PRODUCTION METHOD FOR 2-FLUORO-4-BORONO-L-PHENYLALANINE, AND PRECURSOR OF 2-FLUORO-4-BORONO-L-PHENYLALANINE

Abstract

The present invention involves preparing compounds represented by the following formula:

##STR00001##

from a compound of the following formula:

##STR00002##

In these formulae: R.sup.1 represents a Br group, an iodine group, a Cl group, an NO.sub.2 group, or an NH.sub.2 group; R.sup.2 represents a halogen group, an NO.sub.2 group, an NH.sub.2 group, Sn(R.sup.6).sub.3, N═N—NR.sup.7R.sup.8, OSO.sub.2R.sup.9, N R.sup.10R.sup.11, phenyliodonium, a heterocyclic group iodine, boric acid, or a borate ester; R.sup.30 represents a protective group PG.sup.1; R.sup.40 or R.sup.50 represent hydrogen, a protective group PG.sup.2, or C.sub.6H.sub.5(C.sub.6H.sub.5)C═N, in which NR.sup.40R.sup.50 are together.

Claims

1. A method for producing a compound represented by the following formula: ##STR00019## (where X represents F or .sup.18F; R.sup.30 represents hydrogen or a protecting group PG.sup.1 for a carboxyl group; R.sup.40 or R.sup.50 independently represents hydrogen or a protecting group PG.sup.2 for an amino group, or NR.sup.40R.sup.50 are combined together to form C.sub.6H.sub.5(C.sub.6H.sub.5)C═N; and R.sup.15 and R.sup.16 are combined together with a boron atom to form a ring serving as a protecting group for boron atom, comprising: reacting a compound represented by the following formula: ##STR00020## where R.sup.1 represents a bromo group, an iodo group, a chloro group, a nitro group, or an amino group; R.sup.2 represents a halogen group, a nitro group, an amino group, Sn(R.sup.6).sub.3, N═N—NR.sup.7R.sup.8, OSO.sub.2R.sup.9, NR.sup.10R.sup.11, substituted or unsubstituted phenyl iodo, a substituted or unsubstituted heterocyclic iodo group, or boric acid or a boric ester (where R.sup.6 represents an alkyl group having 1 to 7 carbon atoms or a benzyl group; R.sup.7 and R.sup.8 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.sup.7 and R.sup.8 are combined together with N to form a 3- to 7-membered cyclic structure; R.sup.9 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.sup.10 and R.sup.11 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 group, or else R.sup.10 and R.sup.11 are combined together with N to form a 3- to 7-membered cyclic structure); and R.sup.30, R.sup.40, and R.sup.50 have the same meaning as described above, wherein said reacting comprises radiating said compound in the presence of a catalyst and a ligand.

2. The method of claim 1, wherein the catalyst is a palladium catalyst.

3. The method of claim 2, wherein the palladium catalyst is selected from the group consisting of a palladium chloride cinnamyl complex, palladium acetate, and trisdibenzylideneacetonedipalladium.

4. The method of claim 1, wherein the radiating comprises microwave radiation.

5. The method of claim 4, wherein the microwave radiation is conducted from room temperature to 200° C.

6. The method of claim 4, wherein the reaction period is from 1 minute to 60 minutes.

7. The method of claim 1, wherein the ligand is a phosphorus-based ligand.

8. The method of claim 7, wherein the phosphorus-based ligand is selected from the group consisting of tricyclohexylphosphine, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl, 2-dicyclohexylphosphino-2,-(N,N)-dimethylaminobiphenyl, 3,5-dimethoxy-2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl, and 3,5-dimethoxy-2-ditert-butylphosphino-2,4,6-triisopropylbiphenyl.

9. The method of claim 1, wherein the reacting is conducted in the presence of a base.

10. The method of claim 9, wherein the base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and trimethylamine.

11. The method of claim 1, wherein the reacting is conducted in a solvent selected from the group consisting of toluene, dioxane, and DMDO.

Description

EXAMPLES

[0220] The present invention will be described in more detail by way of the following Examples; however, such inventions are not limited to this alone.

[0221] Here, in the Examples described below, the following machines and reagents were used for analyzing compounds and isolating/purifying the compounds.

[0222] NMR spectrum: JNM-AL series AL400 manufactured by JEOL Ltd. at 400 MHz

[0223] Microwave radiation: Initiator+ manufactured by Biotage

[0224] UPLC analysis: ACQUITY UPLC system manufactured by Nihon Waters K.K.

Example 1

Production of 4-bromo-2-iodotoluene

[0225] Into 30% sulfuric acid (100 mL), 4-bromo-2-aminotoluene (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%).

[0226] .sup.1H-NMR(CDCl.sub.3); 2.37(s, 3H, CH.sub.3), 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-bromo-2-iodobenzyl bromide

[0227] To carbon tetrachloride (100 mL) were added 4-bromo-2-iodotoluene (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%).

