, all protecting groups were split off almost completely without formation of by-products (spectrum 2, 3 ).

The precursor Ia (where R ¹ = tert-butyl, R ² , R ³ , R ⁴ = Boc, R ⁵ = Me) has been prepared under conditions which have already been known ( Füchtner, F .; Steinbach, J. Appl. Radiat. Iseult. 2003, 58, 575 ) was labeled with [ ¹⁸ F] F ₂ and then deprotected under the conditions of the previous model reaction. For comparison, the previously used precursor Ib (with R ¹ = Et, R ² = CHO, R ³ , R ⁴ = Boc, R ⁵ = Me) of the [ ¹⁸ F] -DOPA synthesis was labeled with [ ¹⁸ ] F ₂ and deprotected under previous conditions (12 M hydrochloric acid, 130 ° C). The radiochemical portion of the [ ¹⁸ F] -DOPA was about twice as large as for the previous precursor Ib when using the new precursor Ia after about 11 minutes. The new precursor Ia also resulted in a lower number of impurities in the [ ¹⁸ F] -DOPA compared to the previous precursor Ib. The sum of the impurities when using the precursor Ia was about 5% less than half as large as when using the precursor Ib with impurities> 10%.

The inventive method for the preparation of the compounds according to the invention is described below on an embodiment explained in more detail. In addition, will an example of the deprotection of a model precursor of the invention Structure II to the product 6-halo-L-DOPA shown.

Examples

example 1

L-tyrosine tert-butyl ester (IV)

14.4 g L-Tyrosine (III) (79.47 mmol) was dissolved in a 500 ml screw-cap laboratory glass with septum under argon dissolved in 120 ml of dioxane. Subsequently was the reaction vessel cooled to -5 ° C and 10 ml of 96% sulfuric acid slowly dropped. At -40 ° C were 120 ml of 2-methylpropene condenses rapidly to the reaction suspension given and the reaction vessel gas-tight closed (sealed with Teflon tape). The mixture was stirred for two days at room temperature. Then, the resulting mixture was dripped slowly with a pipette one, prefabricated in a two liter Erlenmeyer flask in an ice bath, solution of 100 ml of dist. Water and 400 ml of ethyl acetate. One stopped there the pH by adding 100 ml portions of 5 N sodium hydroxide solution ca. 11. The resulting precipitate was filtered off and extracted with ethyl acetate washed. The phases were separated and the aqueous phase was washed with five times Extracted ethyl acetate. The combined organic phases were over sodium sulfate dried, filtered and concentrated in vacuo. After recrystallization hexane gave 8.7 g (46% of theory) of a yellowish white solid, Melting point (m.p.) 136.2-140.1 ° C (140-145 ° C, Roeske J. Org. Chem. 1963, 28, 1251).

N-Boc-L-tyrosine tert-butyl ester (V)

8.7 g of tert-butyl L-tyrosine (IV) and 3.4 g of sodium bicarbonate were dissolved in 98 ml of distilled water in a 500 ml round bottom flask. Dissolved water and 78 ml of acetone. With a further 20 ml of acetone, a solution of 8.8 g of di-tert-butyl dicarbonate was prepared, which was then added slowly to the reaction solution. The mixture was stirred at room temperature overnight, the reaction mixture was filtered and the acetone contained was rotated to 70 mbar. The result was a yellow foam, which was taken up with 200 ml of ethyl acetate. After separation of the phases, the aqueous phase was extracted five times with 100 ml of ethyl acetate. Subsequently, the washed organic phase with 50 ml of 0.1 N hydrochloric acid, dried over sodium sulfate, filtered and concentrated in vacuo. This gave 11.91 g (quant.) Of a white foam, mp. 115.8-116.7 ° C.

N-Boc-L-DOPA tert -butyl ester (VI)

11.91 g N-Boc-L-tyrosine tert-butyl ester (V) was dissolved in a 500 ml round bottomed flask with nitrogen and septum under argon in 200 ml dry Dissolved N, N-dimethylformamide. Subsequently were 9.9 g of 2-iodoxybenzoic acid (IBX) added in argon countercurrent and 30 minutes at room temperature touched. Then, 147 ml of 1M ascorbic acid became slow under ice bath cooling to injected. The result was a light orange solution with white precipitate. One stirred another 30 minutes. The precipitate was filtered off and with dichloromethane washed. The phases were separated and the aqueous phase was extracted six times extracted with 100 ml of dichloromethane. The combined organic Phases were over Dried sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (EtOAc / hexane 1: 4) gave 10.41 g (83% of theory), a yellow oil.

