METHOD FOR THE PREPARATION OF N-MONOFLUOROALKYL TROPANES AND THEIR USE
20230089353 · 2023-03-23
Assignee
Inventors
Cpc classification
A61K51/0455
HUMAN NECESSITIES
C07B2200/05
CHEMISTRY; METALLURGY
C07D451/02
CHEMISTRY; METALLURGY
International classification
C07D451/02
CHEMISTRY; METALLURGY
Abstract
The present invention relates to a method for the preparation of an N-monofluoroalkyl tropane, a method for the preparation of a trialkyltin tropane, a method for the preparation of an iodinated and/or radioiodinated tropane and the use of the N-monofluoroalkyl tropane as a precursor in the method for the preparation of the trialkyltin tropane and/or the iodinated and/or radioiodinated tropane.
Claims
1. A method for the preparation of an N-monofluoroalkyl tropane of formula (VI) ##STR00016## wherein n is 2, 3 or 4, comprising the steps: a) provision of a compound of formula (I) ##STR00017## b) reduction of the carbonyl group to a hydroxyl group to give the compound of formula (II) ##STR00018## c) dehydration reaction to give the compound of formula (III) ##STR00019## d) addition of a 4-bromophenyl moiety to give the compound of formula (IV) ##STR00020## e)N-demethylation to give the compound of formula (V) ##STR00021## f) alkylation with an alkylation agent of formula F—(CH.sub.2).sub.n—Br in the presence of a base to give the N-monofluoroalkyl tropane of formula (VI), wherein n is 2, 3 or 4.
2. The method of claim 1, wherein compound of formula (I) is provided according to step a) by addition of a carbomethoxy group in 2-position to a 3-tropinone according to formula (Ia) ##STR00022##
3. The method of claim 1, wherein the reduction of the carbonyl group to a hydroxyl group according to step b) is carried out using at least one reducing agent selected from hydrogen or sodium borohydride.
4. The method of claim 1, wherein the dehydration reaction according to step c) is carried out using a reagent selected from the group comprising phosphoryl chloride, hydrochloric acid, hydrobromic acid or 4-Dimethylaminopyridine, triethylamine and trifluoroacetic anhydride.
5. The method of claim 1, wherein the addition of a 4-bromophenyl moiety according to step d) is carried out by an organometallic reaction.
6. The method of claim 1, wherein the N-demethylation according to step e) is carried out using chloroethyl chloroformates or 2,2,2-Trichloroethoxycarbonyl chloride, Zinc and acetic acid.
7. The method of claim 1, wherein the base in step f) is potassium carbonate.
8. The method of claim 1 further comprising one chiral resolution.
9. The method of claim 8, wherein the chiral resolution is carried out by high-pressure liquid chromatography (HPLC) using a chiral stationary phase.
10. A method for the preparation of a trialkyltin tropane of formula (VII) ##STR00023## wherein n is 2, 3 or 4, wherein R is a C1 to C4 alkyl group, comprising the steps: i) carrying out the method of claim 1 to give the N-monofluoroalkyl tropane of formula (VI), ii) reaction of the compound of formula (VI) from step (i) with Sn.sub.2R.sub.6 in the presence of at least one catalyst to give the trialkyltin tropane of formula (VII), wherein R is a C1 to C4 alkyl group.
11. A method for the preparation of an iodinated and/or radioiodinated tropane of formula (VIII) ##STR00024## wherein n is 2, 3 or 4, wherein .sup.xI is at least one iodine isotope, comprising the steps: (1) carrying out the method of claim 1 to give the N-monofluoroalkyl tropane of formula (VI), (2) preparing a trialkyltin tropane of formula (VII), ##STR00025## wherein n is 2, 3 or 4, wherein R is a C1 to C4 alkyl group, comprising reaction of the compound of formula (VI) from step (1) with Sn.sub.2R.sub.6 in the presence of at least one catalyst to give the trialkyltin tropane of formula (VII), wherein R is a C1 to C4 alkyl group, (3) reacting the trialkyltin tropane of formula (VII) from step (2) with a supply of .sup.xI in the presence of at least one oxidizing agent to give the iodinated and/or radioiodinated tropane of formula (VIII), wherein .sup.xI is at least one iodine isotope.
