WO2003099746A1

WO2003099746A1 - Method for the production of 18f-fluorinated alpha acids

Info

Publication number: WO2003099746A1
Application number: PCT/DE2003/001692
Authority: WO
Inventors: Simon Mensah Ametamey; Yurij Belokon; Olga S. Fedorova; Raisa N. Krasikova; Stepan Vyskocil
Original assignee: Abx Gmbh
Priority date: 2002-05-25
Filing date: 2003-05-23
Publication date: 2003-12-04
Also published as: DE10223451A1

Abstract

The invention relates to a method for the production of 18F-fluorinated ?-amino acids and 18F-fluorinated α-amino acid derivatives, comprising the following steps: (a) reaction of a 18F-fluorinated compound of formula I, wherein R1 and R2 independently represent hydrogen, a hydroxy group, a benzyloxy group or an alkoxy group with 1 - 5 carbon atoms or Rl and R2 jointly represent a -0-CH2-0 group; and X represents a halogen, a tosyl-, mesyl- or trifluoromethane-sulphonyl group; with an achiral or chiral Ni(II)-complex of a Schiff base of a compound of formula II wherein R3 represents hydrogen or a non-branched or branched alkyl group with 1-5 carbon atoms, in the presence of a chiral catalyst and an auxiliary base; and (b) cleavage of the compound obtained in step (a).

Description

description

Process for the preparation of ¹⁸ F-fluorinated alpha-amino acids

The invention relates to a process for the preparation of ¹⁸ F-fluorinated α-amino acids and ¹⁸ F-fluorinated α-amino acid derivatives. It relates in particular to a process for the preparation of 2- [ ¹⁸ F] -fluoro-L-tyrosine.

2- [ ¹⁸ F] -fluoro-L-tyrosine (2-amino-3- (4-hydroxyphenyl) propionic acid, hereinafter abbreviated as L-FTYR) is an indicator substance (tracer) which is used in nuclear medicine, especially as Contrast medium is used in positron emission tomography. Essential area of application of

¹⁸ F-labeled L-FTYR is the diagnosis and evaluation of brain tumors.

Due to the comparatively high half-life of ¹⁸ F (110 min), PET centers with positron emitters marked in this way can be supplied by the so-called satellite concept. The satellite concept provides that the radioactively labeled substances are produced in a synthesis center, which has a cyclotron, when requested by the PET center and then transported to the PET center, for example by plane. The distance between the synthesis center and the PET center should be covered in a time that corresponds to two to four times the half-life of the radionuclide used. However, this satellite concept requires an uncomplicated process for producing the tracer, with which, for example, L-FTYR can be produced in high yields and in a short time. In addition, it is necessary that the production can be carried out using fully automated modules, which are absolutely necessary when using highly radioactive substances in order to avoid contamination and damage to the environment. The previously known manufacturing processes for L-FTYR do not meet these requirements.

L-FTYR has so far mainly been produced by non-regioselective electrophilic fluorination of o-acetyltyrosine via [ ¹⁸ F] - acetyl hypofluoride (Coenen, HH, Kling, P., Stocklin, G., Cerebral metabolism of L- [2-18F] fluoro tyrosine: a new PET tracer of protein synthesis, J. Nucl.

Med. 1989, 30, 1367-1372; Coenen, H.H., Franken, K., Kling, P., Stocklin, G., Direct electrophilic fluorination of phenylalanine, tyrosine and dopa., Appl. Rad. Isot., 1988, 12, 1243-1250). A mixture of the 2-isomer and 3-isomer of L-FTYR is obtained, which is separated by high performance liquid chromatography (HPLC). However, only a very low yield of the desired 2-isomer is obtained.

ϊ Furthermore, a process for the production of L-LTYR is known, in which a chiral inductor is used in the presence of an auxiliary base (Lemaire, C, Damhaut, P., Plenevaux, A., Comar, D., Enantioselective synthesis of 6 - [fluorine-18] - fluoro-L-dopa from no-carrier-added fluorine-18-fluoride, J. Nucl. Med. 1994, 35, 1996-2002; Lemaire,

C, Production of L- [ ¹⁸ F] Fluoro amino acids for protein syn- thesis: overview and recent developments in nucleophilic synthesis. In: PET studies on Amnio Acids Metabolism and Protein Synthesis, editor BM Mazoyer, WD Heiss, D. Comar, Developments in Nuclear Medicine, 1996, Vol. 23, pp. 89-108). The chrial inducer used in the manufacture of the L-FTYR (S) - (-) -l-Boc-2-tert-butyl-3-methyl-4-imidazolidinone, which is extremely unstable and sensitive to moisture, which means high equipment Demands and requires extreme care in the production. In addition, the chiral alkylation step must be carried out at a temperature of -78 ° C or less. Manufacturing in fully automated modules, which are required for highly radioactive substances, is therefore not possible.