N-Boc-3,4-di-O-boc-L-DOPA-tert-butyl ester (VII)

5.93 g N-Boc-L-DOPA tert -butyl ester (VI) was dissolved under argon in a 250 ml round bottom flask with nitrogen and septum in 102 ml dry Dissolved N, N-dimethylformamide. Subsequently 5.1 ml of triethylamine was added. After 8.4 g of di-tert-butyl dicarbonate, dissolved under argon in 30 ml of absolute N, N-dimethylformamide, for Reaction mixture was added, stirred for two days at room temperature under exclusion of light. The reaction solution was washed with 600 ml of ethyl acetate dilute and with 60 ml of saturated Sodium chloride solution washed. The organic phase was dried over sodium sulfate, filtered and concentrated. Chromatography (EtOAc / hexane 1: 4) provided 5.2 g (56%) of a white one Foam of the target compound and 1.59 g (17.1%) of a mixture of regioisomeric Mono'boc'verbindungen.

N-Boc-3,4-di-O-boc-6-iodo-L-DOPA tert -butyl ester (II)

5.1 g N-Boc-3,4-di-O-boc-L-DOPA tert -butyl ester (VII) were in a 250 ml round bottom flask with nitrogen and septum in 138 ml dry Dichloromethane dissolved under inert gas. A solution of 2.4 g of iodine and 4.8 g of [bis (trifluoroacetoxy) iodo] benzene in 130 ml dry dichloromethane was added under ice-bath cooling. At first they moved fifteen more Minutes in an ice bath, then over Night with exclusion of light at room temperature. The reaction solution diluted with 600 ml of dichloromethane and washed this solution six times with 60 ml 1N sodium thiosulfate solution. The organic phase was dried over sodium sulfate, filtered and confined them in a vacuum. By subsequent chromatography (EtOAc / hexane 1: 4 or EtOAc / Hx 3: 7) gave 3.4 g (54%) of a yellowish Solid.

N-Boc-3,4-di-O-boc-6-trimethylstannyl-L-DOPA-tert-butyl ester (Ia)

3.4 g N-Boc-3,4-di-O-boc-6-iodo-L-DOPA-tert-butyl ester (II) and 722 Tetrakistriphenylphosphine palladium [0] was dissolved in a 500 ml Round bottomed flask with septum under inert gas dissolved in 213 ml dioxane. After that were Add 4.7 ml of hexamethyldistannane to the reaction solution using a disposable syringe. One stirred then at 110 ° C overnight under inert gas. After removal of the palladium by filtration and After washing with ethyl acetate, the organic phase was concentrated to reach Dry in a vacuum. column (EtOAc / hexane 1: 4) gave 1.6 g (54%) of a white finely powdered solid.

Example 2

Deprotection of N-Boc-3,4-di-O-Boc-6-trimethylstannyl-L-DOPA-tert-butyl ester (Ia)

10 mg of compound II (with X = I) were incubated with 0.5 ml of 100% trifluoroacetic acid for 10 minutes at room temperature and elevated temperature (40-100 ° C.) in a closed vessel (vial). Subsequently, the reaction was stopped by placing the reaction vessel on ice. TLC controls (EtOAc / hexane 1: 4 and in C / M / AcOH / H ₂ O 25: 15: 0.1: 2) showed complete conversion to a single product. The acid was evaporated in an oil pump vacuum at lower temperature or room temperature, the residue was dissolved in deuterated Nasser and took from the solution to a proton spectrum.

Example 3

45 mg of the precursor I (with R ¹ = tert-butyl, R ² , R ³ , R ⁴ = Boc, R ⁵ = Me) were treated with [ ¹⁸ F] F ₂ as in Fücht ner and Steinbach ( Appl. Radiat. Isotopes 2003, 58, 575 ). Subsequently, the reaction mixture was mixed with 100% trifluoroacetic acid and incubated at room temperature or 80 ° C. in a closed vessel. At intervals of one minute to about 12 minutes after the start of the reaction, samples of about 0.3 ml were taken from the reaction mixture and placed on ice. 90 μl of this was pipetted into 90 μl of an acetic acid-acetate buffer (272 g NaAc · 3H ₂ O, 120 g acetic acid, 500 mL water). Aliquots of this reaction mixture were analyzed by HPLC as in Füchtner and Steinbach (see above). For comparison, the precursor I hitherto used for [ ¹⁸ F] -DOPA preparation was labeled (with R ¹ = Et, R ² = CHO, R ³ , R ⁴ = Boc, R ⁵ = Me) and added with 12 M hydrochloric acid Incubated at 130 ° C. Also at one minute intervals, samples were taken which were treated as above and analyzed by HPLC.

