DE19949237B4 - Precursor compound for radio diagnostics and process for their manufacture - Google Patents

Abstract

in der die Halogenmethylgruppe in m- oder p-Stellung zur Gruppe OR steht, Hal einen Chlorrest oder Bromrest bedeutet, R eine Hydroxylschutzgruppe und R³ ein Wasserstoffrest oder Jodrest ist, der immer vicinal zur Halogenmethylgruppe steht, und R⁴ ein Wasserstoffrest oder eine Hydroxyl liefernde Schutzgruppe ist
ein Enolat eines chiralen Glycin-Auxiliars alkyliert,
wenn R₃ ein Wasserstoffrest ist, im Alkylierungsprodukt diesen durch einen Jodrest substituiert und
anschließend dehalometalliert.Process for the preparation of a precursor compound for a radio diagnostic agent, characterized in that with a compound of the general formula

in which the halomethyl group is in the m- or p-position to the OR group, Hal is a chlorine or bromine radical, R is a hydroxyl protecting group and R ^{3 is} a hydrogen or iodine radical which is always vicinal to the halomethyl group, and R ^{4 is} a hydrogen radical or a hydroxyl is supplying protective group
alkylating an enolate of a chiral glycine auxiliary,
if R _{3 is} a hydrogen radical, this is substituted by an iodine radical in the alkylation product and
then dehalometalated.

Description

The invention relates to a method for the production of precursor compounds for radio diagnostics on the Basis of tyrosine and its derivatives, the precursor compounds and their implementation as a radio diagnostic for positron emission tomography (PET).

Positron emission tomography is a nuclear medicine imaging technique used in drug discovery and medical diagnostics is used. Main applications are tumor diagnostics, neurology and cardiology. By the procedure will have physiological and biochemical functions on cellular Layer made visible. Positron emission tomography allows that quantitative measurement of physiological and pathological bodily functions on living people. As radio diagnostics to make visible body functions this method uses so-called PET tracers in living people, the radioactive properties of which are the basis of detection a PET camera. The chemical properties of the PET tracer determine its specificity.

Usually will not be the so-called PET tracers at PET centers that the Perform positron emission tomography, but delivered precursor compounds that through a simple chemical reaction to be carried out at the PET center be transferred to the radioactive PET tracer.

Radionuclides are used as PET tracers substances marked by a short half-life are used, which the body supplied and emit positrons when they decay. These react with the electrons of the examined tissue, sending out a high energy gamma radiation. Your different depending on the local enrichment intensity distribution is detected by several thousand crystal detectors that detect the Patient ring-shaped surround. As with the rest A downstream computer processes the tomography process Signals to form a slice, the positron emission tomogram.

Compounds routinely used previously as PET radio diagnostics in tumor diagnostics are [ ¹⁸ F] -fluorodesoxy-glucose (FDG) and [ ¹¹ C] -methionine. The measurement signal generated by [ ¹⁸ F] FDG is based on the measurement of a focal increased metabolic activity. However, an increased metabolic activity is only a non-specific indication of a malignant disease and can also have benign causes such as increased functional stress and inflammation. Due to the short half-life of [ ¹¹ C] of around 20 min, the measurement signal generated by [ ¹¹ C] methionine is based predominantly on the absorption of the amino acids into the cells.

Desirable would therefore be a radio diagnostic that directly involves cell division or pathological process itself. It happens during cell division for the synthesis of nucleic acids and more pronounced of proteins. From the labeling of newly synthesized proteins can therefore a very high sensitivity are expected when the tumor is detected. A PET radio diagnostic that analogous to the amino acids in Protein is incorporated without significantly increasing cell physiology to disturb, does not yet exist.