The object of the invention is to eliminate the disadvantages of the prior art. In particular, a comparatively simple process for the production of ¹⁸ F-fluorinated α-amino acids and ¹⁸ F-fluorinated α-amino acid derivatives, in particular 2- [ ¹⁸ F] -fluoro-L-tyrosine, is to be specified, which is carried out in fully automated modules can be.

This object is achieved by the features of claim 1 and claim 16. Expedient embodiments of the inventions result from the features of claims 2 to 15 and 17 to 20.

According to the invention, a process for the preparation of ¹⁸ F-fluorinated α-amino acids and ¹⁸ F-fluorinated α-amino acid derivatives provided which comprises the following steps:

(a) Reacting an ¹⁸ F-fluorinated compound of the formula

I

in the

Rx and R ₂ independently represent hydrogen, a hydroxy group, a benzyloxy group or an alkoxy group having 1 to 5 carbon atoms or R _x and R ₂ together form a -0-CH ₂ -0 group; and

X represents a halogen, a tosyl, mesyl or trifluoromethanesulfonyl group; with an achiral or chiral Ni (II) complex of a Schiff base of a compound of formula II

in which R _{3 represents} hydrogen or an unbranched or branched alkyl group having 1 to 5 carbon atoms, in the presence of a chiral catalyst and an auxiliary base; and (b) cleaving the compound obtained in step (a).

The process according to the invention is a stereoselective nucleophilic asymmetric synthesis process which is based on phase transfer catalysis, the chiral catalyst serving as the phase transfer catalyst. An important advantage of this method is that step (a) and step (b) can be carried out at room temperature. The automation of this process step is made possible due to these mild reaction conditions. Therefore, the Processes according to the invention are used in fully automated modules, so that the production of ¹⁸ F-fluorinated α-amino acids and ¹⁸ F-fluorinated α-amino acid derivatives, in particular L-FTYR, in connection with the satellite concept is made possible for the first time.

In addition, the yields of the process mentioned are high, depending on the selected Schiff base, the solvent and the workup. The process usually results in reaction products with an enantiomeric purity (e.e.) of more than 90%. For these high yields, it is essential that the reaction mixture obtained in step (a) is quenched. The complex obtained in step (a) is cleaved. The quenching is also carried out at room temperature in which, for example, an acid How 57% hydroiodic acid (HI) is added to the reaction mixture obtained in step (a).

The ¹⁸ F-fluorinated α-amino acids and ¹⁸ F-fluorinated α-amino acid derivatives which can be obtained by the process according to the invention have the following general formula IV:

where RI, R2 and R3 are as defined above. The L or D form of these ¹⁸ F-fluorinated α-amino acids and ¹⁸ F-fluorinated α-amino acid derivatives can be produced using the process according to the invention. Preferred ¹⁸ F-fluorinated α-amino acids and ¹⁸ F-fluorinated α-amino acid derivatives are shown in Table 1. The enantiomeric forms were not shown. For example, the statement 2- [ ¹⁸ F] -fluoro-p-tyrosine means both 2- [ ¹⁸ F] -fluoro-pL-tyrosine and 2- [ ¹⁸ F] -fluoro-pD-tyrosine.

X has the meaning given above for the compound of the formula I. It should be expressly mentioned that X in compound I represents a leaving group, so that other suitable groups can also be used as X in addition to those already specified.

It is readily understandable for the person skilled in the art that certain functional groups which represent R _x or R ₂ are present suitable protective groups must be provided during the implementation in step (a), the protective groups again having to be separated off after the method has been carried out.

An Ni (II) complex is preferably an achiral Ni (II) complex of a Schiff base of N- (2-benzoylphenyl) pyridine-2-carbamide and a compound of the formula II

in which R _{3 represents} hydrogen or an unbranched or branched alkyl group having 1 to 5 carbon atoms. The compound of formula (II) is preferably glycine or alanine.