[0228] .sup.1H-NMR(CDCl.sub.3); 4.53(s, 2H, CH.sub.2), 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-bromo-2-iodophenyl)-2-(diphenylmethyleneamino)propanoate

[0229] 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-N-9-anthracenylmethylcinchonidium bromide (1.10 g, 1.67 mmol, 0.1 equiv). The resultant was cooled to 0° C. 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-3-(4-bromo-2-iodophenyl)propanoate

[0230] The compound benzyl 3-(4-bromo-2-iodophenyl)-2-(diphenylmethyleneamino)propanoate (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=1/1) to yield the target compound (2.40 g, with a yield of 31%).

[0231] .sup.1H-NMR(CDCl.sub.3); 2.90(dd, J=8.4, 13.6, 1H, CH.sub.2-α), 3.18(dd, J=6.4, 13.6, 1H, CH.sub.2-(3), 3.83(dd, J=6.4, 8.2, 1H, CH), 5.14(m, 2H, CH.sub.2Ar), 7.01(d, J=8.4, 1H, Ar), 7.26-7.39(m, J=6.0, 8.4, 1H, Ar), 7.96(d, J=2.4, 1H, Ar).

Production of benzyl 3-(2-bromo-4-iodophenyl)-2-(benzyloxycarbonylamino)propanoate

[0232] The above-mentioned compound benzyl 2-amino-3-(4-bromo-2-iodophenyl)propanoate (2.32 g, 5.44 mmol) was dissolved into THF (50 mL). Thereto were added H.sub.2O (50 mL) and K.sub.2CO.sub.3 (903 mg, 6.53 mmol), and the resultant was stirred while the system was being cooled with ice. Thereinto, a solution obtained by adding benzyl chloroformate (1.11 g, 6.53 mmol) to acetonitrile (10 mL) was slowly added, and the resultant was stirred at room temperature for 12 hours. The reaction solution is subjected to extraction with AcOEt (50 mL) for three times, and the organic layer is washed with a 10% aqueous solution of citric acid (50 mL) for three times and further with a saturated saline solution (50 mL) for two times, followed by drying over MgSO.sub.4. After the organic layer was concentrated, the resultant was purified through flash column chromatography (hexane:AcOEt=6:1) to yield the target compound as a colorless oily substance (2.68 g, 83%).

[0233] .sup.1H-NMR(CDCl.sub.3); 3.10(dd, J=8.0, 14.8, 1H, CH.sub.2-α), 3.26(dd, J=6.4, 14.8, 1H, CH.sub.2-β), 4.73(m, 1H, CH), 5.06(m, 2H, CH.sub.2Ar), 5.15(s, 2H, CH.sub.2Ar), 5.30(m, J=8.0, 1H, NH), 7.24-7.36(m, 11H, Ar), 7.91(d, J=1.7, 1H, Ar).

Production of benzyl 2-(benzyloxycarbonylamino)-3-(4-bromo-2-(tri-n-butylstannyl)phenyl)propanoate

[0234] PdCl.sub.2(dppf) (40 mg, 0.049 mmol), bis(tributyltin) (627 mg, 1.08 mmol), and potassium acetate were dissolved into DMSO (5 mL) in an Ar atmosphere, and the resultant was kept being stirred at room temperature. After a DMSO solution (2 mL) of the above-mentioned compound benzyl 3-(2-bromo-4-iodophenyl)-2-(benzyloxycarbonylamino)propanoate (515 mg, 0.979 mmol) was added thereinto, the resultant was stirred at 80° C. for 24 hours. The reaction solution was diluted with ethyl acetate (70 mL) and subjected to Celite filtration. Thereafter, the resultant was washed with water and a saline solution, and the organic layer was dried over MgSO.sub.4. The organic layer was filtrated, and the organic solvent was concentrated and then purified through column chromatography (hexane:ethyl acetate=9:1) to yield the target compound as a colorless oily substance (381 mg, 74%).

[0235] .sup.1H-NMR(CDCl.sub.3); 0.85(t, J=7.6, 9H, —CH.sub.2CH.sub.2CH.sub.3×3), 1.05(m, 6H, −CH.sub.2CH.sub.2CH.sub.3×3), 1.27-1.45(m, 6H, —CH.sub.2CH.sub.2CH.sub.3×3), 3.01(dd, J=9.2, 14.4, 1H, CH.sub.2-α), 3.48(dd, J=4.4, 14.4, 1H, CH.sub.2-β), 4.53(m, 1H, CH), 5.04(s, 2H, CH.sub.2Ar), 5.20(m, 2H, CH.sub.2Ar), 6.95(d, J=7.6, 1H, Ar), 7.10-7.44(m, 12H, Ar).

Production of (2-(3benzyloxy-2-(benzyloxycarbonylamino)-3-oxopropyl)-5-bromophenyl)(3-methoxyphenyl)iodonium tosylate

[0236] Trifluoroethanol (2 mL) was added to the above-mentioned compound benzyl 2-(benzyloxycarbonylamino)-3-(4-bromo-2-(tri-n-butylstannyl)phenyl)propanoate (154 mg, 0.228 mmol), and the resultant was stirred in an ice water bath under a nitrogen gas flow for 1 hour. Thereto was added an iodonium salt (96.10 mg, 0.228 mmol) while the system was being cooled with ice. The resultant was stirred for 15 minutes in an ice water bath. From the reaction mixture liquid, the solvent was distilled off at room temperature. Hexane (10 mL) was added to the obtained mixture, and the mixture was washed and subjected to decantation to remove the solution part. The same operation was carried out for two times, and the residual solvent in the obtained mixture was completely removed under a reduced pressure, thereby to obtain a target compound (159 mg, 80%).