Due to the short half-life of ¹¹ C, the previously available ¹¹ C-labeled amino acids can only be used to represent the transport of amino acids, but not to quantify protein synthesis. In addition, metabotization causes a further loss of signal strength, or a distribution of the signal to various metabolites and thus in the entire body. It is only the ¹⁸ F label that enables the protein synthesis to be shown due to the longer half-life of 110 minutes. However, previously used ¹⁸ F-labeled amino acids cannot either be used for the quantification because, as in the case of 4- [ ¹⁸ F] -phenylalanine, the signal is superimposed by a signal from other metabolic processes by incorporation into proteins, or the amino acid , as in the case of DOPA or m-tyrosine, is not or only to a small extent incorporated into proteins. In contrast, both the formation of the associated tRNA and the incorporation into proteins in the mouse system were detected for 2- [ ¹⁸ F] -tyrosine (J. nucl. Med. (1989), 30, 1367-1372). On the basis of these data, it can be expected that 2- [ ¹⁸ F] -Lp-tyrosine can also be incorporated into human proteins without problems, so that a visualization of protein synthesis in tumor cells can be measured macroscopically as a spatial concentration of protein-bound radioactivity.

So far, 2- [ ¹⁸ F] -Lp-tyrosine can only be produced by complex, multi-step syntheses (Eur. J. Nucl. Med. (1997), 24, 1056), which rule out routine use for diagnostic purposes.

In contrast, 6- [ ¹⁸ F] -m-tyrosine is not or only rarely incorporated into proteins. It mainly serves to illustrate the transport of aromatic amino acids through the blood-brain barrier, the dopa metabolism and the dopamine receptor distribution. No enantioselective synthesis has been described for m-tyrosine. So far, Lm-tyrosine has been obtained by enzymatic and physical separation of the racemate.

The US 5,510,522 relates to the synthesis of a tin-containing precursor compound to provide fluorine-labeled L-dopa and related compounds. Starting from 3,4-dimethoxy-L-phenylalanine ethyl ester hydrochloride, the amino group is formylated, then the aromatic nucleus is iodinated in the 2-position, the stannylation of the compound obtained and finally the tin ion is replaced by a fluorine ion. The US 5,393,908 describes the corresponding procedure.

The basis of the invention The task is to use a PET diagnostic agent in the To provide diagnostics, in particular tumor diagnostics, that behaves neutrally in terms of cell physiology and with high sensitivity Places elevated Localization of protein synthesis in the living organism allowed. Another object of the invention is to provide a precursor compound, from which the PET diagnostic is obtained in a simple manner.

in der die Halogenmethylgruppe in m- oder p-Stellung zur Gruppe OR steht, Hal einen Chlorrest oder Bromrest bedeutet, R eine Hydroxylschutzgruppe und R³ ein Wasserstoffrest oder Jodrest ist, der immer vicinal zur Halogenmethylgruppe steht, und R⁴ ein Wasserstoffrest oder eine Hydroxyl liefernde Schutzgruppe ist, ein Enolat eines chiralen Glycin-Auxiliars alkyliert, wenn R³ ein Wasserstoffrest ist, im Alkylierungsprodukt diesen durch einen Jodrest substituiert und anschließend dehalometalliert.This object is achieved by a process for the preparation of a precursor compound for a radio diagnostic agent, in which a compound of the general formula is used

in which the halomethyl group is in the m- or p-position to the OR group, Hal is a chlorine or bromine radical, R is a hydroxyl protecting group and R ^{3 is} a hydrogen or iodine radical which is always vicinal to the halomethyl group, and R ^{4 is} a hydrogen radical or a hydroxyl is a protecting group, alkylates an enolate of a chiral glycine auxiliary when R ^{3 is} a hydrogen radical, in the alkylation product this is substituted by an iodine radical and then dehalometallized.

In the case where the halomethyl group is in the m-position to the OR group, R ^{4 is} a hydrogen radical.

worin X ein Rest ist, der in eine Hydroxylrest umgewandelt werden kann, R eine Schutzgruppe für die Hydroxygruppe in m- oder p-Stellung zum α-Aminocarbonsäurerest ist, R¹ und R² vom daran gebundenen Stickstoff leicht abspaltbare Schutzgruppen sind und R¹ und X miteinander unter Ausbildung eines fünf- oder sechsgliedrigen Rings verbunden sein können, wobei R¹ oder R² auch ein Wasserstoffrest sein kann, R⁵ SnAlk₃, HgAlk, GeAlk₃ oder SiAlk₃ bedeutet und Alk eine Alkylgruppe mit etwa 1 bis 5 Kohlenstoffatomen bedeutet.The precursor compounds according to the invention are compounds of the general formula (1)