The Ni (II) complex from a boat base from

N- (2-benzoylphenyl) pyridine-2-carbamide and glycine or alanine thus has the following structure:

where R _{3 is} hydrogen when glycine was used and CH ₃ when alanine was used.

Alternatively, a chiral Ni (II) complex of a Schiff base of (S) -o- [(N-benzylprolyl) amino] benzophenone and a compound of formula II

The chiral Ni (II) complex from a Schiff base of (S) -o- [(N-benzylprolyl) amino] benzophenone and glycine or alanine thus has the following structure:

where R _{3 is} hydrogen if glycine has been used, and

CH ₃ is when alanine was used.

A compound of the formula III is preferably used as the chiral catalyst

in which R ₄ and R ₅ independently of one another represent hydrogen, an unbranched or branched alkyl group having 1 to 5 carbon atoms, a phenyl group, an adamantyl group or a - (CH ₂ ) _n OH group, where n represents 1 to 3. The preferred chiral catalyst is (S) -2'-amino-2-hydroxy-l, l'-binaphthyl (= (S) -NOBIN). In this case, R4 and R5 in formula III are each hydrogen.

Alternatively, the chiral catalyst can be a compound of formula IV

in which R ₆ and R _{7 are} independently hydrogen, a benzyl group or an unbranched or branched alkyl group having 1 to 3 carbon atoms and R _{8 is} hydrogen, a phenyl group or naphthyl group. Such a chiral catalyst is, for example, (4R, 5R) -2, 2-dimethyl-1,3-dioxolane-4,5-bis (diphenylmethanol) (= 4R, 5R-TADDOL). In this case, in formula IV, R ₆ and R are each hydrogen and R _{8 is} a phenyl group.

An alkali metal hydroxide, alkali metal hydride or alkali metal tert-butyrate can be used as the auxiliary base. LiOH, NaOH, KOH, CsOH, NaH and potassium tert-butyrate are preferred. NaOH is particularly preferred.

The quenching of the compound obtained in step (a) in step (b) can be carried out by adding an acid. Suitable acids are alkanoic acids with 2 to 5 hydrocarbon atoms or halogen acids. Acid is preferably acetic acid, hydrochloric acid, hydrogen bromide or iodine water. substance, with acetic acid and hydrogen iodide being particularly preferred. This step can also be carried out at room temperature.

Process step (a) is preferably carried out in a polar or non-polar organic solvent, methylene chloride or dichloroethane being particularly preferred as the solvent.

The following procedure, which comprises the following steps, has proven to be expedient for the preparation of 2- [ ¹⁸ F] -fluoro-L-tyrosine:

(a) Reacting l-bromomethyl-2- [ ¹⁸ F] -fluoro-4-methoxy-benzene with an achiral nickel (II) complex of a boat base of (S) -2'-amino-2-hydroxy -l, 1 '-binaphthyl and glycine in the presence of (S) -2' -amino-2-hydroxy-1, 1 '-binaphthyl as chiral catalyst and solid NaOH as auxiliary base;

(b) Quenching the compound obtained in step (a) to form 2-amino-3- (2- [ ¹⁸ F] -fluoro-4-metoxyphenyl) propionic acid and

(c) converting the 2-amino-3- (2- [ ¹⁸ F] -fluoro-4-methoxy-phenyl) -propionic acid obtained in step (b) to 2- [ ¹⁸ F] - fluoro-L-tyrosine.

Preferably, 57% hydroiodic acid is used in step (b) to cleave the compound obtained in step (a). Step (a) and step (b) can be carried out at room temperature. In step (c), preferably 57% hydroiodic acid is obtained in step (b)

Compound added and the reaction mixture boiled brought to convert the methoxy group into the OH group (deprotection). Methylene chloride or dichloroethane is preferably used as the solvent for step (a).

If hydroiodic acid has already been used to split the complex in step (b), it is not necessary to add hydroiodic acid again to carry out step (c). Rather, it is then sufficient to remove the solvent from the reaction mixture obtained in step (b) and to treat the resulting reaction mixture at about 170 ° C. under reflux in a closed reaction vessel. This embodiment of the invention is particularly preferred.