[0237] .sup.1H-NMR(DMSO-d.sub.6); 2.29(s, 3H, TsOH-CH.sub.3), 3.23(dd, J=10.8, 14.8, 1H, CH.sub.2-α), 3.39(m, 1H, CH.sub.2-β, overlapped with water), 3.75(s, 3H, —OCH.sub.3), 4.51(m, 1H, CH), 5.00(m, 2H, BnCH.sub.2), 5.17(s, 2H, BnCH.sub.2), 7.12(d, J=8.0, 2H, TsOH-Ar), 7.19-8.06(m, 19H, Ar).

Production of benzyl 2-(benzyloxycarbonylamino)-3-(4-bromo-2-fluorophenyl)propanoate

[0238] The above-mentioned compound (2-(3benzyloxy-2-(benzyloxycarbonylamino)-3-oxopropyl)-5-bromophenyl)(3-methoxyphenyl)iodonium tosylate (100 mg, 0.115 mmol), kryptofix 2.2.2 (43.1 mg, 0.115 mmol), and potassium fluoride (6.7 mg, 0.115 mmol) were stirred in DMF (10 mL) at 100° C. for 15 minutes. After the end of the reaction, the solvent was distilled off under a reduced pressure, and the obtained residue was purified through silica gel column chromatography (hexane:AcOEt =7:1) to yield the target compound (34.0 mg, 61%).

[0239] .sup.1H-NMR(CDCl.sub.3); 3.05(dd, J=6.4, 14.0, 1H, CH.sub.2-α), 3.16(dd, J=5.6, 14.0, 1H, CH.sub.2-β), 4.67(m, 1H, CH), 5.08(m, 2H, BnCH.sub.2), 5.13(s, 2H, BnCH.sub.2), 5.31(d, J=8.0, 1H, NH), 6.86(m, 1H, Ar), 7.09-7.15(m, 2H, Ar), 7.26-7.37(m, 10H, Ar).

Production of benzyl 2-(benzyloxycarbonylamino)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl)-propanoate

[0240] Under a nitrogen gas flow, PdCl.sub.2(dba) (27.5 mg, 0.03 eq.) and tricyclophosphine (16.8 mg, 0.06 eq.) were suspended in dioxane (5 ml). After stirring for 30 minutes, bis(pinacolate)diborane (305 mg, 1.20 mmol) and KOAc (294 mg, 3.00 mmol) were added, and further the above-mentioned compound benzyl 2-(benzyloxycarbonylamino)-3-(4-bromo-2-fluorophenyl)propanoate (486 mg, 1.00 mmol) was added.

[0241] Thereafter, microwave radiation was carried out at 150° C. for 15 minutes to yield the target compound (421 mg, 79%).

[0242] .sup.1H-NMR(CDCl.sub.3); 3.14(dd, J=8.8, 13.6, 1H, CH.sub.2-α), 3.20(dd, J=5.2, 13.6, 1H, CH.sub.2-β), 4.69(m, 1H, CH), 5.08(m, 1H, BnCH.sub.2), 5.14(s, 1H, BnCH.sub.2), 5.30(d, J=8.0, NH), 7.05(t, J=7.3, 1H, Ar), 7.26-7.50(m, 12H, Ar).

Example 2

Production of tert-butyl 2-(tert-butoxycarbonylamino)-3-(2-iodo-4-nitrophenyl)propanoate

[0243] Into trifluoromethanesulfonic acid (5 mL), 4-nitrophenylalanine (1.00 g, 4.76 mmol) was dissolved. To this, N-iodosuccinimide (963 mg, 0.9 eq.) was added in three parts in 15 minutes. Further, the resultant was caused to react at room temperature for 18 hours.

[0244] Thereafter, the above-mentioned reaction liquid was added to ice water, and the pH value was set to be 12 or more with potassium carbonate. Further, an acetonitrile solution (about 10 mL) of Boc.sub.2O (1.25 g, 5.71 mmol) was added, and the mixture was stirred at room temperature for 18 hours. After the end of the reaction, the pH value was set to be 4 or less with citric acid, and the resultant was subjected to extraction with ethyl acetate (50 mL) for three times. Further, this organic layer was washed with water (100 mL) and a saturated saline solution (100 mL). The resultant was dried over magnesium sulfate and thereafter concentrated under a reduced pressure to yield an intermediate crude product. Further, this crude product 503 was dissolved in tert-BuOH (20 mL), and Boc.sub.2O (1.25 g, 5.71 mmol) was added. Subsequently, DMAP (116 mg, 0.951 mmol) was added. Thereafter, the resultant is stirred at room temperature for 18 hours. After the end of the reaction, the solvent was distilled off under a reduced pressure, and then the resultant was purified through silica gel column chromatography to yield the target compound tert-butyl 2-(tert-butoxycarbonylamino)-3-(2-iodo-4-nitrophenyl)propanoate (1.26 g, 54%).