where X is a radical which can be converted into a hydroxyl radical, R is a protective group for the hydroxyl group in the m- or p-position relative to the α-aminocarboxylic acid radical, R ¹ and R ² are protective groups which can easily be removed from the nitrogen bonded to them, and R ¹ and X can be connected to one another to form a five- or six-membered ring, where R ¹ or R ^{2 can} also be a hydrogen radical, R ^{5 is} SnAlk ₃ , HgAlk, GeAlk ₃ or SiAlk ₃ and Alk is an alkyl group having about 1 to 5 carbon atoms ,

The protective group R is in particular a protecting group, usually as a protecting group for Hydroxy groups is used. These are, for example, alkyl groups or alkenyl groups with 1 to 6 carbon atoms, in particular a methyl group.

The protective groups R ¹ and R ² are customary protective groups for the amino group of amino acids, in particular hydroxyaromatic amino acids. These are, for example, benzyl radicals and their derivatives in any form, alkenyl radicals with 2 to 8 carbon atoms, allyl radicals with 3 to 8 carbon atoms or alkylidene radicals with 1 to 8 carbon atoms. R ¹ and R ² can in particular be methylidene, ethylidene, 2-methylpropylidene, 2,2-dimethylpropylidene, vinyl, allyl, benzyl and substituted benzyl, in particular nitrobenzyl. The amino protecting group can also be a BOC group, benzyloxycarbonyl (BZ), formate, acetate or trifluoromethylsulfonyl.

Which provide a hydroxyl group Groups X are common Protecting groups on carbonyl groups, for example esters, amides and Hydroxylamides, which are easy to split off and which release one Deliver hydroxy function. The protecting group providing a hydroxyl group X can also be a group already described as an amino protecting group his.

worin Alk und R die zuvor angegebenen Bedeutungen haben.Precursor compounds are particularly preferred

wherein Alk and R have the meanings given above.

The compounds thus obtained can be fluorinated in a simple manner, for example by reaction with acetyl hypofluorite. In addition, the fluorination can take place through all fluorine compounds which can split off a fluorine cation. Simultaneously or subsequently, the PET diagnostic 2 [ ¹⁸ F] -Lp-tyrosine according to reaction scheme 1 is obtained by deprotection.

Reaction scheme 1

Radiodiagnostics to be obtained according to the invention are therefore, for example, [ ¹⁸ F] -Lp-tyrosine, [F] -Lp-tyrosine, [ ¹⁸ F] -Lm-tyrosine, [F] -Lm-tyrosine, [ ¹⁸ F] -L-dopa and [F] -L-Dopa By using the other enantiomer of the chiral glycine auxiliary, the corresponding enantiomers, ie fluorinated D-amino acids, can also be produced.

The following reaction scheme 2 explains an example the inventive method.

For the synthesis of the [ ¹⁸ F] -tyrosine precursor compound stannylated in the 2-position, 3-iodoanisole 2 was first halomethylated to the corresponding benzyl halide 3. Halomethylation can be carried out, for example, using a chloromethyl methyl ether or a bromomethyl methyl ether. In the chloromethylation, 1 mol of 3-iodoanisole is preferably reacted with 1.95 to 2.2 mol of chloromethyl methyl ether. In the case of bromomethylation, preferably about 1 mol of 3-iodoanisole is reacted with 1 to 2 mol of bromomethyl methyl ether. This halomethylation is described in Tex. J. Sci. (1978), 30, 357. However, it has proven advantageous, contrary to this rule, to carry out extraction with ethyl acetate after quenching the reaction with ice, washing the organic phase with saturated sodium hydrogen carbonate solution and sodium chloride solution and flash chromatography on silica gel with petroleum ether / Ethyl acetate in a ratio of approximately 96: 4. Yields of about 62 are obtained.

To increase the reactivity of the Halomethylation obtained benzyl halide is 3-iodoanisole 2 preferably with a bromomethyl methyl ether instead of with chloromethyl methyl ether converted to the corresponding benzyl bromide 10. The yield is approximately 67%. Since the benzyl bromide is comparatively unstable and about starts to decompose an hour after drying, it is recommended dissolve the benzyl bromide in THF after purification and to implement directly further.