12. The method of claim 11, wherein .sup.xI is .sup.123I.
13. The method of claim 11, further comprising preparation of a pharmaceutical composition.
14. A method of diagnosing Parkinson's disease comprising administering to a subject the iodinated and/or radioiodinated tropane of formula (VIII) prepared according to claim 11.
15. The method of claim 2, wherein the reduction of the carbonyl group to a hydroxyl group according to step b) is carried out using at least one reducing agent selected from hydrogen or sodium borohydride.
16. The method of claim 15, wherein the dehydration reaction according to step c) is carried out using a reagent selected from the group comprising phosphoryl chloride, hydrochloric acid, hydrobromic acid or 4-Dimethylaminopyridine, triethylamine and trifluoroacetic anhydride.
17. The method of claim 16, wherein the addition of a 4-bromophenyl moiety according to step d) is carried out by an organometallic reaction.
18. The method of claim 17, wherein the N-demethylation according to step e) is carried out using chloroethyl chloroformates or 2,2,2-Trichloroethoxycarbonyl chloride, Zinc and acetic acid.
19. The method of claim 18, wherein the base in step f) is potassium carbonate.
20. The method of claim 1 further comprising one chiral resolution, wherein the chiral resolution is performed after the alkylation in step f), and is carried out by high-pressure liquid chromatography (HPLC) using a chiral stationary phase.
Description
[0089] The present invention will now be further explained by the following non-limiting figures and examples.
[0090]
[0091]
[0092]
[0093]
[0094]
[0095]
[0096]
Example 1: Synthesis of 2-Carbomethoxytropinone (I, Methyl 8-Methyl-3-Oxo-8-Azabicyclo[3.2.1]Octane-4-Carboxylate)
[0097] Under argon atmosphere, a solution of dimethyl carbonate (2.2 eq.) in cyclohexane is added to sodium hydride (2 eq.) and heated up to 70° C. After slowly addition of a tropinone (1 eq.) solution in cyclohexane, the temperature is increased to reflux. The suspension is refluxed under argon atmosphere for 30 min and then a catalytic amount of methanol is added carefully. Afterwards, the reaction mixture is refluxed for 4 h. After cooling to room temperature, the suspension is quenched and extracted using an aqueous solution of ammonium chloride. The cyclohexane phase is additionally extracted using water. Then the aqueous phase is extracted several times with chloroform. The combined chloroform phases are dried using magnesium sulfate and filtered. Rotary evaporator leads to a brown, oily product.
[0098] Yield: 89%
Example 2: Synthesis of Methyl 3-Hydroxy-8-Methyl-8-Azabicyclo[3.2.1]Octane-2-Carboxylate (II)
[0099] The synthesized 2-carbomethoxytropinone (I, 1 eq.) is directly used in the synthesis of (II). Therefore, 2-carbomethoxytropinone is dissolved in methanol and cooled to≤30° C., after which sodium borohydride (3 eq.) is added. After reaction the mixture is slowly warmed up and added to ammonium chloride. Rotary evaporator leads to a yellow suspension, which is taken up in water. Subsequently, concentrated ammonia is used to basify the mixture. Afterwards, the mixture is extracted with chloroform. The combined organic phases are dried using magnesium sulfate and filtered. Rotary evaporator leads to an oily residue.
[0100] Yield: 87%
Example 3: Synthesis of Methyl 8-Methyl-8-Azabicyclo[3.2.1]Oct-2-Ene-2-Carboxylate (III)
[0101] Dimethyl aminopyridine (0.02 eq.) and triethylamine (2.9 eq.) are added to a solution of methyl 3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (II; 1 eq.) in dichlormethane. The reaction mixture is cooled down (≤−30° C.) and trifluoroacetic anhydride (1.3 eq.) is added dropwise. After stirring at room temperature (>72 hours), an aqueous potassium carbonate solution is added. The mixture is extracted with chloroform for several times. The combined organic phases are dried over magnesium sulfate, filtered and concentrated using rotary evaporator. The residue is extracted two times by a mixture of n-hexane, chloroform and magnesium sulfate and then filtered, respectively. The combined extracts are concentrated using rotary evaporator. Purification of the crude product is performed by column chromatography under basic conditions. The product fractions are concentrated using rotary evaporator. The product is characterized by .sup.1H NMR spectroscopy.
