Process for Producing Fluorinated Compounds Using Alcohol Solvent Having Unsaturated Hydrocarbon

Abstract

The present invention relates to a process for producing an organofluoro compound including [.sup.18F]fluorine, and by using a solvent represented by Formula 1 in nucleophilic fluorination reaction, an organofluoro compound may be prepared at a high yield. In addition, since the solvent has very excellent solubility for a precursor compound, the solvent is suitable for the automated synthesis of .sup.18F-labeled radiopharmaceuticals.

Claims

1. A process for producing a fluoro compound, the method comprising: reacting a compound having a leaving group (LG) and a fluoride under a solvent, wherein the solvent is represented by the following Formula 1: ##STR00031## in Formula 1, R.sub.1 and R.sub.2 are independently methyl groups, or ethyl groups; and R.sub.3 is ethenyl or ethynyl.

2. (canceled)

3. (canceled)

4. The process for producing a fluoro compound according to claim 1, wherein R.sub.1 and R.sub.2 are each methyl groups; and R.sub.3 is ethenyl or ethynyl.

5. The process for producing a fluoro compound according to claim 1, wherein the fluoride is a [.sup.18F]fluoride.

6. The process for producing a fluoro compound according to claim 1, wherein the reaction is performed for 5 minutes to 60 minutes.

7. The process for producing a fluoro compound according to claim 1, wherein the reaction is performed in a temperature range of 60 C. to 160 C.

8. The process for producing a fluoro compound according to claim 1 or 5, wherein the fluoro compound is [.sup.18F]fluoropropylcarbomethoxytropane ([.sup.18F]FP-CIT) represented by the following Formula 3: ##STR00032##

9. The process for producing a fluoro compound according to claim 1 or 5, wherein the fluoro compound is [.sup.18F]fluorodeoxyglucose ([.sup.18F]FDG) represented by the following Formula 4: ##STR00033##

10. The process for producing a fluoro compound according to claim 1 or 5, wherein the fluoro compound is [.sup.18F]fluoro-L-thymidine ([.sup.18F]FLT) represented by the following Formula 5: ##STR00034##

11. The process for producing a fluoro compound according to claim 1 or 5, wherein the fluoro compound is 6-(3-[.sup.18F]fluoro-2-hydroxypropyloxy)-2-(2-(4-methylamino)pyridine-5-yl)benzothiazol ([.sup.18F]FC119S) represented by the following Formula 6: ##STR00035##

12. The process for producing a fluoro compound according to claim 1 or 5, wherein the fluoro compound is 2-(2-(2-[.sup.18F]fluoroethoxy)ethoxy)ethyl azide represented by the following Formula 7: ##STR00036##

13. The process for producing a fluoro compound according to claim 1 or 5, wherein the fluoro compound is 2-(3-([.sup.18F]fluoro)propoxy)naphthalene represented by the following Formula 8: ##STR00037##

14. The process for producing a fluoro compound according to claim 1 or 5, wherein the fluoro compound is 2-(2-([.sup.18F]fluoro)propoxy)naphthalene represented by the following Formula 9: ##STR00038##

Description

DETAILED DESCRIPTION OF THE INVENTION

[0080] Hereinafter, the meaning of each substituent will be explained in particular.

[0081] Alkyl

[0082] Some particular examples may include linear or branched C.sub.1-20 alkyl, linear or branched C.sub.1-15 alkyl, linear or branched C.sub.1-10 alkyl, and linear or branched C.sub.1-5 alkyl, and unsaturated alkyl including a CC bond and/or a CC bond may be also included.

[0083] In addition, one or more carbon atoms constituting the alkyl may be substituted with one or more heteroatoms selected from the group consisting of N, O and S.

[0084] Alkoxy

[0085] Alkoxy may be represented by O-alkyl, and in this case, alkyl is the same as the above-defined alkyl.

[0086] Cycloalkyl

[0087] Some particular examples may include C.sub.3-15 cycloalkyl, C.sub.3-10 cycloalkyl, C.sub.3-8 cycloalkyl, C.sub.3-7 cycloalkyl, C.sub.3-6 cycloalkyl, C.sub.3-5 cycloalkyl, C.sub.3-4 cycloalkyl, etc., and unsaturated cycloalkyl including a CC bond and/or a CC bond may be also included.

[0088] Aryl

[0089] Some particular examples may include C.sub.6-10 aryl, C.sub.6-8 aryl, C.sub.6 aryl, naphthalene, anthracene, etc.

[0090] Heterocycloalkyl

[0091] Cycloalkyl of which one or more carbon atoms are substituted with one or more heteroatoms selected from the group consisting of N, O and S corresponds to the heterocycloalkyl.

