Compounds for use in imaging, diagnosing and/or treatment of diseases of the central nervous system or of tumors
09682944 ยท 2017-06-20
Assignee
Inventors
- Lutz Lehmann (Berlin, DE)
- Andrea Thiele (Berlin, DE)
- Tobias Heinrich (Berlin, DE)
- Thomas Brumby (Berlin, DE)
- Christer HALLDIN (Stockholm, SE)
- Balazs Gulyas (Solna, SE)
- Sangram Nag (Huddinge, SE)
Cpc classification
A61K49/0433
HUMAN NECESSITIES
A61P29/00
HUMAN NECESSITIES
C07D291/08
CHEMISTRY; METALLURGY
C07B59/00
CHEMISTRY; METALLURGY
C07C2602/08
CHEMISTRY; METALLURGY
A61P9/10
HUMAN NECESSITIES
A61P43/00
HUMAN NECESSITIES
A61P1/00
HUMAN NECESSITIES
A61P25/28
HUMAN NECESSITIES
C07D307/52
CHEMISTRY; METALLURGY
A61K51/00
HUMAN NECESSITIES
C07C211/42
CHEMISTRY; METALLURGY
International classification
C07D307/52
CHEMISTRY; METALLURGY
C07B59/00
CHEMISTRY; METALLURGY
C07D291/08
CHEMISTRY; METALLURGY
Abstract
This invention relates to novel compounds suitable for labelling or already labelled by .sup.18F, methods of preparing such a compound, compositions comprising such compounds, kits comprising such compounds or compositions and uses of such compounds, compositions or kits for diagnostic imaging by positron emission tomography (PET).
Claims
1. A compound of formula Ib ##STR00045## wherein W is C(U.sup.1)(U.sup.2)CCH, U.sup.1 and U.sup.2 are each being independently selected from hydrogen and deuterium, G.sup.3 is hydrogen, G.sup.4 is L, L is a leaving group or is F, n is an integer from 0 to 6, and e and f are each independently an integer from 0 to 1, with the proviso that at least one of e and f is 1, including all isomeric forms of said compound, including but not limited to enantiomers and diastereoisomers as well as racemic mixtures, or a pharmaceutically acceptable salt, ester, amide, complex or prodrug thereof.
2. The compound according to claim 1, wherein W is CH.sub.2CCH.
3. The compound according to claim 1, wherein L is a leaving group selected from halo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, nona-fluorobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl) sulfonyloxy, (4-isopropyl-phenyl) sulfonyloxy, (2,4,6-tri-isopropyl-phenyl)sulfonyloxy, (2,4,6-trimethyl-phenyl)sulfonyloxy, (4-tertbutyl-phenyl)sulfonyloxy, and (4-methoxy-phenyl)sulfonyloxy.
4. The compound according to claim 3, wherein L is selected from chloro, bromo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, and (2,4,6-tri-isopropyl-phenyl) sulfonyloxy.
5. The compound according to claim 1 wherein L is a leaving group.
6. The compound according to claim 1, wherein L is .sup.18F.
7. The compound according to claim 1, wherein L is .sup.19F.
8. A method of synthesis of a compound according to claim 1 wherein L is .sup.18F or .sup.19F, said method comprising reacting a compound according to formula 1b in which L is a leaving group with an F-fluorinating agent in which F is .sup.18F or .sup.19F.
9. The method according to claim 8, wherein said F-fluorinating agent is selected from 4, 7, 13, 16, 21, 24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane KF, KF, HF, KH F.sub.2, CsF, NaF and tetraalkylammonium salts of F, and wherein F=.sup.18F or 19F.
10. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
11. A composition comprising a compound according to claim 6 and a pharmaceutically acceptable carrier or diluent.
12. A composition comprising a compound according to claim 7 and a pharmaceutically acceptable carrier or diluent.
13. A compound according to claim 1 for use as a pharmaceutical or diagnostic agent or imaging agent.
14. A compound according to claim 6 for use as a diagnostic agent or imaging agent.
15. A kit comprising a sealed vial containing a predetermined quantity of a compound according to claim 5.
16. A method for detecting the presence of monoamine oxidase in a patient's body comprising: introducing into a patient's body a detectable amount of a compound according to claim 6, and detecting said compound by positron emission tomography (PET).
17. A method of treatment of a disease of the central nervous system associated with monoamine oxidase regulation, said method comprising the step of introducing into a patient a suitable quantity of a compound according to claim 1.
18. A compound according to claim 1, wherein L is .sup.18F or .sup.19F.
19. A compound according to claim 1, wherein n is an integer from 0 to 3.
20. A compound according to claim 1, wherein n is an integer from 0 to 2.
21. The compound according to claim 1, wherein L is a leaving group selected from chloro, bromo, iodo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, nona-fluorobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, (2,4,6-tri-isopropyl-phenyl)sulfonyloxy, (2,4,6-trimethyl-phenyl)sulfonyloxy, (4-tertbutyl-phenyl)sulfonyloxy, and (4-methoxy-phenyl) sulfonyloxy.
22. The compound according to claim 1, wherein said compound is: ##STR00046##
23. A method for preparing a compound according to claim 1, comprising reacting a compound selected from the following compounds: ##STR00047## with an F-fluorinating agent.
24. The method according to claim 16, wherein said method is for imaging a disease of the central nervous system in said patient.
