NZ720609B2 - Production method for 2-fluoro-4-borono-l-phenylalanine, and precursor of 2-fluoro-4-borono-l-phenylalanine - Google Patents

Abstract

The present invention involves preparing phenylalanine derivatives, wherein the –para position of the phenylalanine side chain is substituted with a chloro, bromo, or iodo group, and the –ortho position is substituted with an excellent leaving group or a direct synthetic intermediate. These phenylalanine derivatives can be used in a method to efficiently introduce 18F- into the molecule during the later steps in a synthetic scheme. anine derivatives can be used in a method to efficiently introduce 18F- into the molecule during the later steps in a synthetic scheme.

Description

DESCRIPTION TITLE OF THE INVENTION: PRODUCTION METHOD FOR 2-FLUOROBORONO-L-PHENYLALANINE, AND PRECURSOR OF 2-FLUOROBORONO-L-PHENYLALANINE TECHNICAL FIELD The present invention relates to a method for producing 2-fluoroborono-L-phenylalanine, 4-boronophenylalanine (fluorinated BPA)(BPA:4-Boronophenylalanine), and precursors thereof.

BACKGROUND ART At present, attention has been paid to positron emission tomography (PET) as a technique that is high in sensitivity to be excellent in quantitatively determining performance and can form images easily in light of a principle thereof. This technique has widely been used. The half value period of PET diagnostic reagents (tracers) used for diagnoses is short, and the tracers are each administrated in a fine amount so that any living body is hardly exposed to radiation based thereon.

Therefore, this inspecting method is a low invasive inspecting method, thus is greatly advantageous to PET. Furthermore, PET is highly sensitive even to tumors that are not easily determined by CT (computed tomography) or MRI (magnetic resonance imaging), and tumor tissues thereof can be evaluated according to images. 18 18 F-labeled BPA, in which a F-fluorine atom is introduced into BPA, which is a boronated amino acid used as a boron reagent for BNCT (boron neutron capture therapy), was developed as a molecular probe for PET by Ishiwata in 1991 (Non-Patent Document 1). Thereafter, a PET inspection with the use of F-labeled BPA using the present probe has been an important technique for supporting BNCT. In other words, in clinical and research spots, a F-BPA PET image obtained by measuring a subject beforehand can give data on an internal accumulation distribution of BPA, the ratio of tumor tissues/normal tissues (the T/N ratio) and others. On the basis of these data, curative effects of BNCT can be beforehand assumed and then a research or therapeutic plan can be drawn up.

In Ishiwata’s synthesis method, BPA is directly 18 18 + fluorinated to prepare F-labeled BPA, and F is used as an electrophilic reagent. From deuterium (D) and neon (Ne) accelerated by a cyclotron, F gas is prepared, and then passed through a column filled with sodium acetate to convert the gas -18 + to CH COO F . Thereafter, a solution of BPA in trifluoroacetic acid is bubbled by the introduction of this conversion-obtained compound into the solution. In this way, the synthesis of the target F-labeled BPA is attained.

As another method for synthesizing F-labeled BPA, Vahatalo et al. suggest a method in which such a conventional method is partially improved (Non-Paten Document 2). This method is a method of using H F, which can be obtained in a larger quantity, to attain the synthesis via CH F as an 18 18 intermediate of F . By causing CH I to react with H F, which is obtained through the radiation of protons to H O [through 18 18 18 O(p,n) F reaction], CH F is once synthesized. The resultant compound CH F is discharged to disassociate its C-F bonds to 18 18 prepare F . This compound is used to synthesize F-labeled BPA, equivalently to Ishiwata’s synthesis method.

PRIOR ART DOCUMENTS NON-PATENT DOCUMENTS Non-Patent Document 1: Appl. Radiat. Isot., 42, 325, 1991 Non-Patent Document 2: J. Label. Compd. Radiopharm., 45, 697, 2002 SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION However, the F-labeled BPA obtained by the conventional synthesis method according to Ishiwata et al. is low in specific radioactivity and further extremely small in yield. Even by the improved method, the yield is still small although the specific radioactivity of the resultant F-labeled BPA species is heightened.

One of the objectives of the present invention is to provide a novel BPA derivative that can be an intermediate for synthesizing F- labeled BPA.

Another objective of the present invention is to provide a method for producing such a novel BPA derivative, and a method for producing fluorinated BPA, including F-labeled BPA, using this derivative.

MEANS FOR SOLVING THE PROBLEMS In order to solve the above-mentioned problems, the inventors have made eager investigations to find out a novel method for synthesizing fluorinated BPA. Thus, the present invention has been achieved. [0010a] In one aspect there is provided a compound represented by the following formula: [Formula 1] wherein: R represents a bromo group, an iodo group, a chloro group, a nitro group, or an amino group; 2 6 7 8 + 13 14- + 13 R represents Sn(R ) , N=N-NR R , I R , (R )I R , or B(OH) optionally esterified with pinacol, 2,2-dimethyl-1,3-propanediol, N- methyldiethanolamine, N-methyliminodiacetic acid, 1,1,1- trishydroxymethylethane, or catechol; R represents an alkyl group having 1 to 7 carbon atoms or a benzyl group; R and R are the same or different, each representing hydrogen, an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or a phenyl group optionally substituted with C alkyl or C alkoxy, or else R and R are 1-6 1-6 combined together with N to form a 3- to 7-membered cyclic structure; R represents a C -alkyl-substituted phenyl group, a C -alkoxy- 1-6 1-6 substituted phenyl group, or a phenyl group, or else represents a 5- to 7-membered heterocyclic group having one or more of N, S, and O atoms; R represents halogen, a tetrafluoroborate group, a nitrate group, a triflate group, a sulfonyloxy group, a toluenesulfonyloxy group, or a perchlorate group; R represents hydrogen, an ethyl group, a tert-butyl group, or a benzyl group; and R represents hydrogen, and R represents hydrogen, a benzyloxycarbonyl group, or a tert-butoxycarbonyl group, or R and R independently represents a benzyloxycarbonyl group, or a tert- butoxycarbonyl group, or else NR R are combined together to form C H (C H )C=N. 6 5 6 5 [0010b] In another aspect there is provided a method for producing a compound represented by the following formula: [Formula 2] wherein: X represents F or F; 1 R represents hydrogen or a protecting group PG for a carboxyl group; 40 50 R or R independently represents hydrogen or a protecting group 2 40 50 PG for an amino group, or else NR R are combined together to form C H (C H )C=N; and 6 5 6 5 16 R and R are combined together with B (boron atom) to form a ring serving as a protecting group for B; comprising the step of reacting a compound represented by the following formula: [Formula 3] wherein R represents a bromo group, an iodo group, or a chloro group; 2 6 7 8 + 13 14- + 13 R represents Sn(R ) , N=N-NR R , I R , (R )I R , or B(OH) optionally esterified with pinacol, 2,2-dimethyl-1,3-propanediol, N- methyldiethanolamine, N-methyliminodiacetic acid, 1,1,1- trishydroxymethylethane, or catechol; R represents an alkyl group having 1 to 7 carbon atoms or a benzyl group; R and R are the same or different, each representing hydrogen, an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or a phenyl group optionally substituted with C alkyl or C alkoxy, or else R and R are combined 1-6 1-6 together with N to form a 3- to 7-membered cyclic structure; R represents a C -alkyl-substituted phenyl group, a C -alkoxy- 1-6 1-6 substituted phenyl group, or a phenyl group, or else represents a 5- to 7-membered heterocyclic group having one or more of N, S, and O atoms; R represents halogen, a tetrafluoroborate group, a nitrate group, a triflate group, a sulfonyloxy group, a toluenesulfonyloxy group, or a perchlorate group; R represents hydrogen, an ethyl group, a tert-butyl group, or a benzyl group; R represents hydrogen and R represents hydrogen, a benzyloxycarbonyl group, or a tert-butoxycarbonyl group, or R and R independently represents a benzyloxycarbonyl group, or a tert- butoxycarbonyl group, or else NR R are combined together to form C H (C H )C=N; 6 5 6 5 1 R represents hydrogen or a protecting group PG for a carboxyl group; and 40 50 R and R independently represents hydrogen or a protecting group PG ; wherein said reacting comprises reacting said compound of Formula 3 in presence of hydrogen fluoride in a solvent to obtain a fluorinated compound and then microwave radiating the resulting fluorinated compound in the presence of a pinacol boronation reagent, a palladium catalyst, and a phosphorus-based ligand to form the compound of Formula 2.