The benzyl halide is used in a subsequent reaction to alkylate chiral glycine auxiliaries. It has proven particularly advantageous to use the glycine auxiliaries (2R, 3S) - (-) - 2,3-diphenyl-6-oxo morpholine-4-carboxylic acid tert-butyl ester 11 or (2S) -1-tert-butyloxycarbonyl-2-tert-butyl-3-methyl-4-oxo-imidazolidine (BocBMI) 12. Comparable reactions under the same reaction conditions can also be carried out with the corresponding enantiomeric chiral glycine auxiliaries and then lead to the respective other enantiomer of the product.

Compounds 4 and 8 of Reaction Scheme 2 and Compound 24 of Reaction Scheme 2a are then dehalometalated. In this reaction, the iodine residue in the aromatic system is replaced by an organometallic group. The dehalometalation can be a stannylation reaction using hexaalkylditine, and the alkyl radical can have 1 to 5 carbon atoms. Palladium catalysts can be used as catalysts for this reaction. Preferred catalysts are PdBr ₂ (PPh ₃ ) ₂ , PdCl ₂ (PPh ₃ ) ₂ , Pd (PPh ₃ ) ₄ and those compounds or processes from which the aforementioned catalysts are provided in situ.

Also suitable for substitution of the iodine residue are those compounds which can easily be replaced by a fluorine residue in a subsequent reaction. Such compounds include, for example, alkyl mercury compounds in which the alkyl radical contains 1 to 5 carbon atoms, compounds of the general formula Alk ₃ Si-SiAlk ₃ in which the alkyl radical contains 1 to 5 carbon atoms and Alk ₃ Ge-GeAlk ₃ in which the alkyl radical contains 1 to 5 carbon atoms , The arylalkyl mercury derivatives, silane derivatives or germanane derivatives obtained can easily be subjected to a metal / fluorine exchange with fluorine cations. These reactions are described in J. Fluorine Chem. (1984), 25, 533; Chem. Comm. (1984), 655; J. org. Chem. (1986), 51, 1886; J. organomet. Chem. (1981), 215, 49-58; US 3,772,347.

Dehalometalation is preferred however, a stannylation. This reaction is described in J. Organomet. Chem. (1981), 215, 49-58. The dehalometalation can be used in neutral aprotic solvents like dioxane. The reaction can take place at temperatures of about 110 to 120 ° C under an inert gas atmosphere carried out become.

The following reaction scheme 2a shows for example the preparation of a precursor compound according to the invention in Form of an m-tyrosine derivative. This course of the reaction also shows a reaction pathway to obtain m-tyrosine 25.

The halomethyl compound 21 is in the presence of diisopropylamine and butyllithium with chiral glycine auxiliaries. In the present case, this is (2S) -1-tert-butyloxycarbonyl-3-methyl-4-oxo-imidazoline (Boc-BMI) 12. Compound 23 obtained can be treated with hydroiodic acid be converted into the m-tyrosine. It can be treated with iodine in the presence of a silver trifluoroacetic acid salt be transferred into connection 24. The iodinated compound 24 then undergoes a stannylation reaction subjected and obtained the compound 26. The connection 26 is one obtained according to the invention Precursor. You can, for example, by acetyl hypofluorite be fluorinated. The protective groups of the compound 27 can by hydriodic with increased Temperature are split off, which creates the radio diagnostic.

Otherwise, the description of Reaction Scheme 2 and the subsequent detailed description of the individual reactions.

The fluorination to 15 can be carried out using fluorinating agents known to those skilled in the art. Fluorination with acetyl hypofluorite has proven to be particularly advantageous. The fluorination should be quantitative. The fluorination can be carried out with radioactive or non-radioactive fluorine. On the protective groups are then split off and the PET tracer is retained.

According to a preferred embodiment can deprotection with HJ (about 57%) by heat treatment at about 200 ° C over a Period of about 20 minutes. The protective groups can furthermore by Treatment with hydrochloric or hydrobromic acid. The Concentration of both acids the reaction medium is then about 6N.