25. The method according to claim 17, wherein L in said compound is .sup.18F.
26. The method according to claim 17, wherein L in said compound is .sup.19F.
27. The compound according to claim 1, wherein U.sup.1 and U.sup.2 are each deuterium.
28. The method according to claim 8, wherein said F-fluorinating agent is 4,7,13,16,21,24-Hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane OF, OF, H.sup.18F, KH.sup.18F.sub.2, Cs.sup.18F, Na.sup.18F or a tetraalkylammonium salt of .sup.18F.
29. The compound according to claim 1, wherein said compound is selected from the following compounds: ##STR00048##
30. The compound according to claim 1, wherein said compound is selected from the following compounds: ##STR00049##
31. The compound according to claim 1, wherein said compound is selected from the following compounds: ##STR00050##
32. The compound according to claim 1, wherein said compound is selected from the following compounds in which the H atoms in the CH.sub.2 group of the CH.sub.2CCH structure are replaced by deuterium: ##STR00051##
33. The compound according to claim 1, wherein said compound is selected from the following compounds in which the H atoms in the CH.sub.2 group of the CH.sub.2CCH structure are replaced by deuterium: ##STR00052##
34. The compound according to claim 1, wherein said compound is selected from the following compounds in which the H atoms in the CH.sub.2 group of the CH.sub.2CCH structure are replaced by deuterium: ##STR00053##
Description
DESCRIPTION OF THE FIGURES
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EXPERIMENTAL
(17) General Procedures:
(18) A: Fluorination with Non-Radioactive [F-19] Fluoride
(19) To a solution of 0.25 mmol starting material in 0.5 ml acetonitril 16 mg (0.27 mmol) potassium fluoride and 104 mg (1.1 eq.) kryptofix are added. The reaction mixture is heated by microwave (130 C., 15 min) and cooled to room temperature again. The reaction mixture is diluted with 10 ml diethyl ether and 10 ml water. The organic phase is separated. The aqueous phase is extracted three times with 10 ml diethyl ether. The combined organic phases are washed with brine and dried with magnesium sulfate. The solvent is evaporated and the residue is purified by column chromatography with ethyl acetate-hexane gradient.
(20) B: Fluorination with Radioactive [F-18] Fluoride
(21) To a Wheaton vial (5 ml) charged with 2.5 mg Kryptofix (2.2.2Kryptand) in 0.75 ml acetonitrile and 0.5 mg potassium carbonate and the fluorine containing water (0.5-2.5 GBq, 200-300 l) is added. The solvent is removed by heating at 120 C. for 10 mins under a stream of nitrogen. Anhydrous MeCN (1 ml) is added and evaporated as before. This step is repeated again. A solution of starting material (2 mg) in 0.70 ml anhydrous MeCN is added. After heating at 110 C. for 30 min. The crude reaction mixture is analyzed using analytical HPLC: ACE3-C18 50 mm4.6 mm; solvent gradient: start 5% acetonitril-95% acetonitril in water in 7 min., flow: 2 ml/min. The desired F-18 labeled product is confirmed by co-injection with the corresponding non-radioactive F-19 fluoro-standard on the analytical HPLC. The crude product (50-400 MBq) is purified by preparative HPLC column: The desired product is obtained (15-200 MBq) as reconfirmed by co-injection with the non-radioactive F-19 fluoro standard on the analytical HPLC.
(22) C: Fluorination with [F-18] Fluoride
(23) A solution of [.sup.18F]fluoride in [.sup.18O] enriched water was flashed through a Sep-Pak QMA light cartridge (preconditioned with K.sub.2CO.sub.3 [0.5 M, 10 mL], 18 M H2O, 15 mL) to isolate [.sup.18F]fluoride which was then eluted from the cartridge with a solution of K.sub.2CO.sub.3 (7 mol), Kryptofix 2.2.2 (130 mol) in water (18 M, 43 L) and acetonitrile (2 mL). The solvent was evaporated at 160 C. under continues nitrogen flow and a yellow residue of [.sup.18F]F.sup./K.sub.2CO.sub.3/K.sub.2.2.2 was left. The residue was then cooled to 25 C. and the precursor (0.01 mmol, 2 mg) in DMSO (600 L) was added. The closed reaction vessel was heated at 120 C. for 20 min and cooled down to room temperature. The reaction mixture was generally diluted with water to a total volume of 5 mL before HPLC purification.
(24) E.g., F-18 labelled compounds 13, 39, 8 and 40 were also purified by reverse phase HPLC on a -Bondapak C-18 column (3007.8 mm, 10 m; waters instruments) and MeCNH.sub.3PO.sub.4 (0.01 M) (15:85 v/v) was used as the eluting solvent at a flow rate of 4 mL/min (compare
(25) The stability and radiochemical yield was analyzed with HPLC and TLC on silica gel. TLC plate was scanned with an AR-2000 Imaging Scanner and analyzed with Winscan 2.2 software. The incorporation yield of the fluorination reaction varied from 40% to 70%. The radiochemical purity was more than 99% for all three radioligands. Radioligands were found to be stable in PBS buffer solution for the duration of experiments. Radiochemical purity was >99% at 3 h after formulation with PBS which was determined by HPLC and TLC. Alternatively, compound 13 and 39 were also separated via an preparative HPLC column and method (comp.