Accordingly, the present invention relates to a compound represented by the following formula: AH26(28495578_1):RTK [Formula 1] where R represents a bromo group, an iodo group, a chloro group, a nitro group, or an amino group; R represents a halogen group, 6 7 8 9 10 11 a nitro group, an amino group, Sn(R ) , N=N-NR R , OSO R , NR R , substituted or unsubstituted phenyl iodo, a substituted or unsubstituted heterocyclic iodo group, or boric acid (B(OH) ) or a boric ester selected from the group consisting of pinacol, 2,2-dimethyl-1,3-propanediol, N-methyldiethanolamine, 1,8-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trishydroxymethylethane, and catechol (where R represents an alkyl group having 1 to 7 carbon atoms or a benzyl group; R and R are the same or different, each representing hydrogen, an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or an optionally substituted phenyl group, or else R and R are combined together with N to form a 3- to 7-membered cyclic structure; R represents an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon 11 atoms, or an optionally substituted phenyl group; R and R are the same or different, each representing an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or an optionally substituted phenyl 11 group, or else R and R are combined together with N to form a 3- to 7-membered cyclic structure); R represents hydrogen, an ethyl group, a tert-butyl group, or a benzyl group; R or R independently represents hydrogen, a benzyloxycarbonyl group, or a tert-butoxycarbonyl group, or else NR R are combined together to form C H (C H )C=N; 6 5 6 5 (except that excluded herefrom are the following cases: 3 4 5 2 1) case in which all of R , R , and R are hydrogen, and R is a chloro group, 3 4 5 2 2) case in which all of R , R , and R are hydrogen; R is a bromo group; and R is a bromo group, a chloro group, a nitro group, or an amino group, 3 4 5 2 3) case in which all of R , R , and R are hydrogen; R is an iodo group; and R is a chloro group or a nitro group, 3 2 1 4) case in which R is hydrogen; R is a chloro group; R is a chloro group, a bromo group, or a nitro group; and one of R and R is hydrogen, 3 2 1 ) case in which R is hydrogen; R is a bromo group; R is a chloro group; and one of R and R is hydrogen, 4 5 2 6) case in which R and R are hydrogen; R is a chloro group; and R is a nitro group, 7) case in which NR R are combined together to form C H (C H )C=N, 6 5 6 5 and R is a fluoro group, and 8) case in which R is a chloro group; R is a fluoro group; 4 5 3 R and R are hydrogen; and R is an ethyl group).

In one embodiment, in the above-mentioned compound, R represents a bromo group, an iodo group, a chloro group, a nitro group, or an amino group; R represents a halogen group, a nitro 6 7 8 9 10 11 group, an amino group, Sn(R ), N=N-NR R, OSO R, NR R , substituted or unsubstituted phenyl iodo, a substituted or unsubstituted heterocyclic iodo group, or boric acid (B(OH) ) or a boric ester selected from the group consisting of pinacol, 2,2-dimethyl-1,3-propanediol, N-methyldiethanolamine, 1,8-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trishydroxymethylethane, and catechol (where R represents an alkyl group having 1 to 7 carbon atoms or a benzyl group; R and R are the same or different, each representing hydrogen, an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or an optionally substituted phenyl group, or else R and R are combined together with N to form a 3- to 7-membered cyclic structure; R represents an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon 11 atoms, or an optionally substituted phenyl group; R and R are the same or different, each representing an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or an optionally substituted phenyl 11 group, or else R and R are combined together with N to form a 3- to 7-membered cyclic structure) (here, at least one of R and R necessarily is a bromo group, an iodo group, or a chloro group); R represents hydrogen, an ethyl group, a tert-butyl group, or a benzyl group; R or R independently represents a hydrogen, benzyloxycarbonyl group, or a tert-butoxycarbonyl group, or else NR R are combined together to form C H (C H )C=N; 6 5 6 5 (except that excluded herefrom are the following cases: 3 4 5 2 1) case in which all of R , R , and R are hydrogen, and R is a chloro group, 3 4 5 2 2) case in which all of R , R , and R are hydrogen; R is a bromo group; and R is a bromo group, a chloro group, a nitro group, or an amino group, 3 4 5 2 3) case in which all of R , R , and R are hydrogen; R is an iodo group; and R is a chloro group or a nitro group, 3 2 1 4) case in which R is hydrogen; R is a chloro group; and R is a chloro group, a bromo group, or a nitro group, 3 2 1 ) case in which R is hydrogen; R is a bromo group; R is a chloro group; and one of R and R is hydrogen, 4 5 2 6) case in which R and R are hydrogen; R is a chloro group; and R is a nitro group, 7) case in which NR R are combined together to form C H (C H )C=N, 6 5 6 5 and R is a fluoro group, and 8) case in which R is a chloro group; R is a fluoro group; 4 5 3 R and R are hydrogen; and R is an ethyl group).

In one embodiment, in the above-mentioned compound, R represents a bromo group, an iodo group, a chloro group, a nitro group, or an amino group; R represents a halogen group, a nitro 6 7 8 9 10 11 group, an amino group, Sn(R ), N=N-NR R, OSO R, NR R , substituted or unsubstituted phenyl iodo, a substituted or unsubstituted heterocyclic iodo group, or a boric acid (B(OH) ) or a boric ester selected from the group consisting of pinacol, 2,2-dimethyl-1,3-propanediol, N-methyldiethanolamine, 1,8-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trishydroxymethylethane, and catechol (where R represents an alkyl group having 1 to 7 carbon atoms or a benzyl group; R and R are the same or different, each representing hydrogen, an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or an optionally substituted phenyl group, or else R and R are combined together with N to form a 3- to 7-membered cyclic structure; R represents an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon 11 atoms, or an optionally substituted phenyl group; R and R are the same or different, each representing an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or an optionally substituted phenyl 11 group, or else R and R are combined together with N to form a 3- to 7-membered cyclic structure) (here, at least one of R and R necessarily is a bromo group, an iodo group, or a chloro group); R represents hydrogen, an ethyl group, a tert-butyl group, or a benzyl group; R or R independently represents hydrogen, a benzyloxycarbonyl group, or a tert-butoxycarbonyl group, or else NR R are combined together to form C H (C H )C=N; 6 5 6 5 (except that excluded herefrom are the following cases: 3 4 5 2 1) case in which all of R , R , and R are hydrogen, and R is a chloro group, 3 4 5 2 2) case in which all of R , R , and R are hydrogen; R is a bromo group; and R is a bromo group, a chloro group, a nitro group, or an amino group, 3 4 5 2 3) case in which all of R , R , and R are hydrogen; R is an iodo group; and R is a chloro group or a nitro group, 3 2 1 4) case in which R is hydrogen; R is a chloro group; and R is a chloro group, a bromo group, or a nitro group, 3 2 1 ) case in which R is hydrogen; R is a bromo group; and R is a chloro group, 4 5 2 6) case in which R and R are hydrogen; R is a chloro group; and R is a nitro group, 7) case in which NR R are combined together to form C H (C H )C=N, 6 5 6 5 and R is a fluoro group, and 8) case in which R is a chloro group; R is a fluoro group; 4 5 3 R and R are hydrogen; and R is an ethyl group).

The present invention also relates to a method for producing a compound represented by the following formula: [Formula 2] 18 30 (where X represents F or F; R represents hydrogen or a 1 40 50 protecting group PG for a carboxyl group; R or R independently represents hydrogen or a protecting group PG for 40 50 an amino group, or else NR R are combined together to form 16 C H (C H )C=N; and R and R are combined together with B (boron 6 5 6 5 atom) to form a ring serving as a protecting group for B), comprising the step of using a compound represented by the following formula: [Formula 3] where R represents a bromo group, an iodo group, a chloro group, a nitro group, or an amino group; R represents a halogen group, 6 7 8 9 10 11 a nitro group, an amino group, Sn(R ) , N=N-NR R , OSO R , NR R , substituted or unsubstituted phenyl iodo, a substituted or unsubstituted heterocyclic iodo group, or boric acid or a boric ester (where R represents an alkyl group having 1 to 7 carbon atoms or a benzyl group; R and R are the same or different, each representing hydrogen, an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or an optionally substituted phenyl group, or else R and R are combined together with N to form a 3- to 7-membered cyclic structure; R represents an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or an optionally substituted phenyl group; R and R are the same or different, each representing an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or an optionally substituted 11 phenyl group, or else R and R are combined together with N 40 to form a 3- to 7-membered cyclic structure); and R , R , and R have the same meaning as described above.