The invention is explained in more detail below on the basis of an exemplary embodiment. The embodiment shows the production of 2- [ ¹⁸ F] -fluoro-L-tyrosine according to the method of the present invention.

A. Preparation of l-bromomethyl-2- [ ¹⁸ F] -fluoro-4-methoxy-benzene IV

1-Bromomethyl-2- [ ¹⁸ F] -fluoro-4-methoxy-benzene serves as a precursor for the production of 2- [ ¹⁸ F] -fluoro-L-tyrosine.

AI. Production of the ¹⁸ F radionuclide

The radionuclide ¹⁸ F was generated in a known manner in a water cyclotron target by means of the ¹⁸ 0 (p, n) ¹⁸ F nuclear reaction and collected on QMC resin (QMC = ...) in carbonate form. The radionuclide was obtained from the QMC resin by adding 2 ml of one Eluates (K ₂ C0 ₃ , MeCN, Kryptofix and water; the water content was 4% by volume) were passed over the QMC resin. The solvent was then evaporated to dryness at 130 ° C. under a stream of nitrogen.

A2. Preparation of 2- [rlβ F] -fluoro-4-methoxy-benzaldehyde 1

2- [ ¹⁸ F] -Fluoro-4-methoxy-benzaldehyde 1 is prepared by nucleophilic substitution from 4-methoxy-2-nitro-benzaldehyde 2 in the presence of a crown ether as an ion scavenger. The

Preparation of 4-methoxy-2-nitro-benzaldehyde 2 is known (see C. Lemaire et al., Synthesis of fluorine-18 Substituted Aromatic Aldehydes and Benzyl Bromides, New Intermediates for n. C. A. [ ¹⁸ F] Fluorination, Applied Radiation and Isotopes, Vol. 43, No. 4, pp. 485-494, 1992).

1

The residue obtained in step AI was treated with a solution of 15 mg of compound 1 in 1 ml of DMSO. The reaction mixture was then heated to 180 ° C. for 5 minutes. After cooling, the reaction mixture was diluted with 8.5 ml of water.

A sample of the reaction product was analyzed by radio thin layer chromatography (radio TLC) using a silica gel plate and methylene chloride. The retention time (R _f ) for ¹⁸ F-fluoride was 0, for compound 1 0.45. Based on the radio TLC values, an incorporation rate of ¹⁸ F-fluorine into the aldehyde structure of an average of 86.9% ± 0.9% (number of tests (n) ■ = 4) was calculated.

To separate Compound 2 from unreacted ¹⁸ F fluoride, the diluted reaction mixture was passed over a C18 Supelco column (600 mg C18 packed into a 6 ml column), previously with 10 ml methanol and 15 ml Water had been conditioned. The C18 column was cleaned twice with 5 ml of water.

A3. Preparation of (2- [ ¹⁸ F] -fluoro-4-methoxy-phenyl) -methanol 3

Compound 2 is converted to (2- [ ¹⁸ F] -fluoro-methoxy-phenyl) -methanol 3 by online reduction:

Compound 1 retained in the C18 column was slowly rinsed out with 3.5 ml of ether (alternatively methylene chloride) and the eluate was passed into a combined column which was mixed with NaBH ₄ / Al ₂ 0 ₃ and K ₂ C0 ₃ (80:20) was packed. A standard 1 ml Supelco column was used for packing. The conversion rate was determined by radio TLC and / or HPLC and was 76 to 97% (n = 4). A4. Preparation of l-bromomethyl-2- [ ¹⁸ F] -f luoro-4-methoxy-benzene 4

Compound 3 is then converted to l-bromomethyl-2- [r lβ iF] - fluoro-4-methoxy-benzene 4 according to:

The bromination was carried out in methylene chloride at room temperature using 60 to 80 mg of Ph ₃ PBr ₂ (available from Aldrich) as the standardizing agent. The use of this brominating agent is known from R. Iwata et al. , A new convenient method for the preparation of 4- [ ¹⁸ F] fluorobenzyl halides, Applied Radiation Isotopes, 2000, 52, pp. 87-92. The conversion rate, which was measured by radio TLC and / or HPLC, is between 65 and 93%. The reaction product obtained was purified by passing it through a commercially available Basic Alumina Supleco column (1 g A1B). The purified solution was collected directly in the chiral alkylation vessel.