(26) D: Alkylation of NH-Carbamate with [F-18] Labeled Prosthetic Group
(27) To a suspension of 1 ml dry tetrahydrofuran (THF) and 7.7 mmol sodium hydridewhich has been washed with hexane7 mmol starting material in 1 ml THF is added dropwisely. The reaction mixture is stirred for 20 min. The prepared [F-18]-fluoro-alkyl bromide (100-500 GBq; known from literature) in tetrahydrofuran is dropped into the suspension. The reaction is heated to 50 C. for 20 min. The vigorously reaction mixture is cooled to room temperature. The crude reaction mixture is analyzed using analytical HPLC. The desired F-18 labeled product is confirmed by co-injection with the non-radioactive F-19 fluoro-standard on the analytical HPLC.
(28) E: Fluorination with [F-18] Fluoride Using Tetrabutylammonium Hydroxide and Subsequent Deprotection
(29) compare also: J. Med. Chem. 2007, 50, 1028-1040.
(30) [.sup.18F]fluoride was transferred to a Vacutainer that had previously been treated with tetrabutylammonium hydroxide (2 micro liter). The [.sup.18O] H.sub.2O was removed by azeotropic distillation with acetonitrile (3_times 0.75 mL), N.sub.2, and heat (compare Nucl. Med. Biol. 2003, 30, 397-404). Precursor (3.0 micro mol) was added to the vessel and dissolved in DMSO (400 micro liter). The resulting mixture was heated by microwave irradiation (3 times for 20 sec). The crude mixture was passed over a silica pipet column (50 mg) with CH.sub.3CN (3 mL), and the volatile organics were then removed using reduced pressure. The vial containing a crude mixture of [.sup.18F]product was dissolved in CH.sub.3CN (500 micro L) and was treated with 4N sulfuric acid (0.5 ml). The resulting mixture was heated by microwave irradiation (3 times for 20 sec). The desired product was separated via an preparative HPLC column and method: ACE 5-C18-HL 250 mm10 mm, Advanced Chromatography Technologies; Cat. No.: ACE 321-2510; isocratic, 35% acetonitrile in 0.1% trifluoroacetic acid, flow: 4 ml/min). The collected HPLC fraction was diluted with 40 ml water and immobilized on a Sep-Pak Plus C18 cartridge (Waters), which was washed with 5 ml water and eluted with 1 ml ethanol to deliver compound 13 in a radiochemical purity >99%. The desired product 13 was characterized by co-injection with the non-radioactive F-19 fluoro standard 12 on the analytical HPLC.
(31) F: Alkylation of NH-Carbamate
(32) To a stirred suspension of 20 ml dry DMF and 11 mmol sodium hydridewhich has been washed with hexane10 mmol starting material in 5 ml DMF is added dropwisely at 0 C. The reaction mixture is stirred for 20 min. 15 mmol alkylation agent diluted in 5 ml tetrahydrofuran is added dropwisely to the stirred suspension. The reaction mixture is stirred for 16-10 hours. The reaction mixture is poured onto a vigorously stirred mixture of ice-water and diethyl ether. The organic phase is separated. The aqueous phase is extracted three times with 30 ml diethyl ether. The combined organic phases are washed with brine and dried with magnesium sulfate. The solvent is evaporated and the residue is purified by column chromatography with ethyl acetate-hexane gradient.
(33) G: Alkylation of NH-Amine with [F-18] Labeled Prosthetic Group
(34) To a solution 2 mg secondary amine (starting material) and 3 mg potassium carbonate in 0.7 ml dimethyl formamide was added [F-18]fluoro-alkylating agent (ca. 200-1000 MBq) in dimethyl formamide prepared from literature protocol. The reaction mixture is heated to 110 C. for 20 min. The reaction mixture is cooled to room temperature. The desired F-18 labeled product is confirmed by co-injection with the non-radioactive F-19 fluoro-standard on the analytical HPLC. The crude product (ca. 50-400 MBq) is purified by preparative HPLC column. The desired product is obtained (ca. 15-200 MBq) as reconfirmed by co-injection with the non-radioactive F-19 fluoro standard on the analytical HPLC.
(35) H: Alkylation of NH-Amine (Secondary Amine) or Phenols
(36) To a stirred solution of 2 mmol starting material and 0.415 g (3 mmol) potassium carbonate in 6 ml dimethyl formamide was added 2.5 mmol alkylating agent. The reaction mixture was heated by microwave to 110 C. for 15 min. The solvent of the reaction mixture is evaporated. Water (8 ml) and diethylether or dichloromethane/isopropanol mixture (1:10-8 ml) are added. The organic phase is separated. The aqueous phase is extracted three times with 30 ml diethyl ether. The combined organic phases are washed with water (twice ca. 5 ml), brine and dried with magnesium sulfate. The solvent is evaporated and the residue is purified by column chromatography with ethyl acetate-hexane gradient.
(37) I: Conversion of Alcohol to Corresponding O-Sulfonate (Version 1)
(38) To a solution of 0.5 mmol starting material and 0.103 g (0.8 mmol) diisopropyl ethyl amine in 1.5 ml dichloromethane was added (0.6 mmol) mesyl chloride or mesyl anhydride in 0.1 ml dichloromethane dropwise at 10 C. The stirred reaction mixture was warmed over a period of 4.5 h to room temperature and diluted with dichloromethane. The organic phase was washed with saturated sodium hydrogen carbonate solution, water and brine. The organic phase was dried with magnesium sulfate. The crude product was purified by silica column chromatography (ethyl acetate-hexane gradient).