The present invention also relates to a method for producing F-labeled BPA, comprising the step of using a compound represented by the following formula: [Formula 4] 18 30 40 50 (where X represents F or F; R , R , and R have the same meaning 16 as described above; and R and R are combined together with B (boron atom) to form a ring serving as a protecting group for EFFECT OF THE INVENTION The novel compound and the production method of the present invention are favorably usable, particularly, for producing F-labeled BPA.

MODE FOR CARRYING OUT THE INVENTION The existing methods for synthesizing F-labeled BPA are methods for fluorinating BPA directly, and are attained, in particular, by conducting an electrophilic reaction by use of F as an electrophilic reagent. The inventors have paid attention to the following: in the step of preparing F gas + 18 in a cyclotron, the step of using F from the resultant F gas, and some other steps in such an existing synthesis route, problems are caused, respectively; and further, F-labeled BPA obtained finally has a lowered specific radioactivity by the generation of a reaction product from intermingled F molecules or by some other causes, and the quantity of F-labeled BPA usable for PET diagnosis according to a single synthesis is a quantity for only several persons. A novel method of the present invention for synthesizing F-labeled BPA is entirely different from the conventional methods, and is a synthesis method in which F anions are usable. This method imposes little load on the apparatus, and makes it possible to synthesize F-labeled BPA to give a yield larger than the respective yields according to the conventional synthesis methods.

In the present invention, first, a novel method for producing fluorinated BPA, in particular, a method for producing F-labeled BPA, is found out. Further, in such novel method for producing F-labeled BPA, several novel intermediate compounds are obtained. By this novel method for 18 18 producing F-labeled BPA, F-labeled BPA can be obtained at a high yield in a simple and convenient manner.

In the present invention, here, the wording “fluorinated BPA” denotes: [Formula 5] or is used as a term including the following F-labeled BPA.

Here, the F-labeled BPA denotes: [Formula 6] In the present invention, a novel intermediate compound that finally leads to synthesis of these fluorinated BPA compounds is provided.

In the present invention, the novel intermediate compound has the same meaning as a compound represented by the following formula: [Formula 7] where R represents a bromo group, an iodo group, a chloro group, a nitro group, or an amino group; R represents a halogen group, 6 7 8 9 10 11 a nitro group, an amino group, Sn(R ) , N=N-NR R , OSO R , NR R , substituted or unsubstituted phenyl iodo, a substituted or unsubstituted heterocyclic iodo group, or boric acid (B(OH) ), or a boric ester selected from the group consisting of pinacol, 2,2-dimethyl-1,3-propanediol, N-methyldiethanolamine, 1,8-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trishydroxymethylethane, and catechol (where R represents an alkyl group having 1 to 7 carbon atoms or a benzyl group; R and R are the same or different, each representing hydrogen, an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or an optionally substituted phenyl group, or else R and R are combined together with N to form a 3- to 7-membered cyclic structure; R represents an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon 11 atoms, or an optionally substituted phenyl group; R and R are the same or different, each representing an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or an optionally substituted phenyl 11 group, or else R and R are combined together with N to form a 3- to 7-membered cyclic structure); R represents hydrogen, an ethyl group, a tert-butyl group, or a benzyl group; R or R independently represents hydrogen, a benzyloxycarbonyl group, or a tert-butoxycarbonyl group, or else NR R are combined together to form C H (C H )C=N; 6 5 6 5 (except that excluded herefrom are the following cases: 3 4 5 2 1) case in which all of R , R , and R are hydrogen, and R is a chloro group, 3 4 5 2 2) case in which all of R , R , and R are hydrogen; R is a bromo group; and R is a bromo group, a chloro group, a nitro group, or an amino group, 3 4 5 2 3) case in which all of R , R , and R are hydrogen; R is an iodo group; and R is a chloro group or a nitro group, 3 2 1 4) case in which R is hydrogen; R is a chloro group; R is a chloro group, a bromo group, or a nitro group; and one of R and R is hydrogen, 3 2 1 ) case in which R is hydrogen; R is a bromo group; R is a chloro group; and one of R and R is hydrogen, 4 5 2 6) case in which R and R are hydrogen; R is a chloro group; and R is a nitro group, 7) case in which NR R are combined together to form C H (C H )C=N, 6 5 6 5 and R is a fluoro group, and 8) case in which R is a chloro group; R is a fluoro group; 4 5 3 R and R are hydrogen; and R is an ethyl group).

Though not particularly limited, it is preferable further that R represents a bromo group, an iodo group, a chloro group, a nitro group, or an amino group; R represents a halogen group, 6 7 8 9 10 11 a nitro group, an amino group, Sn(R ) , N=N-NR R , OSO R , NR R , substituted or unsubstituted phenyl iodo, a substituted or unsubstituted heterocyclic iodo group, or boric acid (B(OH) ) or a boric ester selected from the group consisting of pinacol, 2,2-dimethyl-1,3-propanediol, N-methyldiethanolamine, 1,8-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trishydroxymethylethane, and catechol (where R represents an alkyl group having 1 to 7 carbon atoms or a benzyl group; R and R are the same or different, each representing hydrogen, an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or an optionally substituted phenyl group, or else R and R are combined together with N to form a 3- to 7-membered cyclic structure; R represents an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon 11 atoms, or an optionally substituted phenyl group; R and R are the same or different, each representing an alkyl group having 1 to 7 carbon atoms, halogen-substituted alkyl group having 1 to 7 carbon atoms, or an optionally substituted phenyl 11 group, or else R and R are combined together with N to form a 3- to 7-membered cyclic structure) (here, at least one of R and R necessarily is a bromo group, an iodo group, or a chloro group); R represents hydrogen, an ethyl group, a tert-butyl group, or a benzyl group; R or R independently represents hydrogen, a benzyloxycarbonyl group, or a tert-butoxycarbonyl group, or else NR R are combined together to form C H (C H )C=N; 6 5 6 5 (except that excluded herefrom are the following cases: 3 4 5 2 1) case in which all of R , R , and R are hydrogen, and R is a chloro group, 3 4 5 2 2) case in which all of R , R , and R are hydrogen; R is a bromo group; and R is a bromo group, a chloro group, a nitro group, or an amino group, 3 4 5 2 3) case in which all of R , R , and R are hydrogen; R is an iodo group; and R is a chloro group or a nitro group, 3 2 1 4) case in which R is hydrogen; R is a chloro group; and R is a chloro group, a bromo group, or a nitro group, 3 2 1 ) case in which R is hydrogen; R is a bromo group; R is a chloro group; and one of R and R is hydrogen, 4 5 2 6) case in which R and R are hydrogen; R is a chloro group; and R is a nitro group, 7) case in which NR R are combined together to form C H (C H )C=N, 6 5 6 5 and R is a fluoro group, and 8) case in which R is a chloro group; R is a fluoro group; 4 5 3 R and R are hydrogen; and R is an ethyl group).

Further, in another embodiment, it is preferable that R represents a bromo group, an iodo group, a chloro group, a nitro group, or an amino group; R represents a halogen group, a nitro 6 7 8 9 10 11 group, an amino group, Sn(R ), N=N-NR R, OSO R, NR R , substituted or unsubstituted phenyl iodo, a substituted or unsubstituted heterocyclic iodo group, or boric acid (B(OH) ) or a boric ester selected from the group consisting of pinacol, 2,2-dimethyl-1,3-propanediol, N-methyldiethanolamine, 1,8-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trishydroxymethylethane, and catechol (where R represents an alkyl group having 1 to 7 carbon atoms or a benzyl group; R and R are the same or different, each representing hydrogen, an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or an optionally substituted phenyl group, or else R and R are combined together with N to form a 3- to 7-membered cyclic structure; R represents an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon 11 atoms, or an optionally substituted phenyl group; R and R are the same or different, each representing an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or an optionally substituted phenyl 11 group, or else R and R are combined together with N to form a 3- to 7-membered cyclic structure) (here, at least one of R and R necessarily is a bromo group, an iodo group, or a chloro group); R represents hydrogen, an ethyl group, a tert-butyl group, or a benzyl group; R or R independently represents hydrogen, a benzyloxycarbonyl group, or a tert-butoxycarbonyl group, or else NR R are combined together to form C H (C H )C=N; 6 5 6 5 (except that excluded herefrom are the following cases: 3 4 5 2 1) case in which all of R , R , and R are hydrogen, and R is a chloro group, 3 4 5 2 2) case in which all of R , R , and R are hydrogen; R is a bromo group; and R is a bromo group, a chloro group, a nitro group, or an amino group, 3 4 5 2 3) case in which all of R , R , and R are hydrogen; R is an iodo group; and R is a chloro group or a nitro group, 3 2 1 4) case in which R is hydrogen; R is a chloro group; and R is a chloro group, a bromo group, or a nitro group, 3 2 1 ) case in which R is hydrogen; R is a bromo group; and R is a chloro group, 4 5 2 6) case in which R and R are hydrogen; R is a chloro group; and R is a nitro group, 7) case in which NR R are combined together to form C H (C H )C=N, 6 5 6 5 and R is a fluoro group, and 8) case in which R is a chloro group; R is a fluoro group; 4 5 3 R and R are hydrogen; and R is an ethyl group).