[0092] Heteroaryl

[0093] Aryl of which one or more carbon atoms are substituted with one or more heteroatoms selected from the group consisting of N, O and S corresponds to the heteroaryl.

[0094] Cycloalkyl-alkyl

[0095] Cycloalkyl-alkyl may be represented by -alkyl-cycloalkyl, and in this case, alkyl and cycloalkyl are the same as the above-defined alkyl and cycloalkyl, respectively.

[0096] Aryl-alkyl

[0097] Aryl-alkyl may be represented by -alkyl-aryl, and in this case, alkyl and aryl are the same as the above-defined alkyl and aryl, respectively.

[0098] Heterocycloalkyl-alkyl

[0099] Heterocycloalkyl-alkyl may be represented by -alkyl-heterocycloalkyl, and in this case, alkyl and heterocycloalkyl are the same as the above-defined alkyl and heterocycloalkyl, respectively.

[0100] Heteroaryl-alkyl

[0101] Heteroaryl-alkyl may be represented by -alkyl-heteroaryl, and in this case, alkyl and heteroaryl are the same as the above-defined alkyl and heteroaryl, respectively.

[0102] Cycloalkyloxy

[0103] Cycloalkyloxy may be represented by O-cycloalkyl, and in this case, cycloalkyl is the same as the above-defined cycloalkyl.

[0104] Aryloxy

[0105] Aryloxy may be represented by O-aryl, and in this case, aryl is the same as the above-defined aryl.

[0106] Heterocycloalkyloxy

[0107] Heterocycloalkyloxy may be represented by O-heterocycloalkyl, and in this case, heterocycloalkyl is the same as the above-defined heterocycloalkyl.

[0108] Heteroaryloxy

[0109] Heteroaryloxy may be represented by O-heteroaryl, and in this case, heteroaryl is the same as the above-defined heteroaryl.

[0110] Halogen may be one or more selected from F, Cl, Br, and I; hydroxyl means OH; nitro means NO.sub.2; nitrile (cyano) means CN; oxo means O; and carbonyl means CO.

[0111] In addition, the substituents including alkyl, alkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, cycloalkyl-alkyl, aryl-alkyl, heterocycloalkyl-alkyl, heteroaryl-alkyl, cycloalkyloxy, aryloxy, heterocycloalkyloxy, heteroaryloxy, halogen, hydroxyl, nitro, nitrile (cyano), oxo (O), carbonyl, etc.,

[0112] may be further substituted with the aforementioned substituents including alkyl, alkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, cycloalkyl-alkyl, aryl-alkyl, heterocycloalkyl-alkyl, heteroaryl-alkyl, cycloalkyloxy, aryloxy, heterocycloalkyloxy, heteroaryloxy, halogen, hydroxyl, nitro, nitrile (cyano), oxo (O), carbonyl, etc., without limitation.

[0113] Further, the present invention provides a process for producing a .sup.18F-radiopharmaceutical through an automated synthesis module using a solution of a precursor compound dissolved in an alcohol solvent having an unsaturated hydrocarbon group. The process for producing a .sup.18F-radiopharmaceutical has substantially the same configuration as the process for producing the fluorinated compound, and particular explanation will be omitted to avoid repeated description.

[0114] The present invention uses the compound represented by Formula 1 as a solvent in the nucleophilic fluorination reaction of a precursor compound, and since the solvent represented by Formula 1 includes an alcohol functional group, side reactions due to a base is suppressed to increase the yield of a product, and the solubility of the precursor compound is good. Since the solubility of the precursor compound is low in the conventional alcohol solvent, mixing with another solvent or heating is unfavorably required for dissolving. However, the solvent represented by Formula 1 of the present invention itself dissolves the precursor compound well, and the solvent is suitable for the synthesis of a .sup.18F-coupled organofluoro compound, which requires an automated synthesis module. Since compounds and reagents required for the automated synthesis module are used in liquid states, if the solvent represented by Formula 1 of the present invention is used, the stable automated synthesis of a .sup.18F-labeled organofluoro compound becomes possible. In addition, since the solvent represented by Formula 1 of the present invention is dissolved in water well, deprotection reaction using an aqueous solution or a purification process such as solid phase extraction may become easy after performing nucleophilic fluorination reaction.

[0115] In order to verify the effects of the present invention, a case of using an alcohol solvent having an unsaturated hydrocarbon group of the present invention was compared to cases using t-butanol and t-amyl alcohol as solvents, and it was confirmed that organofluorinated compound could be produced at a relatively markedly excellent yield in the present invention (see Examples and Experimental Examples).