(39) K: Conversion of Alcohol to Corresponding O-Sulfonate (Version 2)
(40) To a solution of 3 mmol starting material in 5 ml dichloromethane and 5 ml pyridine was added (3.3 mmol) aryl sulfonyl chloride in 3 ml dichloromethane dropwisely at 10 C. The stirred reaction mixture was warmed over a period of 4.5 h to room temperature and diluted with dichloromethane. The organic phase was washed with 0.5N sulfuric acid (three times), saturated sodium hydrogen carbonate solution, water and brine. The organic phase was dried with magnesium sulfate. The crude product was purified by silica column chromatography (ethyl acetate-hexane gradient).
(41) M: Deprotection of Acid Labile Protecting Group (Version 1)
(42) A solution of 5 mmol starting material in wet trifluoro acetic acid-dichloromethane mixture (1:1) was stirred for 4-7 hours. The reaction mixture is evaporated. The residue is solved in dichloromethane and the solution is evaporated again. The last step is repeated three times. The residue is purified by column chromatography (dichloromethanepentane gradient, amino phase).
(43) N: Deprotection of Acid Labile Protecting Group (Version 2)
(44) (According to J. Am. Chem. Soc., 6644, 92, (1970))
(45) To a stirred solution of 0.5 mmol starting material in 1 ml ethanol is added 1 ml of 3N aqueous hydrogen chloride at 0 C. The solution is stirred for 16 h at room temperature. The reaction is treated with NaOH aq. (4N) until pH=9.5. Ethanol is evaporated. Water (10 ml) and dichloromethan-isopropanol (10 ml; 10:1) are added. The organic phase is separated. The aqueous phase is extracted three times with 10 ml dichloromethan-isopropanol (10:1). The combined organic phases are washed with brine and dried with magnesium sulfate. The solvent is evaporated and the residue is purified by column chromatography with ether-pentane gradient or by preparative HPLC methods.
(46) P: Reduction of Acids to Alcohols Via Mixed Anhydride
(47) According to Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15, p. 4544, compound 94. A stirred solution of 11 mmol carboxylic acid (start material) and triethylamine (1.9 mL, 14 mmol) in THF (300 mL) was added ethyl chloroformate (13 mL, 14 mmol) at 5 C. The mixture was stirred for 20 min, and then sodium borohydride (1.72 g, 44 mmol) and methanol (32 mL) were added consecutively. The mixture was stirred for 30 min at 5 C., and then saturated NH.sub.4Cl was added to quench the reaction. The mixture was extracted with Et2O (ca. 50 ml), and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated. Flash chromatography (hexane/AcOEt 1/1) of the residue gave the desired product.
(48) Q: Reduction of Oxazolidinones Towards N-Methyl Amino-Alcohols
(49) To a stirred solution of 5 mmol starting material (oxazolidinone) in 10 ml THF were added 10 mmol lithium aluminium hydride at 0 C. The reaction suspension was stirred for 4 h at room temperature. The vigorously stirred reaction mixture was treated dropwisely with 10 ml of a 1 m NaOH(aq) solution. The reaction mixture was stirred for 30 min and filtered. The filtrate was concentrated and the residue was purified by silica chromatography (ethyl acetate/hexane gradients).
(50) S: Reduction of Esters Towards Alcohols
(51) To a solution of 15 mmol (555 mg) NaBH4 in 15 ml water/THF (1:1) is added 10 mmol ester (starting material), dissolved in 20 ml THF, drop by drop. The reaction mixture is stirred for 4 hours. The reaction mixture is poured into stirred mixture of ice-cold water and diethyl ether (200 ml, 1:1). The organic phase is separated. The aqueous phase is extracted three times with 10 ml diethyl ether. The combined organic phases are washed with brine and dried with magnesium sulfate. The solvent is evaporated and the residue is purified by column chromatography with ethyl acetate-hexane gradient.
(52) T: Conversion of Alcohol to Corresponding Triflate
(53) According to Chem. Eur. J. (2007), 13, 115-134:
(54) Pyridine (0.25 ml, 3.13 mmol) and Tf.sub.2O (0.32 ml, 1.88 mmol) were successively added to a solution of starting material (1.34 mmol) in CH.sub.2Cl.sub.2 (50 mL) at 20 C. and the resulting mixture was stirred for 1 h at that temperature. The pale pink solution was transferred into a separation funnel containing aq. KHSO.sub.4 (30 mL, 10%) and ice. The aqueous layer was extracted with CH.sub.2Cl.sub.2, the combined organic phases were dried over Na.sub.2SO.sub.4, and the solvent was carefully evaporated while keeping the temperature at 0 C. The desired product is filtered through a silica bed using ethyl acetate hexane solvent mixture.
(55) U: Reduction of Mesylate Towards Alkane
(56) Similar to Org. Lett.; 2004; 6(24) pp 4439-4442:
(57) To a solution of starting material (0.5 mmol) in anhydrous ether (20 mL) was added lithium aluminium hydride (65 mg) at 0 C., stirred for 24 h at the same temperature. After addition of 0.263 ml 2M NaOH solution at 10 C. the reaction mixture was stirred for 30 min at room temperature and filtered. The filtrate was concentrated and the residue was used without further purification.