Further, in another embodiment, it is preferable that R represents a bromo group, an iodo group, a chloro group, a nitro group, or an amino group; R represents a halogen group, a nitro 6 7 8 9 10 11 + 13 group, an amino group, Sn(R ) , N=N-NR R , OSO R , NR R , I R , 14- + 13 (R )I R , or boric acid or a boric ester selected from the group consisting of pinacol, 2,2-dimethyl-1,3-propanediol, N-methyldiethanolamine, 1,8-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trishydroxymethylethane, 6 7 8 and catechol (where R represents methyl or n-butyl; R and R are the same or different, each representing hydrogen, methyl, ethyl, propyl, butyl, heptyl, trifluoromethyl, or an optionally substituted phenyl group, or else R and R are combined together with N to form aziridine, azetidine, pyrrolidine, or piperidine; R represents methyl, ethyl, propyl, butyl, heptyl, trifluoromethyl, or an optionally substituted phenyl group; R and R are the same or different, each representing methyl, ethyl, propyl, butyl, heptyl, trifluoromethyl, or an optionally 11 substituted phenyl group, or else R and R are combined together with N to form aziridine, azetidine, pyrrolidine, or piperidine; R represents a C -alkyl-substituted phenyl group, a C -alkoxy-substituted phenyl group, or a phenyl group, or else represents a 5- to 7-membered heterocyclic group having one or more of N, S, and O atoms; and R represents halogen, a tetrafluoroborate group, a nitrate group, a triflate group, a sulfonyloxy group, a toluenesulfonyloxy group, or a perchlorate group) (here, at least one of R and R necessarily is a bromo group, an iodo group, or a chloro group); R represents hydrogen, an ethyl group, a tert-butyl group, or a benzyl group; R represents hydrogen; R represents hydrogen, a benzyloxycarbonyl group, or a tert-butoxycarbonyl group, or else NR R are combined together to form C H (C H )C=N; 6 5 6 5 (except that excluded herefrom are the following cases: 3 4 5 2 1) case in which all of R , R , and R are hydrogen, and R is a chloro group, 3 4 5 2 2) case in which all of R , R , and R are hydrogen; R is a bromo group; and R is a bromo group, a chloro group, a nitro group, or an amino group, 3 4 5 2 3) case in which all of R , R , and R are hydrogen; R is an iodo group; and R is a chloro group or a nitro group, 3 2 1 4) case in which R is hydrogen; R is a chloro group; and R is a chloro group, a bromo group, or a nitro group (here, one of R and R can be hydrogen; however, a case in which neither of R nor R is hydrogen is also included), 3 2 1 ) case in which R is hydrogen; R is a bromo group; and R is a chloro group (here, one of R and R can be hydrogen; however, a case in which neither of R nor R is hydrogen is also included), 4 5 2 6) case in which R and R are hydrogen; R is a chloro group; and R is a nitro group, 7) case in which NR R are combined together to form C H (C H )C=N, 6 5 6 5 and R is a fluoro group, and 8) case in which R is a chloro group; R is a fluoro group; 4 5 3 R and R are hydrogen; and R is an ethyl group).

The novel intermediate compound of the present invention is particularly preferably the compound described above, wherein R represents a bromo group, an iodo group, or a chloro 2 6 7 8 9 10 11 + 13 group, and R represents Sn(R ) , N=N-NR R , OSO R , NR R , I R , 14- + 13 (R )I R, or boric acid or one of pinacol, 2,2-dimethyl-1,3-propanediol, N-methyldiethanolamine, 1,8-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trishydroxymethylethane, and catechol.

The novel intermediate compound of the present invention is particularly preferably the compound described above, wherein R is an iodo group or a bromo group.

The novel compound of the present invention is particularly preferably provided, for example, as an intermediate compound for preparing PET diagnostic pharmaceuticals, although not limited thereto.

In the present invention, a compound represented by the following formula: [Formula 9] 18 30 (where X represents F or F; R represents hydrogen or a 1 40 50 protecting group PG for a carboxyl group; and R or R independently represents hydrogen or a protecting group PG for 40 50 an amino group, or else NR R are combined together to form 16 C H (C H )C=N; and R and R are combined together with B (boron 6 5 6 5 atom) to form a ring serving as a protecting group for B) can be produced by using a compound represented by the following formula: [Formula 8] where R represents a bromo group, an iodo group, a chloro group, a nitro group, or an amino group; R represents a halogen group, 6 7 8 9 10 11 a nitro group, an amino group, Sn(R ) , N=N-NR R , OSO R , NR R , substituted or unsubstituted phenyl iodo, a substituted or unsubstituted heterocyclic iodo group, or boric acid or a boric ester (where R represents an alkyl group having 1 to 7 carbon atoms or a benzyl group; R and R are the same or different, each representing hydrogen, an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or an optionally substituted phenyl group, or else R and R are combined together with N to form a 3- to 7-membered cyclic structure; R represents an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or an optionally substituted phenyl group; R and R are the same or different, each representing an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or an optionally substituted 11 phenyl group, or else R and R are combined together with N to form a 3- to 7-membered cyclic structure) (it is preferable that at least one of R and R necessarily is a bromo group, 40 50 an iodo group, or a chloro group); and R , R , and R have the same meaning as described above. Thus obtained compound can be used to finally produce fluorinated BPA, in particular, F-labeled BPA.

In the present invention, F-labeled BPA can be produced by using a compound represented by the following formula: [Formula 10] where R represents a bromo group, an iodo group, a chloro group, a nitro group, or an amino group; R represents a halogen group, 6 7 8 9 10 11 a nitro group, an amino group, Sn(R ) , N=N-NR R , OSO R , NR R , substituted or unsubstituted phenyl iodo, a substituted or unsubstituted heterocyclic iodo group, boric acid, or a boric ester (particularly preferably pinacol, 2,2-dimethyl-1,3-propanediol, N-methyldiethanolamine, 1,8-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trishydroxymethylethane, or catechol) (where R represents an alkyl group having 1 to 7 carbon atoms or a benzyl group; R and R are the same or different, each representing hydrogen, an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or an optionally substituted phenyl group, or else R and R are combined together with N to form a 3- to 7-membered cyclic structure; R represents an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon 11 atoms, or an optionally substituted phenyl group; R and R are the same or different, each representing an alkyl group having 1 to 7 carbon atoms, a halogen-substituted alkyl group having 1 to 7 carbon atoms, or an optionally substituted phenyl 11 group, or else R and R are combined together with N to form a 3- to 7-membered cyclic structure) (here, at least one of R and R necessarily is a bromo group, an iodo group, or a chloro 1 group); R represents hydrogen or a protecting group PG for 40 50 a carboxyl group; and R or R independently represents hydrogen or a protecting group PG for an amino group, or else 40 50 NR R are combined together to form C H (C H )C=N. 6 5 6 5 In the present specification, the wording “are combined together with N to form a cyclic structure having 3 to 7 atoms” denotes a saturated or unsaturated ring having carbon and nitrogen. Although not limited, examples thereof include piperidine, piperazine, pyrrolidine, pyridine, pyrimidine, pyrazine, pyrazole, and imidazole.

In the present specification, the wording heterocyclic group denotes a group having a saturated or unsaturated cyclic structure having carbon and an atom other than carbon and, in particular, thienyl group, furanyl group, pyridinyl group, piperidinyl group, piperazinyl group, and the like are preferable. 1 R represents hydrogen or a protecting group PG for a carboxylic acid. Here, PG is not particularly limited and denotes any protecting group known by those skilled in the art for a carboxylic acid. Examples thereof include protecting groups described in Greene Wuts, “Protective Groups in Organic Synthesis”, 3rd edition (a company, Wiley-Interscience in USA).

Typically, the group concerned can be converted into an ester type to be protected, using ester condensation conditions or alkylation conditions. PG is, for example, an alkyl group having 1 to 7 carbon atoms or an aromatic group such as a benzyl group. Specific examples thereof include alkyl groups such as a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, and an n-pentyl group, and aromatic groups such as a benzyl, p-methoxybenzyl, and p-nitrobenzyl groups.