[0116] Hereinafter, the present invention will be explained in detail referring to examples and experimental examples.

[0117] However, the examples and experimental examples are only for the illustration of the present invention, and the present invention is not limited thereto.

<Example 1> Preparation of [.SUP.18.F]fluoropropylcarbomethoxytropane ([.SUP.18.F]FP-CIT) Using 2-methyl-3-butene-2-ol as a Solvent

[0118] ##STR00024##

[0119] An aqueous solution in which [.sup.18F]fluoride (1-10 mCi) ions were dissolved was passed through an ion exchange cartridge (QMA, HCO.sub.3) for entrapment, and then, 3.0 ml of ethanol was passed through. A solution in which 10 mg of a kryptofix 222-potassium methanesulfonate salt (K222-KOMs salt) was dissolved in 1.0 ml of ethanol was made to flow through the cartridge which trapped the [.sup.18F]fluoride, and a nitrogen gas was blown while heating to 100 C. to remove ethanol. 4.0 mg of a precursor compound (1R,2S,3S,5S)-3-(4-iodophenyl)-2-(methoxycarbonyl)spiro[azetidine-1,8-bicyclo[3,2,1]octan]-1-ium p-toluenesulfonate) was dissolved in 0.5 ml of 2-methyl-3-butene-2-ol and then, put in a reaction vessel and reacted at 100 C. to 120 C. for 10 minutes. After the reaction, the reaction product was analyzed by radio-thin layer chromatography (radio-TLC) to obtain .sup.18F-labeled product. The analysis results by the radio-TLC after 10 minutes are shown in [Table 1] below.

<Example 2> Preparation of [.SUP.18.F]fluoropropylcarbomethoxytropane ([.SUP.18.F]FP-CIT) Using 2-methyl-3-butyne-2-ol as a Solvent

[0120] [.sup.18F]fluoropropylcarbomethoxytropane ([.sup.18F]FP-CIT) was prepared by the same method as in <Example 1> except for using 2-methyl-3-butyne-2-ol instead of 2-methyl-3-butene-2-ol as the reaction solvent.

<Comparative Example 1> Preparation of [.SUP.18.F]fluoropropylcarbomethoxytropane ([.SUP.18.F]FP-CIT) Using MeCN as a Solvent

[0121] [.sup.18F]fluoropropylcarbomethoxytropane ([.sup.18F]FP-CIT) was prepared by the same method as in <Example 1> except for using MeCN instead of 2-methyl-3-butene-2-ol as the reaction solvent and performing the reaction at 120 C. instead of 100 C.

<Comparative Example 2> Preparation of [.SUP.18.F]fluoropropylcarbomethoxytropane ([.SUP.18.F]FP-CIT) Using t-butanol as a Solvent

[0122] [.sup.18F]fluoropropylcarbomethoxytropane ([.sup.18F]FP-CIT) was prepared by the same method as in <Example 1> except for using t-butanol instead of 2-methyl-3-butene-2-ol as the reaction solvent.

<Comparative Example 3> Preparation of [.SUP.18.F]fluoropropylcarbomethoxytropane ([.SUP.18.F]FP-CIT) Using 10% MeCN/t-amyl Alcohol as a Solvent

[0123] [.sup.18F]fluoropropylcarbomethoxytropane ([.sup.18F]FP-CIT) was prepared by the same method as in <Example 1> except for using 10% MeCN/t-amyl alcohol instead of 2-methyl-3-butene-2-ol as the reaction solvent.

<Comparative Example 4> Preparation of [.SUP.18.F]fluoropropylcarbomethoxytropane ([.SUP.18.F]FP-CIT) Using 1-methoxy-2-methyl-2-propanol as a Solvent

[0124] [.sup.18F]fluoropropylcarbomethoxytropane ([.sup.18F]FP-CIT) was prepared by the same method as in <Example 1> except for using 1-methoxy-2-methyl-2-propanol instead of 2-methyl-3-butene-2-ol as the reaction solvent and performing the reaction at 120 C. instead of 100 C.

[0125] In Table 1 below, the kind of the solvent used, the reaction temperature, the reaction time and product yield in each of Examples 1 and 2, and Comparative Examples 1 to 4 are shown.