The method according to the invention is as follows by way of example using preferred embodiments with reference explained on reaction scheme 2. The explanation applies in the same way to the reaction steps of Reaction Scheme 2a.

Halo methylation

A solution of 3-iodosiol 2 in acetic acid was added according to one reaction described in the literature using chloromethyl methyl ether at 55 ° C chloromethylated to benzyl derivative 9 within 48 hours. to Purification was contrary to the regulation in Tex. J. Sci. (1978) 30, 357 after quenching the reaction with ice with ethyl acetate extracted, the organic phase washed with saturated sodium bicarbonate and sodium chloride solution and over Silica gel with petroleum ether / ethyl acetate 96: 4 flash chromatographed. The yield was 62%. Since the benzyl chloride 9 in the following Alkylation reactions proved not to be reactive enough Analogous reaction worked out in which a solution of 3-iodoanisole 2 in acetic acid 35 ° C inside 48 hours in an argon atmosphere reacted with bromomethyl methyl ether to give the corresponding benzyl bromide 10 has been. After dilution with water was extracted with dichloromethane, the organic phase with saturated Sodium bicarbonate and sodium chloride solution washed and over silica gel flash chromatographed with petroleum ether / ethyl acetate 97: 3. The yield was 67%. The benzyl bromide 10 was immediately after purification dissolved in absolute THF and implemented further.

Surprised was that despite halomethylation of the iodine substituent on the tyrosine aromatic or dopa aromatic only led to by-products to a small extent.

Reaction scheme 3

alkylation chiral glycine auxiliaries

It was made with two chiral glycine auxiliaries worked, (2R, 3S) - (-) - 2,3-diphenyl-6-oxomorpholine-4-carboxylic acid tert-butyl ester 11 and (2S) -1-tert-butyloxycarbonyl-2-tert-butyl-3-methyl-4-oxo-imidazolidine (Boc-BMI) 12.

In enolate chemistry is mostly used Temperatures of around -78 ° C worked. It was surprising that the alkylation according to the invention smooth at temperatures of -40 ° C to room temperature. The shielding effect is presumably the iodine residue for it responsible.

Alkylation reaction with (2R, 3S) - (-) - 2,3-diphenyl-6-oxomorpholine-4-carboxylic acid tert-butyl ester

A solution of 11 in THF (abs.) Was mixed at -40 ° C under an argon atmosphere with 1 equivalent of a 1 M solution of sodium hexamethyldisilazide in THF. 2 equivalents of DMPU were added dropwise and a solution of 1.5 equivalents of 2-iodo-4-methoxybenzyl chloride in THF (abs.) Was finally added. It was stirred for 24 hours at -40 ° C, then thawed to -20 ° C and quenched with saturated NH ₄ Cl solution. It was extracted with CH ₂ Cl ₂ , the organic phase was washed with saturated NaHCO ₃ and NaCl solution and dried over Na ₂ SO ₄ . The mixture was then purified chromatographically on silica gel using petroleum ether / ethyl acetate 7: 3. The yield of product 17 was 34%. NMR spectra and HPLC chromatograms were recorded for analysis. The absolute configuration of the benzylic substituent has not yet been elucidated. The product of methylation with methyl iodide, which we also worked out, has the S configuration at the same point, so that the S configuration can also be assumed at 17. The other diastereomer has not yet been found.

Reaction scheme 4

Alkylation with Boc-BMI

A solution of 1.1 equivalents of diisopropylamine in THF (abs.) Was added at -40 ° C and under an argon atmosphere with 1.1 equivalents of a 2.5 M solution of butyllithium in hexane. A solution of 1 equivalent of Boc-BMI 12 in THF (abs.) Was then added dropwise. The mixture was stirred at -40 ° C. for 30 min, then a solution of 1.5 equivalents of 2-iodo-4-methoxybenzyl halide in THF was added dropwise. The stirring was continued for 1 to 2 hours at -40 ° C, then thawed overnight. It was quenched with saturated NH ₉ Cl solution, extracted with ether and the organic phase washed with saturated NaHCO ₃ and NaCl solution. The mixture was then dried over NaSO ₄ and flash chromatographed over silica gel using petroleum ether / ethyl acetate 70:30. In the reaction with the benzyl chloride as alkylation reagent, product 14 was obtained in a yield of 6%, in the reaction with the benzyl bromide in a yield of 67%. The second diastereomer has not yet been found. For analysis, NMR spectra, HPLC chromatograms and an X-ray structure analysis were prepared, which confirmed the S configuration on the benzylic substituted carbon atom.