PG is in particular preferably a tert-butyl or a benzyl group, which is not easily affected by racemization when de-protection 3 is carried out. Also, R may have the same meaning as R . 40 50 R or R independently represents hydrogen or a protecting group PG for an amino group. The protecting group for an amino acid may be any protecting group known by those skilled in the art. Examples thereof include protecting groups described in Greene Wuts, “Protective Groups in Organic Synthesis”, 3rd edition (the company, Wiley-Interscience in USA). Preferred examples thereof include a benzyloxycarbonyl group, an acetyl group, a trifluoroethylcarboxy group, a tert-butyloxycarbonyl group, a fluorenylmethyloxycarbonyl group, a trichloroethoxycarbonyl group, a trifluoroacetyl group, an allyloxycarbonyl group, a benzyl group, a propargyloxycarbonyl group, a benzoyl group, a phthaloyl group, a toluenesulfonyl group, and a nitrobenzenesulfonyl group, although the protecting group is not limited thereto. Of these examples, a benzyloxycarbonyl group and a tert-butyloxycarbonyl group are preferred, which can be subjected to de-protection in a short period of time. R or 50 4 5 R may have the same meaning as R and R , respectively. 16 In the present specification, when R and R are combined together with B (boron atom) to form a ring as a protecting group 16 for B, R and R are preferably a group that forms a saturated or unsaturated 3- to 10-membered ring which may be substituted.

Examples of the structure of the ring herein also include spiro-rings and condensed rings. Examples of the group that can form the ring include pinacol, 2,2-dimethyl-1,3-propanediol, N-methyldiethanolamine, 1,8-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trishydroxymethylethane, and catechol, although the group is not limited. In particular, pinacol is preferred.

In the present specification, the alkyl group having 1 to 7 carbon atoms is in particular preferably a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, or an n-pentyl group. The halogen-substituted alkyl group denotes an alkyl group having 1 to 7 carbon atoms wherein an arbitrary number of the hydrogen atoms thereof are substituted with one or more halogens. The halogen-substituted alkyl group is preferably a trifluoromethyl group, although the group is not limited. The substituted phenyl group denotes a phenyl group, or a phenyl group having, at one to three positions of the phenyl group, one or more substituents independently of each other. The substituted 3- to 10-membered ring denotes a 3- to 10-membered ring, or a 3- to 10-membered ring having, at one to three positions of the 3- to 10-membered ring, one or more substituents independently of each other. The substituted heterocyclic group denotes a heterocycle, or a heterocyclic group having, at one to three positions of the heterocycle, one or more substituents independently of each other. Examples of the substituent(s) of the phenyl group, the 3- to 10-membered ring, or the heterocycle include a C alkyl group, a C alkoxyl 1-6 1-6 group, a hydroxyl group, an amino group, and a nitro group, although the substituent(s) is/are not limited.

In the novel method for producing F-labeled BPA of the present invention, for example, the following step S, step T, step U, or step V may be exemplified, although the steps are not limited thereto. Here, the protecting groups used in the following reaction formulae may be appropriately changed, so that the protecting groups are not limited to these examples.

Step S [Formula 11] AH26(28495578_1):RTK Step T [Formula 12] Step U AH26(28495578_1):RTK [Formula 13] AH26(28495578_1):RTK [Formula 14] Step V AH26(28495578_1):RTK [Formula 15] In the reaction in each of the steps S to V, the reaction temperature varies in accordance with the solvent, the starting materials, the reagent(s), and others, and is appropriately selected. Also, the reaction period varies in accordance with the solvent, the starting materials, the reagent(s), the reaction temperature, and others, and is appropriately selected.

In the reaction in each of the steps, the target compound of each step may be isolated from the reaction mixture by a routine procedure after the end of each reaction.

The target compound is obtained, for example, by (i) filtrating away the catalyst and other insoluble substances in accordance with the needs, (ii) adding, to the reaction mixture, water and a solvent immiscible in water (for example, ethyl acetate, chloroform, or the like) to extract the target compound, (iii) washing the organic layer with water and using a drying agent such as anhydrous magnesium sulfate to dry the resultant in accordance with the needs, and (iv) distilling off the solvent. The obtained target compound may be further purified by a known method (for example, silica gel column chromatography or the like) in accordance with the needs. Also, the target compound in each of the steps may be supplied to the next reaction without being purified.

(Step S) In other words, Step S-1 is a step of causing a compound (401) to react with a nitrite in an acidic aqueous solution to produce a diazonium salt, so as to produce a compound (402) which is a halogen derivative. The compound (401) is known and is commercially available; however, the compound (401) may be obtained by synthesis from a commercially available compound.

The diazonium reaction reagent may be, for example, sodium nitrite, potassium nitrite, or further an alkyl nitrite such as isobutyl nitrite. Also, the iodinating reagent may be, for example, sodium iodide, potassium iodide, or iodine, which is known.

Examples of the solvent to be used include water, acetone, acetonitrile, THF, methanol, ethanol, and mixed solvents each composed of two or more kinds of these solvents. Among these, acetone is preferred, since this solvent is inactive to the diazotization reaction.

The reaction temperature is preferably from -20 C to room temperature, more preferably from -10 C to 5 C. The reaction period is preferably from 30 minutes to 2 hours, more preferably from 30 minutes to 1 hour.

(Step S-2) Step S-2 is a step of causing the compound (402) to react with a halogenating reagent in the presence of a catalyst to produce a compound (403).

Examples of the halogenating reagent to be used include N-bromosuccinimide and dibromoisocyanuric acid. In the case in which a halogenating reagent other than a bromo group is used, examples of the halogenating reagent to be used include 1,3-diiodo-5,5’-dimethylhydantoin and N-iodosuccinimide.

Meanwhile, the catalyst to be used is a radical polymerization agent such as a peroxide or AIBN.

The solvent to be used is not particularly limited and may be, for example, benzene, chloroform, carbon tetrachloride.

Carbon tetrachloride is particularly preferred.

The reaction temperature is preferably from room temperature to 120 C, more preferably from 70 C to 100 C.

The reaction period is preferably from 1 hour to 24 hours, more preferably from 6 hours to 18 hours.

Step S-3 is a step of causing the compound (403) to react with a phase-transfer catalyst and a modified amino acid that are generally used in Maruoka’s reaction in the presence of a base to produce a compound (404) newly.

The modified amino acid to be used in Maruoka’s reaction is not limited. Preferred examples thereof include a methyl ester of N-diphenylmethyleneglycine, an ethyl ester of N-diphenylmethyleneglycine, a t-butyl ester of N-diphenylmethyleneglycine N-diphenylmethyleneglycine, a t-butyl ester of 4-chlorobenzylideneglycine, and a benzyl ester ester of N-diphenylmethyleneglycine. Of these examples, particularly preferred is a t-butyl ester of N-diphenylmethyleneglycine.

The base to be used is not limited. Preferred examples thereof include lithium hydroxide, sodium hydroxide, potassium hydroxide, and further, triethylamine. In view of the reaction rate, potassium hydroxide is particularly preferred.

Preferred examples of the modified amino acid to be used in Maruoka’s reaction include O-allyl-N-(9-anthracenylmethyl)cinchonidinium bromide, and (S)-(+)-4,4-dibutyll-2,6-bis(3,4,5-trifluorophenyl)-4,5-dih ydro-3H-dinaphtho[7,6,1,2-CDE]azemipium bromide.

Preferred examples of the solvent to be used include toluene, dichloromethane, and chloroform. Toluene is particularly preferred in view of the environment.

The reaction temperature is preferably from -20 C to 100 C, more preferably from -4 C to room temperature.

The reaction period is preferably from 30 minutes to 24 hours, more preferably from 1 hour to 18 hours.

The obtained compound may be purified; however, the compound may be shifted to the next step without being purified.

(Step S-4) Step S-4 is a step of putting the compound (404) to an acidic aqueous solution to eliminate an amino-group protector thereof. The solvent to be used therefor may be a mixed solvent of citric acid or oxalic acid in water and acetone, acetonitrile, THF, DMF, or DMSO; however, a preferable example is a mixed solvent of citric acid or oxalic acid in water and acetone, acetonitrile, or THF in view of distilling off the solvent.

Here, the reaction temperature is preferably from room temperature to 100 C, more preferably from room temperature to 80 C. The reaction period is preferably from 30 minutes to 24 hours, more preferably from 1 hour to 3 hours.

(Step S-5) Step S-5 is a step of using a protecting reagent for the compound (405) to protect an amino group thereof under basic conditions. The protecting reagent to be used may be, for example, benzyl chloroformate, or di-t-butyl dicarbonate, although the reagent is not limited to the exemplified compounds.