TABLE-US-00001 TABLE 1 Temper- Radio- ature Time TLC Solvent ( C.) (min) (%) Note Example 1 2-methyl-3-butene- 100 10 92 The 2-ol present invention Example 2 2-methyl-3-butyne- 100 10 87 The 2-ol present invention Comparative MeCN 120 10 11 Example 1 Comparative t-butanol 100 10 56 KR 10- Example 2 0789847 Comparative 10% MeCN/t-amyl 100 10 63 KR 10- Example 3 alcohol 0789847 Comparative 1-methoxy-2- 120 10 11 KR 10- Example 4 methyl-2-propanol 1605291

[0126] As shown in Table 1, Comparative Example 1 showed experimental results obtained by using the MeCN solvent in general .sup.18F-labeling reaction, and the yield of a product after 10 minutes was mere 11%. Comparative Example 2 and Comparative Example 3 showed comparative results corresponding to the prior art (KE 10-0789847), and t-butanol showed a radio-TLC yield of 56%, and in contrast, t-amyl alcohol showed a yield of 63%. However, the precursor compound was rarely dissolved in t-butanol and t-amyl alcohol at room temperature.

[0127] Comparative Example 4 showed comparative results corresponding to the prior art (KR 10-1605291), obtained by reacting using a 1-methoxy-2-methyl-2-propanol solvent, and a radio-TLC yield of 11% was shown. This yield is smaller by about five times that of the prior art (KR 10-0789847) and is a smaller level by about 8.36 times that of Example 1 of the present invention.

[0128] Example 1 and Example 2 showed experimental results obtained by using the solvent according to the present invention. The 2-methyl-3-butene-2-ol of Example 1 showed a radio-TLC yield of 92%, and the 2-methyl-3-butyne-2-ol of Example 2 showed a radio-TLC yield of 87%. Through this, it could be confirmed that relatively higher yield was obtained as synthetic results than that of the prior art.

[0129] In addition, the solvents used in Example 1 and Example 2 had characteristics of well dissolving the precursor compounds at room temperature.

[0130] That is, the solvent used in the prior arts such as t-butanol, t-amyl alcohol and 1-methoxy-2-methyl-2-propanol could not dissolve the precursor compounds at room temperature (in a range of about 20 to 25 C.). On the contrary, the 2-methyl-3-butene-2-ol and 2-methyl-3-butyne-2-ol, which were solvents used in the present invention showed characteristics of dissolving the precursor compounds at room temperature well.

[0131] In case of using commercially produced .sup.18F-labeled radiopharmaceuticals, the synthesis is required to conduct through an automated synthesis module, and compounds, reagents, etc. are necessary to put in the automated synthesis module in liquid states. If the solubility of the precursor in a solvent is low, the injection of the precursor to an automated synthesis module in a solution state might become difficult.

[0132] Since the solvent used in the prior art may not dissolve the precursor compound well at room temperature, a mixture of the precursor compound and the solvent could be heated to prepare a temporarily dissolved solution state to be put in the automated synthesis module, but after putting the solution in the automated synthesis module, if the temperature is reduced to room temperature, the precursor compound dissolved is solidified again, resulting in blocking a tube in the module, where the solution flows, and restraining the inflowing of a sufficient amount of the precursor. As a result, the production yield of the .sup.18F-labeled radiopharmaceutical may be markedly reduced and defects of production fail may be generated.

[0133] However, in case of dissolving the precursor compound in the solvent used in the present invention well, effects of stable production of the .sup.18F-labeled radiopharmaceutical may be achieved.

<Example 3> Preparation of [.SUP.18.F]FDG (fluorodeoxyglucose) Using 2-methyl-2-butene-2-ol as a Solvent

[0134] ##STR00025##

[0135] An aqueous solution in which [.sup.18F]fluoride (1-10 mCi) ions were dissolved was passed through a cartridge filled with an ion exchange solid phase (QMA) for entrapment, and then, 3.0 ml of ethanol was passed therethrough. A solution in which 10 mg of a kryptofix 222-potassium methanesulfonate salt (K222-KOMs salt) was dissolved in 1.0 ml of ethanol was made to flow through the cartridge which trapped the [.sup.18F]fluoride, and a nitrogen gas was blown while heating to 100 C. to remove ethanol. 25 mg of a FDG precursor compound (1,3,4,6-tetra-O-acetyl-2-O-trifluoro-methanesulfonyl-beta-D-mannopyranose) was dissolved in 0.5 ml of 2-methyl-3-butene-2-ol and then, put in a reaction vessel and reacted at 100 C. for 10 minutes. After 10 minutes, the reaction product was analyzed by radio-TLC, and the results are shown in [Table 2] below.

<Example 4> Preparation of [.SUP.18.F]FDG (fluorodeoxyglucose) Using 2-methyl-2-butyne-2-ol as a Solvent

[0136] [.sup.18F]FDG (fluorodeoxyglucose) was prepared by the same method as in <Example 3> except for using 2-methyl-3-butyne-2-ol instead of 2-methyl-3-butene-2-ol as the reaction solvent.