[0245] .sup.1H-NMR(CDCl.sub.3); 1.35(s, 12H, 9H, t-Bu), 1.42(s, 9H, t-Bu), 3.10(dd, J=8.4, 13.6, 1H, CH.sub.2-α), 3.18(dd, J=6.4, 13.6, 1H, CH.sub.243), 3.83(dd, J=6.4, 8.2, 1H, CH), 5.14(m, 2H, CH.sub.2Ar), 7.41(d, J=8.4, 1H, Ar), 8.13(dd, J=2.0, 8.4, 1H, Ar), 8.68(d, J=2.0, 1H, Ar).

Production of tert-butyl 2-(tert-butoxycarbonylamino)-3-(4-amino-2-iodophenyl)propanoate

[0246] The above-mentioned compound tert-butyl 2-(tert-butoxycarbonylamino)-3-(2-iodo-4-nitrophenyl)propanoate (2.32 g, 4.71 mmol) was dissolved into ethanol (23 mL), and further iron powder (0.657 g, 2.5 eq.) was added. Thereafter, the temperature was raised to 80° C. Subsequently, an aqueous solution obtained by dissolving ammonium chloride (0.252 g, 1.0 eq.) into water (2 mL) was added all at a time. Further, the resultant was caused to react at 80° C. for 1 hour. After the end of the reaction, iron powder and the like were filtrated, and thereafter the filtrate was concentrated under a reduced pressure. The concentrate was dissolved in ethyl acetate (50 mL) and washed with water (50 mL) and a saturated saline solution (50 mL). The resultant was dried over magnesium sulfate and then filtrated. Thereafter, the filtrate was concentrated under a reduced pressure. This residue was purified through silica gel column chromatography (AcOEt/n-hexane=1/2) to yield the target compound (1.00 g, 46%).

[0247] .sup.1H-NMR(CDCl.sub.3); 1.39(s, 9H, t-Bu), 1.42(s, 9H, t-Bu), 2.92(dd, J=7.2, 14.0, 1H, CH.sub.2-α), 3.11(dd, J=5.6, 14.0, 1H, CH.sub.2-β), 4.45(m, 1H, CH), 4.99(m, J=8.4, 1H, NH), 6.59(dd, J=2.4, 8.4, 1H, Ar), 6.95(d, J=8.4, 1H, Ar), 7.18(d, J=2.4, 1H, Ar).

Production of tert-butyl 2-(tert-butoxycarbonylamino)-3-(4-bromo-2-iodophenyl)propanoate

[0248] The above-mentioned compound tert-butyl 2-(tert-butoxycarbonylamino)-3-(4-amino-2-iodophenyl)propanoate (2.5 g, 5.41 mmol) was subjected to conventional Sandmeyer's reaction to yield the target brominated compound tert-butyl 2-(tert-butoxycarbonylamino)-3-(4-bromo-2-iodophenyl)propanoate (1.56 g, 55%).

[0249] .sup.1H-NMR(CDCl.sub.3); 1.37(s, 9H, t-Bu), 1.43(s, 9H, t-Bu), 2.98(dd, J=8.4, 13.6, 1H, CH.sub.2-α), 3.20(dd, J=5.6, 14.0, 1H, CH.sub.2-β), 4.51(m, 1H, CH), 5.04(d, J=9.2, 1H, NH), 7.10(d, J=8.0, 1H, NH), 7.39(dd, J=1.6, 8.0, 1H, Ar), 7.97(d, J=1.6, 1H, Ar).

[0250] Further, a pinacol boronated compound can be prepared by using the compound tert-butyl 2-(tert-butoxycarbonylamino)-3-(4-bromo-2-iodophenyl)propanoate in the same manner as in Example 1.

Example 3

Production of 4-bromo-2-nitrobenzyl bromide

[0251] The target compound 4-bromo-2-nitrobenzyl bromide was obtained by a method similar to that of the bromination of Example 1 described above.

[0252] .sup.1H-NMR(CDCl.sub.3); 4.78(s, 2H, CH.sub.2), 7.46(d, J=8.0, 1H, Ar), 7.74(m, J=2.0, 8.1, 1H, Ar), 8.18(d, J=1.7, 1H, Ar).

Production of tert-butyl 2-amino-3-(4-bromo-2-nitrophenyl)propanoate

[0253] The target compound was obtained by a method similar to that of the production of benzyl 3-(4-bromo-2-iodophenyl)-2-(diphenylmethyleneamino)propanoate and benzyl 2-amino-3-(4-bromo-2-iodophenyl)propanoate in Example 1.

[0254] .sup.1H-NMR(CDCl.sub.3); 1.45(s, 9H, t-Bu), 3.08(dd, J=8.8, 13.6, 1H, CH.sub.2-α), 3.29(dd, J=5.6, 13.6, 1H, CH.sub.2-β), 3.62(dd, J=5.6, 8.5, 1H, CH), 7.31(d, J=8.4, 1H, Ar), 7.66(dd, J=2.0, 8.4, 1H, Ar), 8.10(d, J=2.0, 1H, Ar).