Preferred examples of the base to be used include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and further, triethylamine, although the base is not limited thereto. In particular, sodium carbonate and potassium carbonate are preferred, which are mild.

The solvent to be used is preferably an amphipathic solvent. In particular, examples thereof include acetone, acetonitrile, THF, DMF, and DMSO. The solvent is preferably acetone, acetonitrile, or THF in view of distilling off the solvent.

The reaction temperature is preferably from -20 C to 100 C, more preferably from -4 C to room temperature. The reaction period is preferably from 30 minutes to 24 hours, more preferably from 3 hours to 18 hours.

(Step S-6) Step S-6 is a step of producing, from the compound, a trialkyltin compound by a Suzuki-Miyaura coupling reaction.

The reaction reagent to be used is benzyltin, and the catalyst to be used may be a palladium catalyst that is generally used in Suzuki-Miyaura coupling reaction, examples thereof including a palladium chloride cinnamyl complex, palladium acetate, trisdibenzylideneacetonedipalladium, and tetrakistriphenylphenylphosphinopalladium, although the catalyst is not limited to these. Of these examples, preferred is tetrakistriphenylphenylphosphinopalladium.

Examples of the base to be used include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, and further, triethylamine; however, sodium acetate and potassium acetate are preferred, which are milder.

A preferred solvent to be used is, for example, toluene or dioxane. The reaction temperature is preferably from room temperature to 150C, more preferably from 80 C to 120 C. The reaction period is preferably from 1 hour to 48 hours, more preferably from 2 hours to 24 hours.

(Step S-7) Further, Step S-7 for converting the compound (407) to a compound (408) may be, for example, as follows, although not limited.

The compound (407) is dissolved into a solvent, and thereto is added an iodonium, such as Koser’s reagent, under a nitrogen gas flow.

Examples of the solvent to be used include water, dichloromethane, acetone, acetonitrile, THF, methanol, ethanol, trifluoroethanol, and mixed solvents each composed of two or more kinds of these solvents. Among these, dichloromethane is preferred.

The reaction temperature is preferably from -20 C to room temperature, more preferably from -10 C to 5 C. The reaction period is preferably from 30 minutes to 2 hours.

(Step S-8) A reagent used in Step S-8 for converting the compound (408) to a compound (409) may be, for example, hydrogen fluoride.

Examples of the solvent to be used include water, dichloromethane, acetone, acetonitrile, THF, methanol, ethanol, DMF, DMSO, and mixed solvents each composed of two or more kinds of these solvents. Of these examples, preferred is dichloromethane alone or a combination with acetonitrile, DMF, or DMSO.

The reaction temperature is preferably from -20 C to 180 C, more preferably from 80 C to 160 C. The reaction period is preferably from 5 minutes to 2 hours, more preferably from 10 minutes to 1 hour.

(Step S-9) Step S-9 is a step of using a pinacol boronation reagent to produce a pinacol boric acid derivative from the compound 409 using a microwave radiation or the like in the presence of a palladium catalyst and a ligand. The catalyst to be used may be a palladium catalyst that is generally used in Suzuki-Miyaura coupling reaction, examples thereof including a palladium chloride cinnamyl complex, palladium acetate, and trisdibenzylideneacetonedipalladium, although the catalyst is not limited to these.

The microwave radiation conditions are preferably from room temperature to 200 C, more preferably from 80 C to 180.

The reaction period is preferably from 1 minute to 60 minutes, more preferably from 5 minutes to 30 minutes.

The ligand to be used may be a phosphorus-based ligand that is generally used in Suzuki-Miyaura coupling reaction, examples thereof including tricyclohexylphosphine, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl, 2-dicyclohexylphosphino-2,-(N,N)-dimethylaminobiphenyl, 3,5-dimethoxydicyclohexylphosphino-2,4,6-triisopropylbip henyl, and 3,5-dimethoxyditert-butylphosphino-2,4,6-triisopropylbip henyl, although the ligand is not limited to these.

Examples of the base to be used include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and further, triethylamine, although the base is not limited thereto. In particular, sodium carbonate and potassium carbonate are preferred, which are mild.

Preferred examples of the solvent to be used include toluene, dioxane, and DMDO.

(Step T-1) Step T-1 is a step of producing a compound 502 by iodinating the compound 501. The method for iodination reaction may be, for example, a method of causing a metal perchlorate such as sodium perchlorate or sodium perchlorate to react with iodine or a metal iodide such as sodium iodide, or further a method of using an iodinating reagent such as N-iodosuccinimide in a strong acid such as sulfuric acid or trifluoromethanesulfonic acid.

(Step T-2) Step T-2 is a step of using a protecting reagent for the compound (502) to protect an amino group thereof under basic conditions. The protecting reagent to be used may be, for example, benzyl chloroformate, or di-t-butyl dicarbonate, although the reagent is not limited to the exemplified compounds.

Preferred examples of the base to be used include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and further, triethylamine, although the base is not limited thereto. In particular, sodium carbonate and potassium carbonate are preferred, which are mild.

The solvent to be used is preferably an amphipathic solvent. In particular, examples thereof include acetone, acetonitrile, THF, DMF, and DMSO. The solvent is preferably acetone, acetonitrile, or THF in view of distilling off the solvent.

The reaction temperature is preferably from -20 C to 100 C, more preferably from -4 C to room temperature. The reaction period is preferably from 30 minutes to 24 hours, more preferably from 3 hours to 18 hours.

(Step T-3) Step T-3 is a step of using a protecting reagent for the compound (503) to protect a carboxyl group thereof.

Examples of the solvent to be used include acetone, ethyl acetate, chloroform, THF, dioxane, methanol, and ethanol.

Among these, methanol and ethanol are preferred, since these solvents are inactive to the reduction reaction.

The reaction temperature is preferably from -20 C to 100 C, more preferably from room temperature to 50 C. The reaction period is preferably from 30 minutes to 24 hours, more preferably from 3 to 18 hours.

(Step T-4) Step T-4 is a step of producing a compound 505 by reducing the compound 504 to turn the nitro group thereof into an amino group. Examples of the reducing agent include those causing reaction with an inorganic salt such as calcium chloride or an acid such as hydrochloric acid in the presence of iron, zinc, or tin, and further those reducing with a hydrogen gas in the presence of palladium, rubidium, ruthenium, or a complex thereof, although the reducing agent is not limited thereto.

Examples of the solvent to be used include acetone, acetonitrile, THF, methanol, and ethanol. Among these, methanol and ethanol are preferred, since these solvents are inactive to the reduction reaction.

The reaction temperature is preferably from -20 C to 100 C, more preferably from room temperature to 50C. The reaction period is preferably from 30 minutes to 24 hours, more preferably from 3 to 18 hours.

(Step T-5) Step T-5 is a step of producing a halogen derivative (506) from the compound (505) via a diazonium. The diazonium reaction reagent may be, for example, sodium nitrite, potassium nitrite, or further an alkyl nitrite such as isobutyl nitrite. Also, the iodinating reagent may be, for example, sodium iodide, potassium iodide, or iodine, which is known.

Examples of the solvent to be used include water, acetone, acetonitrile, THF, methanol, ethanol, and mixed solvents each composed of two or more kinds of these solvents. Among these, acetone is preferred, since this solvent is inactive to the diazotization reaction.

The reaction temperature is preferably from -20 C to room temperature, more preferably from -10 C to 5 C. The reaction period is preferably from 30 minutes to 2 hours, more preferably from 30 minutes to 1 hour.

The halogen derivative (506) obtained in this manner is subjected to synthesis of a compound similar to the compound 410 in the same manner as in Steps S-6 to S-9.

(Step U-1 to Step U-4) Further, Steps U-1 to U-4 are steps similar to Steps S-2 to S-5 and are steps of preparing compounds 601, 602, 603, 604, and 605.

(Step U-5) Step U-5 is a step of subjecting the compound (605) to hydrogenating reduction to produce an aniline derivative. A catalyst to be used therefor is, for example, palladium hydroxide or palladium carbon, although the catalyst is not limited thereto.

Examples of the solvent to be used include acetone, acetonitrile, THF, methanol, and ethanol. Among these, methanol and ethanol are preferred, since these solvents are inactive to the reduction reaction.

The reaction temperature is preferably from -20 C to 100 C, more preferably from room temperature to 50 C. The reaction period is preferably from 30 minutes to 24 hours, more preferably from 3 to 18 hours.

(Step U-6) Step U-6 is a step of producing, from the compound (606), a triazene derivative (607) via a diazonium.