[0137] The kind of the solvents used, and production yields of Example 3 and Example 4 are shown, respectively, in Table 2 below.

TABLE-US-00002 TABLE 2 Solvent Radio-TLC (%) Example 3 2-methyl-3-butene-2-ol 92 Example 4 2-methyl-3-butyne-2-ol 90

[0138] As shown in Table 2,

[0139] if the 2-methyl-3-butene-2-ol solvent according to the present invention was used for producing [.sup.18F]FDG (fluorodeoxyglucose), a very excellent radio-TLC yield of 92% could be obtained (Example 3), and if the 2-methyl-3-butyne-2-ol solvent according to the present invention was used, a very excellent radio-TLC yield of 90% could be obtained (Example 4). Accordingly, it was confirmed that if the solvent according to the present invention was used for producing [.sup.18F]FDG (fluorodeoxyglucose), all products could be obtained at a very excellent yield of 90% or more. Through this, it was confirmed that the alcohol solvent having an unsaturated hydrocarbon group according to the present invention might be used as a very suitable solvent for the production of an organofluoro compound.

<Example 5> Preparation of [.SUP.18.F]FLT (fluorothymidine) Using 2-methyl-3-butene-2-ol as a Solvent

[0140] ##STR00026##

[0141] An aqueous solution in which [.sup.18F]fluoride (1-10 mCi) ions were dissolved was passed through a cartridge filled with an ion exchange solid phase (QMA) for entrapment, and then, 3.0 ml of ethanol was passed therethrough. A solution in which 10 mg of kryptofix 222-potassium methanesulfonate salt (K222-KOMs salt) was dissolved in 1.0 ml of ethanol was made to flow through the cartridge which trapped the [.sup.18F]fluoride, and a nitrogen gas was blown while heating to 100 C. to remove ethanol. 20 mg of a FLT precursor compound (3-N-Boc-5-O-trityl-3-O-nosyl-thymidine) was dissolved in 0.5 ml of 2-methyl-3-butene-2-ol and then, put in a reaction vessel and reacted at 100 C. for 10 minutes. After 10 minutes, the reaction product was analyzed by radio-TLC, and the results are shown in [Table 3] below.

<Example 6> Preparation of [.SUP.18.F]FLT (fluorothymidine) Using 2-methyl-3-butyne-2-ol as a Solvent

[0142] [.sup.18F]FLT (fluorothymidine) was prepared by the same method as in <Example 5> except for using 2-methyl-3-butyne-2-ol instead of 2-methyl-3-butene-2-ol as the reaction solvent.

TABLE-US-00003 TABLE 3 Solvent Radio-TLC (%) Example 5 2-methyl-3-butene-2-ol 92 Example 6 2-methyl-3-butyne-2-ol 77

[0143] As shown in Table 3,

[0144] if the 2-methyl-3-butene-2-ol solvent according to the present invention was used for producing [.sup.18F]FLT (fluorothymidine), a very excellent radio-TLC yield of 92% could be obtained (Example 5), and if the 2-methyl-3-butyne-2-ol solvent according to the present invention was used, an excellent radio-TLC yield of 77% could be obtained (Example 6). Accordingly, it was confirmed that if the solvent according to the present invention was used for producing [.sup.18F]FLT (fluorothymidine), all products could be obtained at an excellent yield. Through this, it was confirmed that the alcohol solvent having an unsaturated hydrocarbon group according to the present invention might be used as a very suitable solvent for the production of an organofluoro compound.

<Example 7> Preparation of [.SUP.18.F]FC119S Using 2-methyl-3-butene-2-ol as a Solvent

[0145] ##STR00027##

[0146] An aqueous solution in which [.sup.18F]fluoride (1-10 mCi) ions were dissolved was passed through a cartridge filled with an ion exchange solid phase (QMA) for entrapment, and then, 3.0 ml of ethanol was passed therethrough. A solution in which 10 mg of a kryptofix 222-potassium methanesulfonate salt (K222-KOMs salt) was dissolved in 1.0 ml of ethanol was made to flow through the cartridge which trapped the [.sup.18F]fluoride, and a nitrogen gas was blown while heating to 100 C. to remove ethanol. 5.0 mg of FC119S ((2S)-3-((2-(6-((tert-butoxycarbonyl) (methyl)amino)pyridin-3-yl)benzo[d]thiazol-6-yl)oxy)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl 4-nitrobenzenesulfonate) was dissolved in 0.5 ml of 2-methyl-3-butene-2-ol and then, put in a reaction vessel and reacted at 100 C. for 10 minutes. After 10 minutes, the reaction product was analyzed by radio-TLC, and the results are shown in [Table 4] below.