(58) V: Fluorination of Secondary Alcohol (DBU/NfF):
(59) According to Tetrahedron Letters, Vol. 36, No. 15, pp. 2611-2614, 1995:
(60) To a cooled solution of secondary alcohol (2.5 mmol) and DBU (1.12 mL, 7.5 mmol) in toluene (20 mmol), C.sub.4F.sub.9SO.sub.2F (nona-fluoro-butyl-sulfonyl-fluoride) (1.13 g, 3.75 mmol) was added with stirring at 0 C. After 1 h at 0 C., the reaction mixture was evaporated in vacuo and the residue chromatographed in hexane/ethylacetate gradient on a silica column.
(61) For the following examples, NMR spectra were recorded on 400 MHz, 600 MHz (.sup.1H), 100 MHz and 151 MHz (.sup.13C) NMR instruments. .sup.1H NMR spectra were referenced internally on CDCl.sub.3 (.sup.1H 7.26) and .sup.13C NMR spectra were referenced internally on CDCl.sub.3 (.sup.13C 77.20). Liquid chromatographic analysis (LC) was performed with a Merck-Hitachi gradient pump and a Merck-Hitachi, L-4000 variable wavelength UV-detector. A -Bondapak C-18 column (3007.8 mm, 10 m; waters instruments) was used with a flow of 2 ml/min. LC-MS was performed using a Waters Quattra-Tof Premier micro mass coupled with Waters Acquity UPLC instrument. The ionization mode used was electro spray positive ionization (ESI+). Analytical TLC was carried out on 0.25 mm silica gel plates.
(62) All solvents and chemicals were obtained from commercial sources and used without further purification.
Example 1
a) Synthesis of ((S)-1-Hydroxymethyl-2-phenyl-ethyl)-methyl-carbamic acid tert-butyl ester (Ia)
(63) S)-2-(tert-Butoxycarbonyl-methyl-amino)-3-phenyl-propionic acid (Fluka) is reduced according to general method P to obtain compound Ia in 80% yield (8.8 mmol, 2.34 g
(64) MS-ESI: 266 (M.sup.++1, 100).
(65) Elementary Analysis:
(66) TABLE-US-00001 Calculated: C 67.90% H 8.74% N 5.28% Determined: C 67.87% H 8.72% N 5.27%
b) Synthesis of (S)-2-Methylamino-3-phenyl-propan-1-ol (1b)
(67) Compound 1a is deprotected according to general procedure M to obtain compound 1b in 77% yield (630 mg, 3.8 mmol).
(68) MS-ESI: 166 (M.sup.++1, 100).
(69) Elementary Analysis:
(70) TABLE-US-00002 Calculated: C 72.69% H 9.15% N 8.48% Determined: C 72.66% H 9.13% N 8.47%
c) Synthesis of (S)-2-(Methyl-prop-2-ynyl-amino)-3-phenyl-propan-1-ol (1c)
(71) Compound 1c is synthesized according to general procedure H from starting material 1b using 2.5 mmol of propargyl bromide (298 mg). The desired compound is obtained in 60% yield (243 mg, 1.2 mmol).
(72) MS-ESI: 204 (M.sup.++1, 100).
(73) Elementary Analysis:
(74) TABLE-US-00003 Calculated: C 76.81% H 8.43% N 6.89% Determined: C 76.77% H 8.42% N 6.88%
d) Synthesis of Methanesulfonic acid (S)-2-(methyl-prop-2-ynyl-amino)-3-phenyl-propyl ester (1d)
(75) Compound 1d is synthesized by general procedure I from starting material 1c in 91% yield (126 mg, 0.45 mmol).
(76) MS-ESI: 282 (M.sup.++1, 100).
(77) Elementary Analysis:
(78) TABLE-US-00004 Calculated: C 59.76% H 6.81% N 4.98% Determined: C 59.78% H 6.82% N 4.99%
e) Synthesis of ((S)-1-Fluoromethyl-2-phenyl-ethyl)-methyl-prop-2-ynyl-amine (1e)
(79) Compound 1e is synthesized by general procedure A from starting material 1d in 48% yield (24 mg, 0.12 mmol).
(80) MS-ESI: 206 (M.sup.++1, 100).
(81) Elementary Analysis:
(82) TABLE-US-00005 Calculated: C 76.07% H 7.86% N 6.82% Determined: C 76.04% H 7.85% N 6.83%
f) Synthesis of ((S)[18F]1-Fluoromethyl-2-phenyl-ethyl)-methyl-prop-2-ynyl-amine (1e)
(83) Compound 1f is prepared from compound 1e by general procedure B. The desired product 1e is obtained with 254 MBq starting from 1.12 GBq F-18 fluoride (decay corrected).
g) Synthesis of (2S)-2-(methylamino)-3-phenylpropan-1-ol (1b)
(84) To a solution of N-methyl-L-phenylalanine (Sigma, 10 g, 55.8 mmol) in dry THF (600 mL) was added 3.18 g (83.7 mmol) lithium aluminium hydride at 5 C. The reaction mixture was stirred over night and cooled to 5 C. Additional 2.12 g (55.8 mmol) lithium alanate were added. The reaction mixture was refluxed overnight and cooled then to 5 C. To this mixture was added 21.5 ml NaOH solution (2N) drop by drop. and stirred at room temperature for additional 30 min. The mixture was filtered and the filtercake was washed with diethyl ether (50 mL). The filtrate was dried over MgSO.sub.4 and solvent was removed under reduced pressure to obtain the product 1b as light yellow solid.