B. Preparation of the catalyst

Methods for making the complexes used in the present invention are described in Belokon, YN, et al. , J. Am. Chem. Soc. 1983, 105, 2010; Belokon, YN, et al., J. Chem. Soc, Perkin. Trans. 1986, 1, 1865; and Belokon, YN, et al., J. Chem. Soc. Perkin. Trans. 1988, 1, 305-312; known.

The preparation of a chiral Ni (II) complex of a Schiff base of (S) -o- [(N-benzyl-prolyl) amino] benzophenone and glycine is described below. The ligand of (S) -o- [(N-benzylprolyl) amino] benzophenone

is available from Merk.

2.996 g (7.9 mmol) of (S) -o- [(N-benzylprolyl) amino] benzophenone and 4.45 g of Ni (N0 ₃ ) ₂ • 6 H ₂ 0 were placed in a 100 ml two-necked flask with a reflux condenser. dissolved in 40 ml of absolute methanol. The reaction mixture was warmed to 50 ° C. 2.89 g (0.038 mmol) of glycine, dissolved in 30 ml of 1.2 N MeONa in methanol, were then added with stirring. The reaction mixture was kept at 50 ° C. for 2 hours, during which time the color of the mixture changed from blue to dark red. The reaction mixture was diluted with 50 ml of water and the reaction product, Ni-BPB, extracted with chloroform. The solvent was evaporated in vacuo and the residue was then purified by column chromatography (column 50 × 3.5 cm; silica gel 40/100 micron; chloroform: acetone 5: 1: flow rate 5 ml / min). The reaction product Ni-BPB had a melting point of 207 to 210 ° C and a dark red color. The reaction product was stable at room temperature.

The preparation of the achiral nickel (II) complex of a Schiff base of (S) -2'-amino-2-hydroxy-l, 1'-binaphthyl and glycine (hereinafter referred to as Ni-PBP) is described in Belelkon, Y., et al, Angew. Chemie 2001, 113, No. 10, p. 2004. The following reaction product is obtained:

C. Preparation of 2- [ ¹⁸ F] -fluoro-L-tyrosine

The following is the preparation of 2- [ ¹⁸ F] -fluoro-L-tyrosine by reacting l-bromomethyl-2- [ ¹⁸ F] -fluoro-4-methoxy-benzene 4 with Ni-PBP in the presence of (S) - 2'-Amino-2-hydroxy-l, l '-binaphthyl ((S) -NOBIN) as a chiral catalyst and solid NaOH as an auxiliary base.

Cl. Reaction of Ni-PBP with l-bromomethyl-2- [ ¹⁸ F] -fluoro-4-methoxy-benzene 4

l-Bromomethyl-2- [ ¹⁸ F] -fluoro-4-methoxy-benzene 4 is reacted with Ni-BPB to form a diastereomeric complex 5:

Ni-PBP, (S) -NOBIN 40 ° C, CH ₂ C1 ₂

The asymmetric alkylation was carried out under phase transfer catalysis conditions. Solid, freshly finely powdered NaOH (20 mg) with Ni-PBP (22 mg) and (S) -NOBIN (2 mg) in anhydrous CH ₂ C1 ₂ (1 ml; the solvent comes from the preparation of compound 4), which was stirred under argon for 3 min at room temperature by vortex. Then compound 4 was added under argon and the reaction mixture was stirred for 3 to 5 minutes by vortex. The reaction was then stopped by adding 0.5 ml of 57% HI Heating quenched. The solvent was evaporated at 40 ° C under vacuum and the crude product refluxed for 5 minutes at 170 ° C in a closed reaction vessel (deprotection) to give the target compound. L-FTYR 7 was then obtained by reverse phase HPLC.

HI 57%

Alkylation of the achiral nickel (II) complex under phase transfer catalytic conditions in methylene chloride gave L-FTYR 7 with an enantiomeric purity of 90% and a radiochemical yield of 25 to 30% (EOB).

Quenching the reaction before removing the solvent by evaporation is essential to prevent heat induced racemization of the (S) complex, as can be seen from Table 2:

Table 2

* RT = room temperature

Claims

claims

1. A process for the preparation of ¹⁸ F-fluorinated α-amino acids and ¹⁸ F-fluorinated α-amino acid derivatives, comprising the steps:

(a) Reacting an ¹⁸ F-fluorinated compound of the formula

in which Ri and R ₂ independently represent hydrogen, a hydroxyl group, a benzyloxy group or an alkoxy group having 1 to 5 carbon atoms or R _x and R ₂ together form a -0-CH ₂ -0 group; and

^R - _ II,

H, N OH in which R _{3 represents} hydrogen or an unbranched or branched alkyl group having 1 to 5 carbon atoms, in the presence of a chiral catalyst and an auxiliary base; and (b) cleaving the compound obtained in step (a).