<Example 8> Preparation of [.SUP.18.F]FC119S Using 2-methyl-3-butyne-2-ol as a Solvent

[0147] [.sup.18F]FC119S was prepared by the same method as in <Example 7> except for using 2-methyl-3-butyne-2-ol instead of 2-methyl-3-butene-2-ol as the reaction solvent.

TABLE-US-00004 TABLE 4 Solvent Radio-TLC (%) Example 7 2-methyl-3-butene-2-ol 93 Example 8 2-methyl-3-butyne-2-ol 65

[0148] As shown in Table 4,

[0149] if the 2-methyl-3-butene-2-ol solvent according to the present invention was used for producing [.sup.18F]FC119S, a very excellent radio-TLC yield of 93% could be obtained (Example 7), and if the 2-methyl-3-butyne-2-ol solvent according to the present invention was used, an excellent radio-TLC yield of 65% could be obtained (Example 8). Accordingly, it was confirmed that if the solvent according to the present invention was used for producing [.sup.18F]FC119S, all products could be obtained at an excellent yield. Through this, it was confirmed that the alcohol solvent having an unsaturated hydrocarbon group according to the present invention might be used as a very suitable solvent for the production of an organofluoro compound.

<Example 9> Preparation of 2-(2-(2-([.SUP.18.F]fluoroethoxy)ethoxy)ethyl Azide Using 2-methyl-3-butene-2-ol as a Solvent

[0150] ##STR00028##

[0151] An aqueous solution in which [.sup.18F]fluoride (1-10 mCi) ions were dissolved was passed through a cartridge filled with an ion exchange solid phase (QMA) for entrapment, and then, 3.0 ml of ethanol was passed therethrough. A solution in which 10 mg of a kryptofix 222-potassium methanesulfonate salt (K222-KOMs salt) was dissolved in 1.0 ml of ethanol was made to flow through the cartridge which trapped the [.sup.18F]fluoride, and a nitrogen gas was blown while heating to 100 C. to remove ethanol. 5.0 mg of 2-(2-(2-azidoethoxy)ethoxy)ethyl methanesulfonate was dissolved in 0.5 ml of 2-methyl-3-butene-2-ol and then, put in a reaction vessel and reacted at 100 C. for 10 minutes. After 10 minutes, the reaction product was analyzed by radio-TLC, and a very high yield of 90% was shown.

<Example 10> Preparation of 2-(3-([.SUP.18.F]fluoro)propoxy)naphthalene Using 2-methyl-3-butene-2-ol as a Solvent

[0152] ##STR00029##

[0153] An aqueous solution in which [.sup.18F]fluoride (1-10 mCi) ions were dissolved was passed through a cartridge filled with an ion exchange solid phase (QMA) for entrapment, and then, 3.0 ml of ethanol was passed therethrough. A solution in which 10 mg of a kryptofix 222-potassium methanesulfonate salt (K222-KOMs salt) was dissolved in 1.0 ml of ethanol was made to flow through the cartridge which trapped the [.sup.18F]fluoride, and a nitrogen gas was blown while heating to 100 C. to remove ethanol. 5.0 mg of 3-(naphthalene-2-yloxy)propyl methanesulfonate was dissolved in 0.5 ml of 2-methyl-3-butene-2-ol and then, put in a reaction vessel and reacted at 100 C. for 10 minutes. After 10 minutes, the reaction product was analyzed by radio-TLC, and the results are shown in [Table 5] below.

<Example 11> Preparation of 2-(3-([.SUP.18.F]fluoro)propoxy)naphthalene Using 2-methyl-3-butyne-2-ol as a Solvent

[0154] 2-(3-([.sup.18F]fluoro)propoxy)naphthalene was prepared by the same method as in <Example 10> except for using 2-methyl-3-butyne-2-ol instead of 2-methyl-3-butene-2-ol as the reaction solvent.

TABLE-US-00005 TABLE 5 Solvent Radio-TLC (%) Example 10 2-methyl-3-butene-2-ol 97 Example 11 2-methyl-3-butyne-2-ol 95

[0155] As shown in Table 5,

[0156] if the 2-methyl-3-butene-2-ol solvent according to the present invention was used for producing 2-(3-([.sup.18F]fluoro)propoxy)naphthalene, a very excellent radio-TLC yield of 97% could be obtained (Example 10), and if the 2-methyl-3-butyne-2-ol solvent according to the present invention was used, a very excellent radio-TLC yield of 95% could be obtained (Example 11). Accordingly, it was confirmed that if the solvent according to the present invention was used for producing 2-(3-([.sup.18F]fluoro)propoxy)naphthalene, all products could be obtained at an excellent yield of 95% or more. Through this, it was confirmed that the alcohol solvent having an unsaturated hydrocarbon group according to the present invention might be used as a very suitable solvent for the production of an organofluoro compound.