Claims (14)

Compound of formula I

wherein R ^{1 is} unsubstituted or substituted C ₃ -C ₆ alkyl; R ^{2 is} alkyloxycarbonyl wherein the alkyl group is unsubstituted or substituted C ₁ -C ₆ alkyl; formyl; Alkylcarbonyl wherein the alkyl group is unsubstituted or substituted C ₁ -C ₆ alkyl; unsubstituted or substituted trityl; Phenyl or diphenylene; R ³ and R ^{4 are} independently alkyloxycarbonyl wherein the alkyl group is unsubstituted or substituted C ₁ -C ₆ alkyl; Alkyloxymethyl or alkyloxyethyl wherein the alkyl group is unsubstituted or substituted C ₁ -C ₆ alkyl; unsubstituted or substituted C ₃ -C ₈ cycloalkyl; unsubstituted or substituted C ₃ -C ₈ cycloalkenyl; Tetrahydrofuranyl or tetrahydropyranyl; and R ^{5 is} unsubstituted or substituted C ₁ -C ₆ alkyl. A compound according to claim 1, characterized in that R ¹ is selected from the group comprising isopropyl, tert -butyl and neopentyl; R ² is selected from the group consisting of tert-butyloxycarbonyl, formyl and alkylcarbonyl such as acetyl, trifluoroacetyl, trichloroacetyl; Trityl, phenyl and diphenylene; R ³ and R ^{4 are} independently selected from the group comprising tert-butyloxycarbonyl, methyloxymethyl, ethyloxymethyl, ethyloxyethyl, cyclopentyl, cyclohexenyl, tetrahydrofuranyl and tetrahydropyranyl; and R ^{5 is} methyl or butyl. A compound according to claim 1 or claim 2, characterized in that it is a compound of formula Ia

is. Process for the preparation of a compound according to one of Claims 1 to 3, characterized in that it comprises the reaction of

with 2-iodoxybenzoic acid and then with ascorbic acid to give

includes. Method according to claim 4, characterized in that that the Reaction in a chlorinated solvent carried out becomes. A method according to claim 4 or claim 5, characterized characterized in that Reaction is carried out at room temperature. Method according to one of claims 3 to 6, characterized in that it further comprises the halogenation of

after protecting the two phenolic hydroxy groups, too

wherein X represents Br or I. Method according to claim 7, characterized in that that if X is iodine, halogenation with [bis (trifluoro-etoxy) iodo] benzene and iodine performed becomes. Method according to claim 7 or claim 8, characterized in that it involves the conversion of

with an organotin compound to a compound of formula I. Use of a compound according to any one of claims 1 to 3 for the preparation of 6-halo-3,4-dihydroxy-L-phenylalanine (6-halo-L-DOPA), wherein the halogen is selected from the group consisting of F, ¹⁸ F , I, I-123, I-125 and I-131. Use according to claim 10, characterized in that the preparation of 6-halo-L-DOPA, the reaction of the compound of formula I, first with an X-containing compound to

wherein XF, ^{18 is} F, I, I-123, I-125 and I-131, followed by reaction with an unsubstituted or substituted C ₁ -C ₆ -alkylcarboxylic acid or a mixture containing an unsubstituted or substituted C ₁ -C ₆ -alkylcarboxylic acid. Use according to claim 11, characterized in that when a mixture containing an unsubstituted or substituted C ₁ -C ₆ -alkylcarboxylic acid is used, the mixture further comprises a mineral acid and / or water. Use according to Claim 11 or Claim 12, characterized in that the C ₁ -C ₆ -alkylcarboxylic acid is trifluoroacetic acid. Use according to any one of claims 10 to 13, characterized in that the reaction with the unsubstituted or substituted C ₁ -C ₆ -alkylcarboxylic acid or a mixture containing the unsubstituted or substituted C ₁ -C ₆ -alkylcarboxylic acid at a temperature of room temperature up to 100 ° C takes place.