Production of tert-butyl 3-(4-bromo-2-nitrophenyl)-2-(tert-butoxycarbonylamino)propanoate

[0255] The target compound was obtained by an amino-group protection reaction similar to that of Example 1 by using tert-butyl N-(diphenylmethylene)glycinate and the compound obtained in the previous step as starting materials.

[0256] .sup.1H-NMR(CDCl.sub.3); 1.37(s, 9H, t-Bu), 1.44(s, 9H, t-Bu), 3.08(dd, J=8.0, 13.2, 1H, CH.sub.2-α), 3.29(dd, J=5.2, 13.5, 1H, CH.sub.2-β), 4.54(m, 1H, CH), 5.15(d, J=8.0, 1H, NH), 7.29(d, J=8.4, 1H, Ar), 7.65(dd, J=1.7, 8.0, 1H, Ar), 8.11(d, J=1.7, 1H, Ar).

Production of tert-butyl 3-(2-amino-4-bromophenyl)-2-(tert-butoxycarbonylamino)propanoate

[0257] The compound obtained in the previous step (1.0 g, 2.25 mmol) was dissolved into ethanol (10 mL), and further iron powder (0.314 g, 2.5 eq.) was added. Thereafter, the temperature was raised to 80° C. Subsequently, an aqueous solution obtained by dissolving ammonium chloride (0.120 g, 1.0 eq.) into water (2 mL) was added all at a time. Further, the resultant was caused to react at 80° C. for 1 hour. After the end of the reaction, iron powder and the like were filtrated, and thereafter the filtrate was concentrated under a reduced pressure. The concentrate was dissolved in ethyl acetate (50 mL) and washed with water (50 mL) and a saturated saline solution (50 mL). The resultant was dried over magnesium sulfate and then filtrated. Thereafter, the filtrate was concentrated under a reduced pressure. This residue was purified through silica gel column chromatography (AcOEt/n-hexane=1/2) to yield the target compound 606 (0.457 g, 49%).

[0258] .sup.1H-NMR(CDCl.sub.3); 1.34(s, 9H, t-Bu), 1.44(s, 9H, t-Bu), 2.77(dd, J=8.8, 14.0, 1H, CH.sub.2-α), 3.14(dd, J=3.6, 13.6, 1H, CH.sub.2-β), 4.59(m, 1H, CH), 5.41(d, J=8.0, 1H, NH), 6.56(d, J=1.7, 1H, Ar), 6.86(d, J=8.0, 1H, Ar), 7.03(dd, J=1.6, 8.0, 1H, Ar).

Production of tert-butyl 3-(4-bromo-2-(pyrrolidine-1-yldiazenyl)phenyl)-2-(tert-butoxycarbonylamino)propanoate

[0259] The compound obtained in the previous step (60.0 mg, 0.144 mmol) is dissolved in MeCN (2 mL), and further water (5 mL) is added. Thereafter, the resultant is cooled to 0° C., and further 12N HCl (1.2 mL) is added. While 0° C. is maintained, sodium nitrite (10.5 mg, 0.152 mmol) dissolved in water (1 mL) is dropwise added. After the dropwise addition, the resultant is further stirred at 0° C. for 30 minutes.

[0260] While 0° C. is maintained, the above-mentioned diazonium hydrochloride is dropwise added into a mixture solution which is separately obtained in advance by dissolving pyrrolidine (12.8 mg, 0.181 mmol) and potassium carbonate (100 mg, 0.722 mmol) into MeCN (5 mL) and water (10 mL). Further, the resultant is stirred at 0° C. for 30 minutes and then subjected to extraction with chloroform (20 mL) for two times. The chloroform layer is washed with water (15 mL) and a saturated saline solution (15 mL) and then dried over magnesium sulfate. After filtration, the filtrate is concentrated under a reduced pressure. The obtained residue is purified through silica gel column chromatography to yield the target compound (32.3 mg, 45%).

[0261] .sup.1H-NMR(CDCl.sub.3); 1.37(s, 9H, t-Bu), 1.39(s, 9H, t-Bu), 2.05(brs, 4H, pyrrolidines-CH.sub.2CH.sub.2—), 3.06(dd, J=9.2, 13.2, 1H, CH.sub.2-α), 3.16(dd, J=4.0, 13.2, 1H, CH.sub.2-β), 3.76(brs, 2H, pyrrolidines-NCH.sub.2—), 3.97(brs, 2H, pyrrolidines-NCH.sub.2—), 4.31(m, 1H, CH), 6.47(d, J=6.4, 1H, NH), 7.04(d, J=8.0, 1H, Ar), 7.16(dd, J=2.0, 8.0, 1H, Ar), 7.56(d, J=2.0, 1H, Ar).

Production of tert-butyl 3-(4-bromo-2-iodophenyl)-2-(tert-butoxycarbonylamino)propanoate

[0262] The target compound was obtained from tert-butyl 3-(2-amino-4-bromophenyl)-2-(tert-butoxycarbonylamino)propanoate by a step similar to that of the reaction using N-iodosuccinimide in Example 1.