(85) MS-ESI: 204 (M.sup.++1, 100).
(86) Elementary Analysis:
(87) TABLE-US-00006 Calculated: C 72.69% H 9.15% N 8.48% Determined: C 72.65% H 9.13% N 8.45%
h) Synthesis of a mixture of N-[(2S)-1-chloro-3-phenylpropan-2-yl]-N-methylprop-2-yn-1-amine (1h) and N-(2-chloro-3-phenylpropyl)-N-methylprop-2-yn-1-amine (1i)
(88) To a stirred solution of 1c (100 mg, 0.49 mmol) and triethyl amine (1.0 mmol), in THF (2 ml) was stirred at room temperature for 30 min. To the stirred mixture mesylchloride (0.60 mmol) was added drop wise at 7 C. and the reaction mixture was stirred at room temperature for additional 30 min. Saturated Na.sub.2CO.sub.3 solution (1 mL) was added and stirred for 30 more min. The organic layer was partitioned between CH2Cl2 (15 ml) and water (10 ml). The organic phase was separated and washed with saturated NaHCO.sub.3 (10 ml) and brine (10 ml) and dried over MgSO.sub.4 and filtered. The solvent was removed under reduced pressure to obtain the crude product as light yellow oil. The crude product was purified by silica-gel column chromatography (hexane/ether 3:1) and analyzed by NMR, HPLC and LC-MS. The final product was obtained as mixture of 1h and 1i.
(89) 1h:
(90) .sup.1H NMR (600 MHz, CHLOROFORM-d) ppm 2.21 (t, J=2.38 Hz, 1H) 2.38 (s, 3H) 2.73 (d, J=6.97 Hz, 2H) 2.95 (dd, J=14.31, 8.07 Hz, 1H) 3.23 (dd, J=14.31, 4.77 Hz, 1H) 3.43 (dd, J=10.45, 2.38 Hz, 2H) 4.10-4.18 (m, 1H) 7.28-7.35 (m, 5H)
(91) .sup.13C NMR (151 MHz, CHLOROFORM-d) ppm 34.77 (1C) 38.29 (1C) 43.58 (1C) 44.24 (s, 1C) 64.28 (1C) 73.37 (1C) 79.24 (1C) 126.38 (1C) 128.54 (1C) 129.24 (1C) 138.86 (1C)
(92) 1i
(93) .sup.1H NMR (600 MHz, CHLOROFORM-d) ppm 2.21 (t, J=2.38 Hz, 1H) 2.38 (s, 3H) 2.73 (d, J=6.97 Hz, 2H) 2.95 (dd, J=14.31, 8.07 Hz, 1H) 3.23 (dd, J=14.31, 4.77 Hz, 1H) 3.43 (dd, J=10.45, 2.38 Hz, 2H) 4.10-4.18 (m, 1H) 7.28-7.35 (m, 5H)
(94) .sup.13C NMR (151 MHz, CHLOROFORM-d) ppm 42.08 (1C) 42.33 (1C) 45.94 (1C) 60.43 (1C) 61.52 (1C) 73.49 (1C) 77.98 (1C) 126.76 (1C) 128.33 (1C) 129.50 (1C) 138.94 (1C)
i) Synthesis of N-[(2S)-1-fluoro-3-phenylpropan-2-yl]-N-methylprop-2-yn-1-amine (1e) and N-(2-fluoro-3-phenylpropyl)-N-methylprop-2-yn-1-amine (1k)
(95) To the stirred solution of 1c (300 mg, 1.48 mmol) in dichloromethane (5 mL) DAST (2.0 mmol) was added drop wise at 5 C. and the reaction mixture was stirred for additional 20 min at the same temperature. Saturated sodium carbonate (4.0 mL) was added to quench the untreated DAST. The organic layer was partitioned between CH2Cl2 (25 ml) and water (15 ml). The organic phase was separated and washed with brine (10 ml) and dried over MgSO.sub.4 and filtered. The solvent was removed under reduced pressure to obtain the crude product as light yellow oil. The crude product was purified by silica-gel column chromatography (hexane/ether 3:1) to obtain 1e and 1k as isolated products (compare TLC:
(96) 1e:
(97) .sup.1H NMR (600 MHz, CHLOROFORM-d) ppm 2.27 (t, 1H) 2.52 (s, 3H) 2.74 (dd, J=13.39, 10.09 Hz, 1H) 2.97-3.03 (m, 1H) 3.03-3.14 (m, 1H) 3.53 (t, J=2.75 Hz, 2H) 4.38 (ddd, J=47.32, 10.09, 4.95 Hz, 1H) 4.51 (ddd, J=48.05, 10.27, 2.57 Hz, 1H).
(98) .sup.13C NMR (151 MHz, CHLOROFORM-d) ppm 32.91 (d, J=6.13 Hz, 1C) 38.20 (d, J=1.67 Hz, 1C) 43.94 (d, J=2.23 Hz, 1C) 63.83 (d, J=17.54 Hz, 1C) 72.83 (1C) 80.15 (s, 1C) 82.27 (d, J=172.08 Hz, 1C) 126.31 (1C) 128.51 (1C) 129.24 (1C) 139.01 (1C).