2. The method according to claim 1, wherein the Ni (II) complex is an achiral Ni (II) complex of a Schiff base

N- (2-benzoylphenyl) pyridine-2-carbamide and a compound of formula II

in which R _{3 represents} hydrogen or an unbranched or branched alkyl group having 1 to 5 carbon atoms.

3. The method according to claim 1, wherein the Ni (II) complex is a chiral Ni (II) complex of a Schiff base of (S) -o- [(N-benzylprolyl) amino] benzophenone and a compound of formula II

4. The method according to any one of the preceding claims, wherein the chiral catalyst is a compound of formula III

in which R ₄ and R ₅ independently of one another represent hydrogen, an unbranched or branched alkyl group having 1 to 5 carbon atoms, a phenyl group, an adamantyl group or a - (CH ₂ ) _n OH group, where n represents 1 to 3.

5. The method according to any one of the preceding claims, wherein the chiral catalyst (S) is -2'-amino ~ 2-hydroxy-1, 1 '-binaphthyl.

6. Procedure according to a. Claims 1 to 3, wherein the chiral catalyst is a compound of formula IV

in which Rg and R _{7 are} independently hydrogen, a benzyl group or an unbranched or branched alkyl group having 1 to 3 carbon atoms and e is hydrogen, a phenyl group or naphthyl group.

7. The method according to any one of claims 1 to 3 and claim 6, wherein the chiral catalyst (4R, 5R) -2,2-dimethyl-

1, 3-dioxolan-, 5-bis (diphenylmethanol).

8. The method according to any one of the preceding claims, wherein the auxiliary base is an alkali metal hydroxide, alkali metal hydride or alkali metal tert-butyrate.

9. The method according to claim 8, wherein the auxiliary base is selected from LiOH, NaOH, KOH, CsOH, NaH and potassium tert-butyrate.

10. The method of claim 8 or claim 9, wherein the auxiliary base is solid NaOH.

11. The method according to any one of the preceding claims, wherein step (a) is carried out at room temperature.

12. The method according to any one of the preceding claims, wherein step (b) is carried out by adding an acid.

13. The method of claim 12, wherein the acid is an alkanoic acid having 2 to 5 hydrocarbon atoms or a halogen acid.

14. The method of claim 13, wherein the acid is acetic acid, hydrochloric acid, hydrogen bromide or hydrogen iodide.

15. The method according to any one of the preceding claims, wherein a polar or non-polar organic solvent is used as solvent in step (a).

16. The method according to claim 15, wherein the solvent used is methylene chloride or dichloroethane.

17. A process for the preparation of 2- [ ¹⁸ F] -fluoro-L-tyrosine, comprising the steps:

(a) Reacting l-bromomethyl-2- [ ¹⁸ F] -fluoro-4-methoxy-benzene with an achiral nickel (II) complex of a boat base of (S) -2'-amino-2-hydroxy -l, 1 '-binaphthyl and glycine in the presence of (S) -2'-amino-2-hydroxy-1,1'-binaphthyl as chiral catalyst and solid NaOH as auxiliary base;

(b) Cleaving the compound obtained in step (a) to give 2-amino-3- (2- [ ¹⁸ F] -fluoro-4-metoxyphenyl) propionic acid and

(c) converting the 2-amino-3- (2- [ ¹⁸ F] -fluoro-4-methoxy-phenyl) -propionic acid obtained in step (b) to 2- [ ¹⁸ FJ-fluoro-L-tyrosine.

18. The method of claim 17, wherein step (a) and step (b) are carried out at room temperature.

19. The method according to claim 17 or claim 18, wherein in step (b) aqueous acetic acid to cleave the in

Compound obtained in step (a) is used.

20. The method according to any one of claims 17 to 19, wherein in step (c) hydrogen iodide is added to the compound obtained in step (b).

21. The method according to any one of claims 17 to 20, wherein in step (a) methylene chloride or dichloroethane is used as solvent.