[0263] .sup.1H-NMR(CDCl.sub.3); 1.37(s, 9H, t-Bu), 1.43(s, 9H, t-Bu), 2.98(dd, J=8.4, 13.6, 1H, CH.sub.2-α), 3.20(dd, J=5.6, 14.0, 1H, CH.sub.2-β), 4.51(m, 1H, CH), 5.04(d, J=9.2, 1H, NH), 7.10(d, J=8.0, 1H, NH), 7.39(dd, J=1.6, 8.0, 1H, Ar), 7.97(d, J=1.6, 1H, Ar).

Production of tert-butyl 3-(4-bromo-2-fluorophenyl)-2-(tert-butoxycarbonylamino)propanoate

[0264] The target compound was obtained by a method similar to that of Steps S-6 to S-8.

[0265] .sup.1H-NMR(CDCl.sub.3); 1.37(s, 18H, t-Bux2), 2.98(dd, J=6.8, 14.0, 1H, CH.sub.2-α), 3.10(dd, J=6.4, 14.0, 1H, CH.sub.2-β), 4.43(m, 1H, CH), 5.08(d, J=7.6, 1H, NH), 7.09(t, J=8.0, 1H, Ar), 7.20(d, J=8.4, 1H, Ar), 7.21(d, J=8.4, 1H, Ar).

Production of tert-butyl 2-(tert-butoxycarbonylamino)-3-(2-fluoro-4-(4,4,5,5-tetramethyl1,3,2dioxaborolane-2-yl)phenyl)-propanoate

[0266] Under a nitrogen gas flow, PdCl.sub.2(dba) (27.5 mg, 0.03 eq.) and tricyclophosphine (16.8 mg, 0.06 eq.) were suspended in dioxane (5 ml). After stirring for 30 minutes, bis(pinacolate)diborane (305 mg, 1.20 mmol) and KOAc (294 mg, 3.00 mmol) were added, and further the above-mentioned compound 611 (418 mg, 1.00 mmol) was added. Thereafter, microwave radiation was carried out at 150° C. for 15 minutes to yield the target compound (372 mg, 80%).

[0267] .sup.1H-NMR(CDCl.sub.3); 1.33(s, 9H, -Boc), 1.40(s, 21H, t-Bu, pinacol(CH.sub.3).sub.4), 3.06(dd, J=8.8, 13.6, 1H, CH.sub.2-α), 3.16(dd, J=5.2, 13.6, 1H, CH.sub.2-β), 4.45(m, 1H, CH), 5.04(d, J=8.0, 1H, NH), 7.20(m, J=6.7, 7.6, 1H, Ar), 7.42-7.50(m, 2H, Ar).

Example 4

Production of tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-3-(4-bromo-2-iodophenyl)propanoate

[0268] The compound tert-butyl 3-(4-bromo-2-iodophenyl)-2-(tert-butoxycarbonylamino)propanoate (1.50 g, 2.6 mmol) is dissolved into MeCN (15 mL), and Boc.sub.2O (1.16 g, 5.33 mmol) and further DMAP (488 mg, 4.00 mmol) are added thereto. The resultant is heated to 50° C. and caused to react at this temperature for 24 hours. Thereafter, the solvent is concentrated under a reduced pressure and then purified through silica gel column chromatography (hexane:ethyl acetate=9:1) to yield the target compound as a colorless oily substance. (1.50 g, 90%).

[0269] .sup.1H-NMR(CDCl.sub.3); 1.34-1.41(m, 27H, t-Bu), 3.35(dd, J=11.2, 13.6, 1H, CH.sub.2-α), 3.46(dd, J=4.4, 14.0, 1H, CH.sub.2-β), 5.08(dd, J=4.0, 11.2, 1H, CH), 7.00(d, J=8.0, 1H, Ar), 7.36(dd, J=2.0, 8.0, 1H, Ar), 7.94(d, J=2.0, 1H, Ar).

Production of tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-3-(4-bromo-2-(trimethylstannyl)phenyl)propanoate

[0270] The compound obtained in the previous step (876.8 mg, 1.40 mmol) is dissolved into toluene (4 mL), and tetrakistriphenylphosphinepalladium (80.88 mg, 0.07 mmol) and further bis(trimethyltin) (481.6 mg, 1.47 mmol) are added thereto. The resultant is heated to 120° C. and caused to react at this temperature for 3 hours. Thereafter, the solvent is concentrated under a reduced pressure and then purified through silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5) to yield the target compound as a colorless oily substance. (803.3 mg, 86.5%).

[0271] .sup.1H-NMR(CDCl.sub.3); 0.36(s, 9H, SnCH.sub.3×3), 1.39(s, 18H, -Boc), 1.48(s, 9H, t-Bu), 3.28(d, J=7.6, 2H, CH.sub.2), 4.84(t, J=7.6, 1H, CH), 6.95(d, J=8.4, 1H, Ar), 7.33(dd, J=2.0, 8.4, 1H, Ar), 7.48(d, J=2.0, 1H, Ar).

Production of (2-(3-tert-butoxy-2-(benzyloxycarbonylamino)-3-oxopropyl)-5-bromophenyl)(4-methylphenyl)iodonium tosylate

[0272] The compound obtained in the previous step (663 mg, 1.00 mmol) is dissolved into 2,2.2-trifluoroethanol (40 mL), and 4-(hydroxy(tosyloxy)iodo)toluene (406 mg, 1.00 mmol) is added thereto. The resultant is caused to react at room temperature for 15 minutes. Extraction with diethyl ether is carried out, and the diethyl ether layer is dried over magnesium sulfate. After filtration, the resultant is concentrated under a reduced pressure, and the obtained residue is purified through silica gel column chromatography (hexane:ethyl acetate=100:1 to 10: 1) to yield the target compound (180 mg, 20%).