(99) 1k:
(100) .sup.1H NMR (600 MHz, CHLOROFORM-d) ppm 2.21 (t, J=2.38 Hz, 1H) 2.37 (s, 3H) 2.59-2.72 (m, 2H) 2.90-3.01 (m, 2H) 3.41 (dd, J=4.95, 2.38 Hz, 2H) 4.75-4.89 (m, 1H) 7.20-7.32 (m, 5H).
(101) .sup.13C NMR (151 MHz, CHLOROFORM-d) ppm 39.66 (d, J=21.44 Hz, 1C) 42.40 (d, J=1.39 Hz, 1C) 46.30 (d, J=1.67 Hz, 1C) 58.53 (d, J=20.88 Hz, 1C) 73.37 (s, 1C) 78.22 (s, 1C) 92.84 (d, J=173.19 Hz, 1C) 126.63 (1C) 128.45 (1C) 129.37 (1C) 136.85 (d, J=4.46 Hz, 1 C).
j) Synthesis of N-[(2S)-1-(18F)fluoro-3-phenylpropan-2-yl]-N-methylprop-2-yn-1-amine (1f) and N-[2-(18F)fluoro-3-phenylpropyl]-N-methylprop-2-yn-1-amine (1m)
(102) The crude products 1f and 1m were obtained according to general procedure C. The products 1f and 1m were separated according to general procedure C and investigated separately after HPLC separation (compare HPLC chromatograms
Example 2
a) Synthesis of (4R,5S)-4-Methyl-5-phenyl-3-prop-2-ynyl-oxazolidin-2-one (2a)
(103) Compound 2a is synthesized from (4R,5S)-(+)-4-Methyl-5-phenyl-2-oxazolidinone (Aldrich) according to general procedure F using 15 mmol (1.79 g) propargyl bromide (Aldrich). Compound 2a is obtained in 76% yield (7.6 mmol, 1.61 g).
(104) MS-ESI: 216 (M.sup.++1, 100).
(105) Elementary Analysis:
(106) TABLE-US-00007 Calculated: C 72.54% H 6.09% N 6.51% Determined: C 72.52% H 6.11% N 6.52%
b) Synthesis of (1S,2R)-2-(Methyl-prop-2-ynyl-amino)-1-phenyl-propan-1-ol (2b)
(107) Compound 2b is synthesized by general procedure Q from starting material 2a in 89% yield (0.91 g, 4.5 mmol).
(108) MS-ESI: 204 (M.sup.++1, 100).
(109) Elementary Analysis:
(110) TABLE-US-00008 Calculated: C 76.81% H 8.43% N 6.89% Determined: C 76.82% H 8.41% N 6.88%
c) Synthesis of methanesulfonic acid (1S,2R)-2-(methyl-prop-2-ynyl-amino)-1-phenyl-propyl ester (2c)
(111) Compound 2c is synthesized by general procedure T from starting material 2b in 78% yield (352 mg, 1.05 mmol).
(112) MS-ESI: 336 (M.sup.++1, 100).
(113) Elementary Analysis:
(114) TABLE-US-00009 Calculated: C 50.14% H 4.81% N 4.18% Determined: C 50.17% H 4.82% N 4.16%
d) Synthesis of ((1R,2R)-[18F]-2-Fluoro-1-methyl-2-phenyl-ethyl)-methyl-prop-2-ynyl-amine (2d)
(115) Compound 2d is prepared from compound 2c by general procedure B. The desired product 2d is obtained with 198 MBq starting from 1.09 GBq F-18 fluoride (decay corrected).
e) Synthesis of ((1R,2R)-2-Fluoro-1-methyl-2-phenyl-ethyl)-methyl-prop-2-ynyl-amine (2e)
(116) Compound 2e is synthesized by general procedure V from starting material 2b in 58% yield (297 mg, 1.45 mmol).
(117) MS-ESI: 206 (M.sup.++1, 100).
(118) Elementary Analysis:
(119) TABLE-US-00010 Calculated: C 76.07% H 7.86% N 6.82% Determined: C 76.04% H 7.84% N 6.83%
f) Synthesis of N-[(1R,2R)-1-chloro-1-phenylpropan-2-yl]-N-methylprop-2-yn-1-amine (2f)
(120) To a stirred solution of 2b (120 mg, 0.54 mmol) and triethyl amine (1.0 mmol), in THF (2 ml) was stirred at room temperature for 30 min. To the stirred mixture mesylchloride (0.60 mmol) was added drop wise at 7 C. and the reaction mixture was stirred at room temperature for additional 30 min. Saturated Na.sub.2CO.sub.3 solution (1 mL) was added and stirred for 30 more min. The organic layer was partitioned between CH.sub.2Cl.sub.2 (15 ml) and water (10 ml). The organic phase was separated and washed with saturated NaHCO.sub.3 (10 ml) and brine (10 ml) and dried over MgSO.sub.4 and filtered. The solvent was removed under reduced pressure to obtain the crude product as light yellow oil. The crude product was purified by silica-gel column chromatography (hexane/ether 3:1).
(121) MS-ESI: 221 (M.sup.+35Cl+1, 82).
(122) Elementary Analysis:
(123) TABLE-US-00011 Calculated: C 70.42% H 7.27% Cl 15.99% N 6.32% Determined: C 70.38% H 7.25% Cl 15.97% N 6.30%
g) Synthesis of N-[(1S,2R)-1-(18F)fluoro-1-phenylpropan-2-yl]-N-methylprop-2-yn-1-amine (2g)
(124) The desired product (2g) was obtained from 2f according to the general procedure C.