The diazonium reaction reagent to be used may be, for example, sodium nitrite, potassium nitrite, or further an alkyl nitrite such as isobutyl nitrite. Also, the reaction reagent may be, for example, dimethylamine, cyclopentylamine, or cyclohexylamine, which is known.

Examples of the solvent to be used include water, acetone, acetonitrile, THF, methanol, ethanol, and mixed solvents each composed of two or more kinds of these solvents. Among these, acetone is preferred, since this solvent is inactive to the diazotization reaction.

The reaction temperature is preferably from -20 C to room temperature, more preferably from -10 C to 5 C. The reaction period is preferably from 30 minutes to 2 hours, more preferably from 30 minutes to 1 hour. Also, from the compound (607) to (611) can be produced as well.

(Step U-7) Step U-7 is a step of producing a halogen derivative (608) from the compound (606) via a diazonium. The diazonium reaction reagent may be, for example, sodium nitrite, potassium nitrite, or further an alkyl nitrite such as isobutyl nitrite. Also, the iodinating reagent may be, for example, sodium iodide, potassium iodide, or iodine, which is known.

Examples of the solvent to be used include water, acetone, acetonitrile, THF, methanol, ethanol, and mixed solvents each composed of two or more kinds of these solvents. Among these, acetone is preferred, since this solvent is inactive to the diazotization reaction.

The reaction temperature is preferably from -20 C to room temperature, more preferably from -10 C to 5 C. The reaction period is preferably from 30 minutes to 2 hours, more preferably from 30 minutes to 1 hour.

(Step U-8) Step U-8 is a step of producing, from the compound (608), a trialkyltin compound (609) by a Suzuki-Miyaura coupling reaction. The reaction reagent to be used may be, for example, tributyltin or trimethyltin. The catalyst to be used may be a palladium catalyst that is generally used in Suzuki-Miyaura coupling reaction, examples thereof including a palladium chloride cinnamyl complex, palladium acetate, trisdibenzylideneacetonedipalladium, and tetrakistriphenylphenylphosphinopalladium, although the catalyst is not limited to these. Of these examples, preferred is tetrakistriphenylphenylphosphinopalladium.

Examples of the base to be used include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, and further, triethylamine; however, sodium acetate and potassium acetate are preferred, which are milder.

A preferred solvent to be used is, for example, toluene or dioxane. The reaction temperature is preferably from room temperature to 150 C, more preferably from 80 C to 120 C. The reaction period is preferably from 1 hour to 48 hours, more preferably from 2 hours to 24 hours.

(Step U-9) For Step U-9 for converting the compound (609) to a compound (610), the following operation is given as an example, although an operation therefor is not limited.

The compound (609) is dissolved into a solvent, and thereto is then added an iodonium, such as Koser’s reagent, under a nitrogen gas flow.

Examples of the solvent to be used include water, dichloromethane, acetone, acetonitrile, THF, methanol, ethanol, trifluoroethanol, and mixed solvents each composed of two or more kinds of these solvents. Among these, dichloromethane is preferred.

The reaction temperature is preferably from -20 C to room temperature, more preferably from -10 C to 5 C. The reaction period is preferably from 30 minutes to 2 hours.

(Step U-10) A reagent used in step U-10 for converting the compound compound (610) to a compound (611) may be, for example, hydrogen fluoride.

Examples of the solvent to be used include water, dichloromethane, acetone, acetonitrile, THF, methanol, ethanol, DMF, DMSO, and mixed solvents each composed of two or more kinds of these solvents. Of these examples, preferred is dichloromethane alone or a combination with acetonitrile, DMF, or DMSO.

The reaction temperature is preferably from -20 C to 180 C, more preferably from 80 C to 160 C. The reaction period is preferably from 5 minutes to 2 hours, more preferably from 10 minutes to 1 hour.

(Step U-11) Step U-11 is a step of using a pinacol boronation reagent to produce a pinacol boric acid derivative from the compound 611 using a microwave radiation in the presence of a palladium catalyst and a ligand by a method similar to that of Step S-9.

(Step U-12) Step U-12 is a step of using a butoxycarbonylation reagent in the presence of DMAP to produce a di-Boc acid derivative from the compound (608).

Examples of the solvent to be used include toluene, dioxane, acetone, DMF, DMSO, and MeCN, although the solvent is not limited. In particular, acetone and MeCN are preferred.

The reaction temperature is preferably from room temperature to 100 C, more preferably from 30 C to 60 C.

The reaction period is preferably from 8 hours to 48 hours, more preferably from 12 hours to 24 hours.

(Step U-13) Step U-13 is a step of producing, from the compound (613), a trialkyltin compound (614) by a Suzuki-Miyaura coupling reaction. The reaction reagent to be used may be, for example, tributyltin or trimethyltin. The catalyst to be used may be a palladium catalyst that is generally used in Suzuki-Miyaura coupling reaction, examples thereof including a palladium chloride cinnamyl complex, palladium acetate, trisdibenzylideneacetonedipalladium, and tetrakistriphenylphenylphosphinopalladium, although the catalyst is not limited to these. Of these examples, preferred is tetrakistriphenylphenylphosphinopalladium.

Examples of the base to be used include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, and further, triethylamine; however, sodium acetate and potassium acetate are preferred, which are milder.

A preferred solvent to be used is, for example, toluene or dioxane. The reaction temperature is preferably from room temperature to 150 C, more preferably from 80 C to 120 C. The reaction period is preferably from 1 hour to 48 hours, more preferably from 2 hours to 24 hours.

(Step U-14) Step U-14 is a step of obtaining a diaryliodonium salt (615) from the tin compound (614). For the present step, the following operation is given as an example, although an operation therefor is not particularly limited.

Production is made by adding an iodonium, such as Koser’s reagent, to the tin compound (614) under a nitrogen gas flow.

Examples of the solvent to be used include water, dichloromethane, acetone, acetonitrile, THF, methanol, ethanol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoroisopropanol, and mixed solvents each composed of two or more kinds of these solvents. Of these examples, preferred is dichloromethane, 2,2,2-trifluoroethanol, or 1,1,1,3,3,3-hexafluoroisopropanol.

The reaction temperature is preferably from -20 C to 60 C, more preferably from -10 C to room temperature. The reaction period is preferably from 30 minutes to 2 hours.

(Step U-15) Step U-15 is a step of obtaining a fluorinated compound (616) from the diaryliodonium salt (615). Examples of the reagent to be used in Step U-15 include hydrogen fluoride, potassium fluoride, and cesium fluoride.

Examples of the solvent to be used include water, dichloromethane, acetone, acetonitrile, THF, methanol, ethanol, DMF, DMSO, and mixed solvents each composed of two or more kinds of these solvents. Of these examples, preferred is dichloromethane alone, acetonitrile alone, DMF alone, DMSO alone, or a combination of these.

The reaction temperature is preferably from -20 C to 180 C, more preferably from 80 C to 160 C. The reaction period is preferably from 5 minutes to 2 hours, more preferably from 10 minutes to 1 hour.

(Step U-16) Step U-16 is a step of using a pinacol boronation reagent to produce a pinacol boric acid derivative from the compound (616) using a microwave radiation in the presence of a palladium catalyst and a ligand.

The catalyst to be used may be a palladium catalyst that is generally used in Suzuki-Miyaura coupling reaction, examples thereof including a palladium chloride cinnamyl complex, palladium acetate, and trisdibenzylideneacetonedipalladium, although the catalyst is not limited to these.

The microwave radiation conditions are preferably from room temperature to 200 C, more preferably from 80 C to 180.

The reaction period is preferably from 1 minute to 60 minutes, more preferably from 5 minutes to 30 minutes.

The ligand to be used may be a phosphorus-based ligand that is generally used in Suzuki-Miyaura coupling reaction, examples thereof including tricyclohexylphosphine, 2-dicyclohexylphosphino-2,4,6-triiso-propylbiphenyl, 2-dicyclohexylphosphino-2,-(N,N)-dimethylaminobiphenyl, 3,5-dimethoxydicyclohexylphosphino-2,4,6-triisopropylbip henyl, and 3,5-dimethoxyditert-butylphosphino-2,4,6-triisopropylbip henyl, although the ligand is not limited to these.

Examples of the base to be used include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and further, triethylamine, although the base is not limited thereto. In particular, sodium carbonate and potassium carbonate are preferred, which are mild.

Preferred examples of the solvent to be used include toluene, dioxane, and DMDO.

(Step U-17) Step U-17 is a step of subjecting the compound (615) to salt exchange reaction for substituting counter-anions, so as to obtain a compound (618). The reaction reagent may be, for example, sodium chloride or potassium bromide.