[0273] .sup.1H-NMR(CDCl.sub.3); 1.35-1.47(m, 27H, t-Bu), 2.32(s, 3H, TsO-CH.sub.3), 2.37(s, 3H, Ar—CH.sub.3), 3.38(dd, J=8.0, 14.4, 1H, CH.sub.2-α), 3.59(dd, J=7.2, 14.4, 1H, CH.sub.2-β), 5.05(t, J=7.6, 1H, CH), 7.06(d, J=8.0, 2H, TsO—Ar), 7.18(d, J=8.4, 2H, Ar), 7.28(d, J=8.4, 1H, Ar), 7.53(dd, J=1.6, 8.4, 1H, Ar), 7.61(d, J=8.0, 2H, TsO—Ar), 7.87(d, J=1.6, 1H, Ar), 7.91(d, J=8.4, 2H, Ar).

Production of tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-3-(2-fluoro-4-bromophenyl)propanoate

[0274] Into MeCN (4 mL), 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (14.24 mg, 0.04 mmol) is dissolved, and potassium fluoride (2.2 mg, 0.04 mmol) is added. The resultant is concentrated at 60° C. under a reduced pressure. The same operation is repeated for three times, and thereafter the resultant is dried for 12 hours under a reduced pressure with a vacuum pump. To the obtained mixture, 2,2,6,6-tetramethylpiperidine 1-oxyl (1 mg) is added, and further a DMF solution (1 mL) of the compound 615 (28.0 mg, 0.03 mmol) is added. The resultant is heated to 140° C. and caused to react at this temperature for 15 minutes. Extraction with ethyl acetate is carried out, and the ethyl acetate layer is washed with a saturated saline solution and thereafter dried over sodium sulfate. After filtration, the resultant is concentrated under a reduced pressure to yield a mixture containing the target compound.

[0275] .sup.1H-NMR(CDCl.sub.3); 1.37(s, 18H, t-Bux2), 1.43(s, 9H, t-Bu), 2.98(dd, J=8.4, 13.6, 1H, CH.sub.2-α), 3.20(dd, J=5.6, 14.0, 1H, CH.sub.2-β), 4.51(m, 1H, CH), 5.04(d, J=9.2, 1H, NH), 7.10(d, J=8.0, 1H, NH), 7.39(dd, J=1.6, 8.0, 1H, Ar), 7.97(d, J=1.6, 1H, Ar).

[0276] UPLC analysis conditions; column: BEH C18 column (130A 1.7 μm 2.1 mm×150 mm), flow rate: 0.4 mL/min, detection: 254 nm, developing solvent: 0.1% acetic acid water:acetonitrile=30:70, detection period: 3.8 min.

Production of (2-(3-tert-butoxy-2-(benzyloxycarbonylamino)-3-oxopropyl)-5-bromophenyl)(4-methylphenyl)iodonium bromide

[0277] The compound (2-(3-tert-butoxy-2-(benzyloxycarbonylamino)-3-oxopropyl)-5-bromophenyl)(4-methylphenyl)iodonium tosylate (58.9 mg, 0.07 mmol) is dissolved into ethyl acetate-water mixture liquid (1:1, 2 mL), and potassium bromide (39.4 mg, 0.33 mmol) is added thereto. The resultant is caused to react at room temperature for 5 hours. Extraction with ethyl acetate is carried out, and the ethyl acetate layer is dried over sodium sulfate. After filtration, the resultant is concentrated under a reduced pressure to yield the target compound (52.3 mg, 99%).

[0278] .sup.1H-NMR(CDCl.sub.3); 1.38-1.54(m, 27H, t-Bu), 2.37(s, 3H, Ar—CH.sub.3), 3.40(dd, J=8.4, 14.4, 1H, CH.sub.2-α), 3.61(dd, J=7.2, 14.4, 1H, CH.sub.2-β), 5.06(t, J=7.6, 1H, CH), 7.19(d, J=8.0, 2H, Ar), 7.26(d, J=8.0, 1H, Ar), 7.52(dd, J=1.6, 8.0, 1H, Ar), 7.85(d, J=1.6, 1H, Ar), 7.95(d, J=8.4, 2H, Ar).

Production of tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-3-(4-bromo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl)propanoate

[0279] PdCl.sub.2(dppf) (98 mg, 0.120 mmol), Bis(pinacolato)diboran (638 mg, 2.51 mmol), and potassium acetate were dissolved into DMSO (7.5 mL) in an Ar atmosphere, and the resultant was kept being stirred at room temperature. After a DMSO solution (4.5 mL) of the compound tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-3-(4-bromo-2-iodophenyl)propanoate (1.50 g, 2.40 mmol) was added thereinto, the resultant was stirred at 80° C. for 24 hours. The reaction solution was diluted with ethyl acetate (70 mL) and subjected to Celite filtration. Thereafter, the resultant was washed with water and a saline solution, and the organic layer was dried over MgSO.sub.4. The organic layer was filtrated, and the organic solvent was concentrated and then purified through column chromatography (hexane:ethyl acetate=9:1) to yield the target compound as a colorless oily substance (705 mg, 47%).