Reaction scheme 5

Dehalometallierungs- / Stannylierungsreaktion

For the stannylation, a solution of 14 in dioxane (abs.) Was mixed with about 4.5 mol% Pd (PPh ₃ ) ₄ and about 1.9 equivalents of hexamethylditin and heated to boiling under an argon atmosphere at an oil bath temperature of 115 ° C. for 10 hours. The solvent was distilled off. The mixture was then flash chromatographed on silica gel using petroleum ether / ethyl acetate 85:15. Product 1 was obtained in 74% yield. NMR spectra and HPLC chromatograms were recorded for analysis.

Scheme 6

fluorination

The fluorination to 15 is carried out using acetyl hypofluorite according to the methods developed in PET chemistry. It should run quantitatively. The fluorination with ¹⁸ F is carried out in PET centers.

Reaction scheme 7

Deprotection

For deprotection according to reaction scheme 8, compound 15 was mixed with HJ (57%) and heated under reflux for 90 min under an argon atmosphere. The HJ solution was then distilled off, water was added three times and distilled off, and toluene was added three times, distilled off and finally dried under an oil pump vacuum. The mixture was then taken up in H ₂ O and applied to Dowex ^® 50 W x 8-400. It was washed with water and eluted with an aqueous 10% NH ₃ solution. The solvent was distilled off, water was added twice and distilled off.

Reaction scheme 8

The 1 and 2 show ¹ H-NMR spectra of two precursor compounds according to the invention. The 3 shows a ¹ H NMR spectrum of compound 23 of reaction scheme 2a. The 4 shows a ¹ H-NMR spectrum of compound 25, m-tyrosine, of the reaction scheme 2a.

Fig. 1 - (2S, 3R, 5R) -2,3-diphenyl-5- (2-trimethylstannyl-4-methoxybenzyl) -6-oxo-morpholine-4-carboxylic acid tert-butyl ester ¹ H-NMR (in CDCl ₃ )

• d: 0.34 (9H, s, SnMe ₃ ), 0.96 (9H, s, H-8), 1.37 (9H, s, H-11), 2.81 (3H, s, H-6), 3.30 (1H, dd , J _{12a, 12b} = 15.1 Hz, J _{12a, 5} = 3.0 Hz, H-12a), 3.58 (1H, dd, J _{12b, 12a} = 15.3 Hz, J _{12b, 5} = 5.1 Hz, H-12b), 3.76 (3H, s, OCH ₃ ), 4.32 (1H, m, H-5), 4.89 (1H, s, H-2), 6.70 (1H, dd, J _{5 ', 6} ' = 8.7 Hz, J _{5 ', 3'} = 2.8 Hz, H-5 '), 6.84 (1H, d, J _{6', 5 '} = 8.5 Hz, H-6'), 6.93 (1H, d, J _{3 ', 5'} = 2.7 Hz, H-3 ').

Fig. 2 - (2S, 3R, 5R) -2,3-diphenyl-5- (2-tributylstannyl-4-methoxybenzyl) -6-oxo-morpholine-4-carboxylic acid tert-butyl ester ¹ H-NMR (in CDCl ₃ )

• d: 0.88 (9H, t, J _{10 ', 9'} = 7.4 Hz, H-10 '), 0.97 (9H, s, H-8), 1.07-1.14 (6H, m, H-9'), 1.28 -1.39 (6H, m, H-8 '), 1.35 (9H, s, H-11), 1.47-1.61 (6H, m, H-7'), 2.85 (3H, s, H-6 '), 3.27 (1H, dd, J _{12a, 12b} = 15.5 Hz, J _{12a, 5} = 3.1 Hz, H-12a), 3.54 (1H, dd, J _{12b, 12a} = 15.3 Hz, J _{12b, 5} = 5.0 Hz, H- 12b), 3.75 (3H, s, OCH ₃ ), 4.32 (1H, m, H-5), 4.93 (1H, s, H-2), 6.68 (1H, dd, J _{5 ', 6'} = 8.5 Hz , J _{5 ', 3'} = 2.8 Hz, H-5 '), 6.81 (1H, d, J _{6', 5 '} = 8.6 Hz, H-6'), 6.91 (1H, d, J _{3 ', 5 '} = 2.7 Hz, H-3').