[0102] Yield: 33%
[0103] .sup.1H NMR (400.0 MHz, CDCl.sub.3, 298 K): δ 1.50 (m, 1H), 1.82 (m, 2H), 2.15 (m, 2H), 2.34 (s, 3H), 2.62 (d, 1H), 3.23 (t, 1H), 3.73 (s, 3H), 3.78 (d, 1H), 6.81 ppm (t, 1H).
Example 4: Synthesis of Methyl 3-(4-Bromophenyl)-8-Methyl-8-Azabicyclo[3.2.1]Octane-2-Carboxylate (IV)
[0104] Under argon atmosphere 1,4-dibromobenzene (2.1 eq.) is dissolved in dried diethyl ether and stirred, while magnesium (2 eq.) is added under argon flow. The mixture is heated at reflux and stirred for 1 hrs. Afterwards, the reaction mixture is cooled down to −45° C. and a solution of methyl 8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate (III, 1 eq.) in dichloromethane is added dropwise. After stirring for ≥3 hours at −45° C., the reaction mixture is quenched with a solution of trifluoracetic acid (2.1 eq.) in dichloromethane at −78° C. After complete addition, the reaction mixture is slowly warmed up by stirring in the cooling bath. A 1N hydrochloric acid is added to the reaction mixture and stirred for 15 min, whereby the pH is <2. The acidic aqueous phase is washed with diethyl ether. Afterwards, concentrated ammonia is used to basify the aqueous phase, which is then extracted with dichloromethane several times. The combined organic phase is dried using magnesium sulfate, filtered and concentrated using rotary evaporator. Purification of the crude product is performed by column chromatography under basic conditions. The product fractions are concentrated using rotary evaporator. Final purification is performed by crystallization. The colourless solid is isolated and dried in vacuum. The product is characterised by .sup.1H NMR spectroscopy.
[0105] Yield: 40%
[0106] .sup.1H NMR (400.0 MHz, CDCl.sub.3, 298 K): δ 1.66 (m, 3H), 2.15 (m, 5H), 2.55 (t, 1H), 2.87 (t, 1H), 2.94 (m, 1H), 3.36 (m, 1H), 3.50 (s, 3H), 3.56 (m, 1H), 7.13 (d, 2H), 7.38 ppm (d, 2H)
Example 5: Synthesis of Methyl 3-(4-Bromophenyl)-8-Azabicyclo[3.2.1]Octane-2-Carboxylate (V)
[0107] Under argon atmosphere methyl 3-(4-bromophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (IV, 1 eq.) is dissolved in dried 1,2-dichloroethane and 1-chloroethyl chloroformate (4 eq.) is added. The solution is stirred for 16 hours at reflux. Then, the second portion of 1-chloroethyl chloroformate (1 eq.) is added and the solution is refluxed for one hour. After cooling to room temperature, the solvent is removed using rotary evaporator. The residue is dissolved in methanol and stirred for 2 hours at reflux. After evaporation of the solvent, a saturated aqueous sodium hydrogen carbonate solution is added, and the aqueous phase is extracted with dichloromethane several times. The combined organic phase is dried using magnesium sulfate, filtered and concentrated using rotary evaporator.
[0108] Yield: Quantitative
Example 6: Synthesis of (1R,2S,3S,5S)-Methyl 3-(4-Bromophenyl)-8-(3-Fluoropropyl)-8-Azabicyclo[3.2.1]Octane-2-Carboxylate (VI)
[0109] Potassium carbonate (2.2 eq.) is added to a solution of methyl 3-(4-bromophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate (V, 1 eq.) in acetonitrile and stirred for 5 min. 1-Bromo-3-fluoropropane (1.2 eq.) is added and stirred for 3 hours at reflux after which the second portion of 1-bromo-3-fluoropropane (0.12 eq.) is added and stirred for an additional time of 1 hour at reflux. After cooling to room temperature water is added and the aqueous phase is extracted with ethyl acetate. The combined organic phase is dried using magnesium sulfate, filtered and concentrated using rotary evaporator. Purification of the crude product is performed by column chromatography under basic conditions. The product fractions are concentrated using rotary evaporator. Final purification is performed by crystallization. The colorless solid is isolated and dried in vacuum.