[0280] .sup.1H-NMR(CDCl.sub.3); 1.35-1.48(m, 39H, pinacol-CH.sub.3×4, t-Bu), 3.08(dd, J=11.2, 13.6, 1H, CH.sub.2-α), 3.89(dd, J=4.4, 14.0, 1H, CH.sub.2-β), 5.17(dd, J=4.0, 11.2, 1H, CH), 6.91(d, J=8.0, 1H, Ar), 7.41(dd, J=2.0, 8.0, 1H, Ar), 7.89(d, J=2.0, 1H, Ar).

Production of tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-3-(2-fluoro-4-bromophenyl)propanoate

[0281] Tetrakis(pyridine)copper triflate (3.6 mg, 0.0053 mmol) was added to the compound obtained in the previous step (37.6 mg, 0.060 mmol). Further, potassium fluoride (3.8 mg, 0.066 mmol) and a DMF solution (4 mL) of 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (24.8 mg, 0.066 mmol) were added. The resultant was caused to react at 130° C. for 20 minutes. Thereafter, the resultant was filtrated and then concentrated under a reduced pressure to yield a mixture containing the target compound.

[0282] .sup.1H-NMR(CDCl.sub.3); 1.37(s, 18H, t-Bux2), 1.43(s, 9H, t-Bu), 2.98(dd, J=8.4, 13.6, 1H, CH.sub.2-α), 3.20(dd, J=5.6, 14.0, 1H, CH.sub.2-β), 4.51(m, 1H, CH), 5.04(d, J=9.2, 1H, NH), 7.10(d, J=8.0, 1H, NH), 7.39(dd, J=1.6, 8.0, 1H, Ar), 7.97(d, J=1.6, 1H, Ar).

Example 5

Production of 2-fluoro-4-iodobenzyl bromide

[0283] The target compound 2-fluoro-4-iodobenzyl bromide is obtained by employing the same method as that of Step S-2.

[0284] .sup.1H-NMR(CDCl.sub.3); 4.45(s, 2H, CH.sub.2), 7.12(t, J=8.0, 1H, Ar), 7.45(d, J=8.4, 1H, Ar), 7.48(d, J=8.4, 1H, Ar).

Production of ethyl 3-(2-fluoro-4-iodophenyl)-2-(diphenylmethyleneamino)propanoate

[0285] The target compound 703 is obtained by causing the compound obtained in the previous step to react with ethyl N-(diphenylmethylene)glycinate in place of benzyl N-(diphenylmethylene)glycinate by employing the same method as that of Step S-3. Here, the obtained compound is subjected to the next step without being purified.

Production of ethyl 2-amino-3-(2-fluoro-4-iodophenyl)propanoate

[0286] The target compound 704 was obtained by employing the same method as that of Step S-4.

[0287] .sup.1H-NMR(CDCl.sub.3); 1.24(t, J=7.2, 3H, CH.sub.2CH.sub.3), 2.86(dd, J=8.0, 13.6, 1H, CH.sub.2-α), 3.04(dd, J=5.9, 14.0, 1H, CH.sub.2-β), 3.71(dd, J=6.0, 7.6, 1H, CH), 4.16(q, J=7.2, 2H, CH.sub.2CH.sub.3), 6.95(t, J=8.0, 1H, Ar), 7.40(d, J=7.6, 1H, Ar), 7.42(d, J=7.6, 1H, Ar).

Production of ethyl 3-(2-fluoro-4-iodophenyl)-2-(benzyloxycarbonylamino)propanoate

[0288] The target compound 705 was obtained by employing the same method as that of Step S-5.

[0289] .sup.1H-NMR(CDCl.sub.3); 1.24(t, J=7.3, 3H, CH.sub.2CH.sub.3), 3.06(dd, J=6.8, 13.6, 1H, CH.sub.2-α), 3.16(dd, J=4.8, 14.0, 1H, CH.sub.2-β), 4.17(q, J=7.2, 2H, CH.sub.2CH.sub.3), 4.61(m, 1H, CH), 5.08(m, 2H, CH.sub.2Ar), 5.29(d, J=8.0, 1H, NH), 6.84(t, J=7.6, 1H, Ar), 7.31-7.38(m, 7H, Ar).

[0290] Furthermore, the compound obtained in the previous step can be used to prepare a pinacol boronated compound in the same manner as in Example 1 or 3.

Reference Example 1

[0291] De-Protection of Pinacol Boronated Compound Labeled with Fluorine

[0292] The pinacol boronated compounds obtained in Examples 1 to 4 can be each de-protected to prepare a target fluorinated BPA. Specifically, first, Boc and t-Bu are de-protected by 4N HCl AcOEt.

[0293] Next, when elution is made by a reversed-layer column using a 0.1% acetic acid-acetonitrile solvent, pinacol also is removed, whereby the target fluorinated BPA is obtained.