<Example 12> Preparation of 2-(2-([.SUP.18.F]fluoro)propoxy)naphthalene Using 2-methyl-3-butene-2-ol as a Solvent

[0157] ##STR00030##

[0158] An aqueous solution in which [.sup.18F]fluoride (1-10 mCi) ions were dissolved was passed through a cartridge filled with an ion exchange solid phase (QMA) for entrapment, and then, 3.0 ml of ethanol was passed therethrough. A solution in which 10 mg of a kryptofix 222-potassium methanesulfonate salt (K222-KOMs salt) was dissolved in 1.0 ml of ethanol was made to flow through the cartridge which trapped the [.sup.18F]fluoride, and a nitrogen gas was blown while heating to 100 C. to remove ethanol. 10.0 mg of 1-(naphthalene-2-yloxy)propan-2-yl methanesulfonate was dissolved in 0.5 ml of 2-methyl-3-butene-2-ol and then, put in a reaction vessel and reacted at 100 C. for 10 minutes. After 10 minutes, the reaction product was analyzed by radio-TLC, and the results are shown in [Table 6] below.

<Example 13> Preparation of 2-(2-([.SUP.18.F]fluoro)propoxy)naphthalene Using 2-methyl-3-butyne-2-ol as a Solvent

[0159] 2-(2-([.sup.18F]fluoro)propoxy)naphthalene was prepared by the same method as in <Example 12> except for using 2-methyl-3-butyne-2-ol instead of 2-methyl-3-butene-2-ol as the reaction solvent.

TABLE-US-00006 TABLE 6 Solvent Radio-TLC (%) Example 12 2-methyl-3-butene-2-ol 91 Example 13 2-methyl-3-butyne-2-ol 58

[0160] As shown in Table 6,

[0161] if the 2-methyl-3-butene-2-ol solvent according to the present invention was used for producing 2-(2-([.sup.18F]fluoro)propoxy)naphthalene, a very excellent radio-TLC yield of 91% could be obtained (Example 12), and if the 2-methyl-3-butyne-2-ol solvent according to the present invention was used, an excellent radio-TLC yield of 58% could be obtained (Example 13). Accordingly, it was confirmed that if the solvent according to the present invention was used for producing 2-(2-([.sup.18F]fluoro)propoxy)naphthalene, all products could be obtained at an excellent yield. Through this, it was confirmed that the alcohol solvent having an unsaturated hydrocarbon group according to the present invention might be used as a very suitable solvent for the production of an organofluoro compound.

<Experimental Example 1> Comparison of Solubility of Precursor Compounds According to the Kind of Reaction Solvents

[0162] Experiments for comparing the solubility in the 2-methyl-3-butene-2-ol solvent and 2-methyl-3-butyne-2-ol solvent according to the present invention, and the t-amyl alcohol solvent of the prior art (KE 10-0789847) were performed. Each of the precursors of FP-CIT, FDG, FLT, FMISO and FC119S in solid states was put in a vial, and 1.0 ml of each solvent was added thereto, followed by shaking at room temperature and 60 C. for 1 minutes, respectively, for dissolution. The vial was observed with the naked eye, and the observation results are summarized in [Table 7] below.

TABLE-US-00007 TABLE 7 2-methyl-3-butene-2- 2-methyl-3-butyne- Pre- t-amyl alcohol ol (the present 2-ol (the present cursor (KR 10-0789847) invention) invention) Precursor amount Room Room Room compound (mg) temp 60 C. temp 60 C. temp 60 C. FP-CIT 4 Insoluble Dissolved Dissolved Dissolved Dissolved Dissolved FDG 20 Insoluble Dissolved Dissolved Dissolved Dissolved Dissolved FLT 20 Insoluble Insoluble Dissolved Dissolved Insoluble Dissolved FMISO 5 Insoluble Dissolved Insoluble Dissolved Dissolved Dissolved FC119S 5 Insoluble Insoluble Dissolved Dissolved Dissolved Dissolved 3-(naphthalene-2- 5 Dissolved Dissolved yloxy)propyl methanesulfonate 1-(naphthalene-2- 10 Dissolved Dissolved yloxy)propyl methanesulfonate

[0163] As shown in Table 7,

[0164] in case of using the t-amyl alcohol which was the solvent of the prior art, all precursors were insoluble at room temperature, and FLT and FC119S precursors were insoluble even heated to 60 C. The FP-CIT, FGD, and FMISO precursors, dissolved at 60 C. were precipitated again as solids if cooled to room temperature after the lapse of time.