[0110] Yield: 70%
[0111] The racemic resolution is performed with preparative HPLC. The oily enantiomeric pure product is solidified by crystallization. The product is characterized by .sup.1H NMR and .sup.19F NMR spectroscopy, melting point, HPLC for ee-value, mass spectrometry as well as qNMR.
[0112] Yield: 72%
[0113] .sup.1H NMR (400.0 MHz, CDCl.sub.3, 298 K): δ 1.70 (m, 5H), 2.05 (m, 2H), 2.37 (m, 2H), 2.54 (t, 1H), 2.89 (s, 1H), 2.96 (m, 1H), 3.38 ppm (s, 1H), 3.49 (s, 3H), 3.68 (s, 1H), 4.52 (dt, 2H), 7.13 (d, 2H), 7.38 ppm (d, 2H);
[0114] .sup.19F NMR (376.3 MHz, CDCl.sub.3, 298 K): δ−221.2 ppm;
[0115] ESI-MS: m/z=384, 386;
[0116] m.p. 86° C.;
[0117] ee-value by HPLC: 100%;
[0118] assay determined by qNMR: 99.7%
Example 7: Synthesis of (1R,2S,3S,5S)-Methyl 8-(3-Fluoropropyl)-3-[4-(Trimethylstannyl)Phenyl]-8-Azabicyclo[3.2.1]Octane-2-Carboxylate (VII)
[0119] Under argon atmosphere, hexamethylditin (1.9 eq.) dissolved in toluene (45±5 mL.Math.g.sup.−1) is added to a solution of methyl 3-(4-bromophenyl)-8-(3-fluoropropyl)-8-azabicyclo[3.2.1]octane-2-carboxylate (VI, 1 eq.) in toluene (25±5 mL.Math.g.sup.−1). To the resulting mixture, tetrakis(triphenyl-phosphine)palladium(0) (0.18 eq.) is added and the solution is refluxed for at least one hour. The reaction mixture is cooled to room temperature and then filtered, whereby the resulting solution is concentrated using rotary evaporator. The crude product is purified by preparative HPLC under basic conditions. Subsequently, the fractions containing the target compound are dried in vacuum using rotary evaporator and then dried by lyophilization, whereby a colorless oil is obtained.
[0120] Yield: 15% to 40%
[0121] .sup.1H NMR (400.0 MHz, CDCl.sub.3, 298 K): δ 0.25 (s, 9H), 1.70 (m, 5H), 2.05 (m, 2H), 2.37 (m, 2H), 2.59 (dt, 1H), 2.93 (m, 1H), 3.00 (m, 1H), 3.39 ppm (m, 1H), 3.49 (s, 3H), 3.67 (m, 1H), 4.52 (dt, 2H), 7.24 (d, 2H), 7.40 ppm (d, 2H);
[0122] .sup.19F NMR (376.3 MHz, CDCl.sub.3, 298 K): δ−221.1 ppm;
[0123] ESI-MS: m/z=466, 468, 470;
[0124] ee-value by HPLC: 100%
Example 8: Synthesis of (1R,2S,3S,5S)-Methyl 8-(3-Fluoropropyl)-3-(4-[.SUP.123 .l]Iodophenyl)-8-Azabicyclo[3.2.1]Octane-2-Carboxylate (VIII)
[0125] The alkaline solution of [.sup.123I]iodide is transferred from the concentration unit to the reaction vessel. The pH value is adjusted and the carrier added by the addition of [.sup.127I]iodide solved in phosphate buffer (total amount of iodide varies). Subsequently, (1R,2S,3S,5S)-methyl 8-(3-fluoropropyl)-3-[4-(trimethylstannyl)phenyl]-8-azabicyclo[3.2.1]octane-2-carboxylate (VII, 1 eq.) dissolved in ethanol and chloramine-T (55 eq.) dissolved in water for injection (WFI) are added consecutively to the reaction vessel. The reaction mixture is stirred at 30° C. for ≥1 minute. Afterwards, sodium metabisulfite (279 eq.) dissolved in water is added to the reaction vessel and stirred. Purification is performed using preparative HPLC. The product fraction is isolated, formulated and then portioned into vials.
CITED NON-PATENT LITERATURE
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