Fig. 3 - (2S, 3R, 5R) -2,3-diphenyl-5- (3-methoxybenzyl) -6-oxo-morpholine-4-carboxylic acid tert-butyl ester ¹ H-NMR

• d: 0.90 (9H, s, H-8), 1.47 (9H, bs, H-11), 2.78 (3H, bs, H-6), 3.15 (1H, dd, J _{12a, 12b} = 14.0 Hz, J _{12a, 5} = 2.2 Hz, H-12a), 3.71-3.79 (1H, dd, J _{12b, 5} ≅ 6.2 Hz, H-12b), 3.73 (3H, s, OCH ₃ ), 4.28 (1H, bm , H-5), 4.58 (1H, bs, H-2), 6.65-6.75 (3H, m, H-2 ', H-4', H-6 '), 7.08 (1H, dd, J _{5 ', 4'} = 8.0 Hz, J _{5 ', 6'} = 8.0 Hz, H-5 ').

Fig. 4 - m-Tyrosine ¹ H-NMR (in D ₂ O / DCl)

• d: 3.04 (1H, dd, J _{3a, 3b} = 14.8 Hz, J _{3a, 2} = 7.8 Hz, H-3a), 3.18 (1H, dd, J _{3b, 2} = 14.4 Hz, J _{3b, 2} = 5.5 Hz , H-3b), 4.20 (1H, dd, J _2.3a = 7.6 Hz, J _2.3b = 5.6 Hz, H-2), 6.68 (1H, m, H-2 '), 6.71-6.78 (2H , m, H-4 ', H-6'), 7.17 (1H, dd, J _{5 ', 4'} = 7.9 Hz, J _{5 ', 6'} = 7.9 Hz, H-5 ').

Claims (5)

Process for the preparation of a precursor compound for a radio diagnostic agent, characterized in that with a compound of the general formula

in which the halomethyl group is in the m- or p-position to the OR group, Hal is a chlorine or bromine radical, R is a hydroxyl protecting group and R ^{3 is} a hydrogen or iodine radical which is always vicinal to the halomethyl group, and R ^{4 is} a hydrogen radical or a hydroxyl protective group is an enolate of a chiral glycine auxiliary alkylated when R _{3 is} a hydrogen radical, substituted in the alkylation product by an iodine radical and then dehalometallized. A method according to claim 1, characterized in that he as glycine auxiliary (2R, 3S) - (-) - 2,3-diphenyl-6-oxomorpholine-4-carboxylic acid tert-butyl ester or (2S) -1-tert-butyloxycarbonyl-2-tert-butyl -3-methyl-4-oxoimidazolidin (BocBMI) or their enantiomers. A method according to claim 1, characterized in that the Dehalometalation is a stannylation using hexaalkylditine in which the alkyl radical has 1 to 5 carbon atoms, in the presence of a Palladium catalyst. A method according to claim 1, characterized in that he the starting material 2-iodo-4-methoxybenzyl halide by halomethylation of 3-iodoanisole with chloromethyl methyl ether or bromomethyl methyl ether, Precursor compounds for a radio diagnostic agent of the general formula

where X is a radical which can be converted into a hydroxyl radical, R is a protective group for the hydroxyl group in the m- or p-position relative to the α-aminocarboxylic acid radical, R ¹ and R ² are protective groups which can easily be removed from the nitrogen bonded to them, and R ¹ and X can be connected to one another to form a five- or six-membered ring, R ^{5 is} SnAlk ₃ , HgAlk, GeAlk ₃ or SiAlk ₃ and Alk is an alkyl group having about 1 to 5 carbon atoms.