(Step U-18) Examples of the reagent to be used in Step U-18 include hydrogen fluoride, potassium fluoride, and cesium fluoride.

Examples of the solvent to be used include water, dichloromethane, acetone, acetonitrile, THF, methanol, ethanol, DMF, DMSO, and mixed solvents each composed of two or more kinds of these solvents. Of these examples, preferred is dichloromethane alone, acetonitrile alone, DMF alone, DMSO alone, or a combination of these.

The reaction temperature is preferably from -20C to 180 C, more preferably from 80 C to 160 C. The reaction period is preferably from 5 minutes to 2 hours, more preferably from 10 minutes to 1 hour.

(Step U-19) Step U-19 is a step of using a pinacol boronation reagent to produce a pinacol boric acid derivative from the compound (608) in the presence of a palladium catalyst and a ligand. The catalyst to be used may be a palladium catalyst that is generally used in Suzuki-Miyaura coupling reaction, examples thereof including dichlorobis(triphenylphosphine)palladium, a palladium chloride cinnamyl complex, palladium acetate, and trisdibenzylideneacetonedipalladium, although the catalyst is not limited to these.

The ligand to be used may be a phosphorus-based ligand that is generally used in Suzuki-Miyaura coupling reaction, examples thereof including tricyclohexylphosphine, 2-dicyclohexylphosphino-2,4,6-triiso-propylbiphenyl, 2-dicyclohexylphosphino-2,-(N,N)-dimethylaminobiphenyl, 3,5-dimethoxydicyclohexylphosphino-2,4,6-triisopropylbip henyl, and 3,5-dimethoxyditert-butylphosphino-2,4,6-triisopropylbip henyl, although the ligand is not limited to these.

Examples of the base to be used include sodium acetate, potassium acetate, lithium hydroxide, sodium carbonate, potassium carbonate, and further, triethylamine, although the base is not limited thereto. In particular, sodium acetate and potassium acetate are preferred, which are mild.

Preferred examples of the solvent to be used include toluene, dioxane, and DMSO. The reaction temperature is preferably from room temperature to 150 C, more preferably from 80 C to 120 C.

The reaction period is preferably from 30 minutes to 48 hours, more preferably from 2 hours to 18 hours.

(Step U-20) Step U-20 is a step of causing the compound (619) to react with a fluorination reagent in the presence of a copper catalyst to obtain a compound (616). The fluorination reagent to be used may be, for example, hydrogen fluoride or potassium fluoride.

Examples of the solvent to be used include toluene, dioxane, DMF, DMSO, and MeCN, among which DMF and MeCN are preferred.

The reaction temperature is preferably from room temperature to 150 C, more preferably from 80 C to 120 C.

The reaction period is preferably from 1 minute to 60 minutes, more preferably from 5 minutes to 30 minutes.

(Step V-1 to Step V-4) Steps V-1 to V-4 are steps similar to Steps S-2 to S-5 and are steps of preparing compounds 701, 702, 703, 704, and 705.

(Step V-5) Further, Step V-5 is similar to Step U-11.

When F is contained in the compound in each derivative, labeling can be carried out with F instead of F.

For example, accelerated protons may be radiated onto 18 18 18 H O to synthesize H F-hydrofluoric acid through O(p, n) reaction, and then this acid may be passed through an ion exchange resin column to be adsorbed thereon to separate this acid from H O which is a non-adsorbed raw material. This column is subjected to elution with an aqueous solution of K CO +18 - to yield K F , which can be used as a nucleophilic agent.

[Formula 16] When N=N-NR R is present before fluorination among the compounds in the present invention, labeling with F can be achieved by a known method. That is, the obtained F anions are used as a nucleophilic agent, and the anions are heated together with a phase transfer catalyst in an organic solvent, thereby yielding a labeled body.

Further, with respect to Sn(R ) , the labeled body is obtained by a technique of Ermert and others (Non-Patent Document: J. Label. Compd. Radiopharm., 47, 429, 2004.). In other words, the labeled body is yielded with a good efficiency by causing reaction with hydroxyl(tosyloxy)Iodoarene, such as Koser’s reagent, to produce a diallyliodonium salt temporarily, and then causing this salt to react with a nucleophilic agent 18 - Furthermore, each protecting group can be de-protected by a conventional method, whereby the target fluorinated BPA can be prepared.

By using the method of the present invention, such F-labeled compound can be obtained with a comparatively good yield and in a state having a good specific activity.

EXAMPLES The present invention will be described in more detail by way of the following Examples; however, such inventions are not limited to this alone.

Here, in the Examples described below, the following machines and reagents were used for analyzing compounds and isolating/purifying the compounds.

NMR spectrum: JN M-AL series AL400 manufactured by JEOL Ltd. at 400 MHz Microwave radiation: Initiator+ manufactured by Biotage UPLC analysis: ACQUITY UPLC system manufactured by Nihon Waters K.K.

(Example 1) Production of 4-bromoiodotoluene Into 30% sulfuric acid (100 mL), 4-bromoaminotoluene (10.0 g, 53.7 mmol) was suspended. To this, an aqueous solution (15 mL) of sodium nitrite (3.89 g, 56.4 mmol) was dropwise added slowly from a dropping funnel while the system was being cooled with ice. The resultant was stirred at 0 C for 45 minutes.

Thereafter, sodium iodide (12.1 g, 80.6 mmol) was dissolved into water (50 mL). To this aqueous solution was added the above-mentioned diazonium salt solution. The resultant was stirred further for 1 hour at room temperature, and then was subjected to extraction with ethyl acetate for 3 times.

Subsequently, the ethyl acetate layer was washed with a saturated saline solution once, then dried over magnesium sulfate, and concentrated under a reduced pressure.

Thereafter, the resultant was purified with a silica gel column (n-hexane) to yield the target compound (9.0 g, 45%).

H-NMR(CDCl ); 2.37(s, 3H, CH ), 7.08(d, J=8.0, 1H, Ar), 7.35(dd, J=1.6, 8.0, 1H, Ar), 7.93(d, J=2.0, 1H, Ar).

Production of 4-bromoiodobenzyl bromide To carbon tetrachloride (100 mL) were added 4-bromoiodotoluene (9.00 g, 23.9 mmol) obtained in the previous step, N-bromosuccinimide (5.95 g, 33.5 mmol), and 2,2-azobis(2-methylpropionitrile) (39 mg, 2.4 mmol) to cause the reactants to react with each other for 18 hours while the reaction system was refluxed. Thereafter, the reaction liquid was filtrated, and the resultant filtrate was concentrated under a reduced pressure. The resultant was purified through silica gel column chromatography (n-hexane) to yield 7.0 g of the target compound (78%).

H-NMR(CDCl ); 4.53(s, 2H, CH ), 7.32(d, J=8.0, 1H, Ar), 7.46(dd, J=2.0, 8.4, 1H, Ar), 7.93(d, J=2.0, 1H, Ar).

Production of benzyl 3-(4-bromoiodophenyl)(diphenylmethyleneamino)propanoa To toluene (100 mL) were added cesium hydroxide (7.54 g, 50.3 mmol), benzyl N-(diphenylmethylene)glycinate (5.50 g, 16.7 mmol), and O-allyl-Nanthracenylmethylcinchonidium bromide (1.10 g, 1.67 mmol, 0.1 equiv). The resultant was cooled to 0C. Thereafter, while this toluene mixture solution was being violently stirred, a toluene (10 mL) solution of the compound (6.30 g, 16.7 mmol) obtained in the previous step was added all at a time. After the end of dropwise addition, the resultant was stirred for 18 hours while being kept as it was.

Thereafter, the reaction solution was subjected to extraction with ether (50 ml) for two times, and further, this ether layer was washed with a saturated saline solution, then dried over magnesium sulfate, and concentrated under a reduced pressure, thereby to yield a crude target compound (8.7 g).

This compound was subjected to the next step without being purified.

Production of benzyl 2-amino(4-bromoiodophenyl)propanoate The compound benzyl 3-(4-bromoiodophenyl)(diphenylmethyleneamino)propanoa te (8.6 g) obtained in the previous step was dissolved into THF (86 mL), and further, a 30% aqueous solution of citric acid (50 mL) was added thereto. This mixture solution was caused to undergo a reaction under reflux for 1 hour. After the end of the reaction, the reaction solution was washed with ether (80 mL), and then neutralized with potassium carbonate.

Thereafter, the resultant was subjected to extraction with EtOAc (80 mL) for two times, dried over magnesium sulfate, and then concentrated under a reduced pressure. Further, the resultant was purified through silica gel column chromatography (AcOEt / n-hexane =