[0165] Accordingly, since PET radiopharmaceuticals are required to be produced by an automated synthesis module, and a precursor compound is required to be used in a well-dissolved state in a reaction solvent, the t-amyl alcohol has poor solubility and is not suitable for the actual production of pharmaceuticals.

[0166] On the contrary, all precursor compounds except for FMISO were dissolved well in the 2-methyl-3-butene-2-ol according to the present invention at room temperature, and all precursor compounds except for FLT were dissolved well in the 2-methyl-3-butyne-2-ol at room temperature. If heated to 60 C., it was confirmed that all precursor compounds were dissolved in both 2-methyl-3-butene-2-ol and 2-methyl-3-butyne-2-ol. In addition, though the dissolved FLT and FMISO solutions through heating to 60 C. were cooled to room temperature, the precursor compounds were not precipitated as solids.

[0167] For the production of the .sup.18F-radiopharmaceuticals using an automated synthesis module, precursor compounds are required to be used in solution states. Most of the precursor compounds were dissolved well in the 2-methyl-3-butene-2-ol and 2-methyl-3-butyne-2-ol at room temperature or 60 C. through heating, and the solution states were maintained after cooling to room temperature. Accordingly, different from the conventional tertiary alcohol solvent, the solvent of the present invention has excellent solubility with respect to compounds and is a more suitable solvent for producing PET radiopharmaceuticals through an automated synthesis module.

<Experimental Example 2> Automated Synthesis of [.SUP.18.F]fluoropropylcarbomethoxytropane ([.SUP.18.F]FP-CIT) Using 2-methyl-3-butene-2-ol as a Solvent

[0168] By applying the conditions of Example 1, the production experiment of [.sup.18F]FP-CIT using an automated synthesis module was performed. An sCUBE module of CS CHEM Co. Ltd. was used as the automated synthesis module, and a disposable cassette and a reagent kit according to Example 1 were used. 1.5 ml of a 2-methyl-3-butene-ol solution in which 4 mg of a FP-CIT precursor was dissolved was used for the reaction, and after performing the reaction, purification was performed using a high performance liquid chromatography (HPLC) installed on the sCUBE automated synthesis module. The [.sup.18F]FP-CIT thus separated was diluted with 40 ml of distilled water, adsorbed on a C-18 cartridge (SePak), washed with distilled water, and eluted with 2.0 ml of ethanol. This process was repeated twice further. The results of the automated synthesis experiment are summarized in Table 8 below.

TABLE-US-00008 TABLE 8 Number of times 1 2 3 Yield 32.7 34.0 35.2 (%, attenuation correction)

[0169] As above, the present invention has been explained in detail referring to preferred Preparation Examples, Examples and Experimental Examples, but the scope of the present invention is not limited to the specific examples and should be interpreted by the attached claims. In addition, it is understood that various changes and modifications can be made by one ordinary skilled in the art within the spirit and scope of the present invention.

[0170] When a group of materials, compositions, components or compounds is disclosed herein, it is understood that all individual members of those groups and all subgroups thereof are disclosed separately. Every formulation or combination of components described or exemplified herein can be used to practice the invention, unless otherwise stated. Whenever a range is given in the specification, for example, a temperature range, a time range, or a composition range, all intermediate ranges and subranges, as well as all individual values included in the ranges given are intended to be included in the disclosure. Additionally, the end points in a given range are to be included within the range. In the disclosure and the claims, and/or means additionally or alternatively. Moreover, any use of a term in the singular also encompasses plural forms.

[0171] As used herein, comprising is synonymous with including, containing, or characterized by, and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, consisting of excludes any element, step, or ingredient not specified in the claim element. As used herein, consisting essentially of does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. Any recitation herein of the term comprising, particularly in a description of components of a composition or in a description of elements of a device, is understood to encompass those compositions and methods consisting essentially of and consisting of the recited components or elements.

[0172] One of ordinary skill in the art will appreciate that starting materials, device elements, analytical methods, mixtures and combinations of components other than those specifically exemplified can be employed in the practice of the invention without resort to undue experimentation. All art-known functional equivalents, of any such materials and methods are intended to be included in this invention. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Headings are used herein for convenience only.

[0173] All publications referred to herein are incorporated herein to the extent not inconsistent herewith. Some references provided herein are incorporated by reference to provide details of additional uses of the invention. All patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the invention pertains. References cited herein are incorporated by reference herein in their entirety to indicate the state of the art as of their filing date and it is intended that this information can be employed herein, if needed, to exclude specific embodiments that are in the prior art.