Example 3
a) Synthesis of 4-Furan-2-ylmethyl-3-prop-2-ynyl-oxazolidin-2-one (3a)
(125) Compound 3a is synthesized according to general procedure F in 4 mmol scale from starting material 4-furan-2-ylmethyl-oxazolidin-2-one (J. Am. Chem. Soc.; 125; 42; 2003; 12694-12695). The desired compound 3a is obtained in 60% yield (2.4 mmol) using 6 mmol propagyl bromide as alkylating agent.
(126) MS-ESI: 205 (M.sup.++1, 100).
(127) Elementary Analysis:
(128) TABLE-US-00012 Calculated: C 64.38% H 5.40% N 6.83% Determined: C 64.41% H 5.41% N 6.82%
b) Synthesis of 3-Furan-2-yl-2-(methyl-prop-2-ynyl-amino)-propan-1-ol (3b)
(129) Compound 3b is synthesized by general procedure Q (half scale) from starting material 3a in 70% yield (338 mg, 1.75 mmol).
(130) MS-ESI: 194 (M.sup.++1, 100).
(131) Elementary Analysis:
(132) TABLE-US-00013 Calculated: C 68.37% H 7.82% N 7.25% Determined: C 68.37% H 7.81% N 7.26%
c) Methanesulfonic acid 3-furan-2-yl-2-(methyl-prop-2-ynyl-amino)-propyl ester (3c)
(133) Compound 3c is synthesized by general procedure I from starting material 3b in 88% yield (120 mg, 0.44 mmol).
(134) MS-ESI: 272 (M.sup.++1, 100).
(135) Elementary Analysis:
(136) TABLE-US-00014 Calculated: C 53.12% H 6.32% N 5.16% Determined: C 53.15% H 6.34% N 5.18%
d) Synthesis of 1-Fluoromethyl-2-furan-2-yl-ethyl)-methyl-prop-2-ynyl-amine (3d)
(137) Compound 3d is synthesized by general procedure A from starting material 3c in 61% yield (29.9 mg, 0.153 mmol).
(138) MS-ESI: 196 (M.sup.++1, 100).
(139) Elementary Analysis:
(140) TABLE-US-00015 Calculated: C 67.67% H 7.23% N 7.17% Determined: C 67.67% H 7.23% N 7.18%
e) Synthesis of (1-Fluoromethyl-2-furan-2-yl-ethyl)-methyl-prop-2-ynyl-amine (3e)
(141) Compound 3e is synthesized by general procedure A from starting material 3c with F-18 fluoride 0.96 GBq. The desired compound is obtained (124 MBq).
Example 4
a) Synthesis of (S)-4-Benzyl-3-prop-2-ynyl-oxazolidin-2-one (4a)
(142) Compound 4a is synthesized by general procedure F from starting material (S)-4-Benzyl-oxazolidin-2-one (Aldrich) in 72% yield (1.58 g, 7.2 mmol).
(143) MS-ESI: 216 (M.sup.++1, 100).
(144) Elementary Analysis:
(145) TABLE-US-00016 Calculated: C 72.54% H 6.09% N 6.51% Determined: C 72.51% H 6.08% N 6.53%
b) (S)-2-(Methyl-prop-2-ynyl-amino)-3-phenyl-propan-1-ol (4b)
(146) Compound 4b is synthesized by general procedure Q from 4a in 68% yield (690 mg, 3.4 mmol).
(147) MS-ESI: 204 (M.sup.++1, 100).
(148) Elementary Analysis:
(149) TABLE-US-00017 Calculated: C 76.81% H 8.43% N 6.89% Determined: C 76.78% H 8.41% N 6.90%
c) 4-Bromo-benzenesulfonic acid (S)-2-(methyl-prop-2-ynyl-amino)-3-phenyl-propyl ester (4c)
(150) Compound 4c is synthesized by general procedure K from 4b p-bromo-benzene sulfonyl chloride in 47% yield (1.58 g, 1.41 mmol).
(151) MS-ESI: 424 (M.sup.+Br-isotope 80+1, 76).
(152) TABLE-US-00018 Elementary analysis: C 54.03% H 4.77% N 3.32% Determined: C 54.03% H 4.77% N 3.32%
Example 5
a) Synthesis of (S)-4-[4-(2-Methoxymethoxy-ethoxy)-benzyl]-oxazolidin-2-one (5a)
(153) Compound 5a is synthesized by general procedure H from (S)-()-4-(4-hydroxybenzyl)-2-oxazolidinone (Tetrahedron; EN; 57; 39; 2001; 8313-8322) and 2-bromo-ethyl-methoxy-methyl-ether (Aldrich) at 10-fold scale in 77% yield (15.4 mmol, 4.33 g).
(154) MS-ESI: 282 (M.sup.++1, 100).
(155) Elementary Analysis:
(156) TABLE-US-00019 Calculated: C 59.78% H 6.81% N 4.98% Determined: C 59.81% H 6.83% N 4.97%
b) Synthesis of (S)-4-[4-(2-Methoxymethoxy-ethoxy)-benzyl]-3-prop-2-ynyl-oxazolidin-2-one (5b)
(157) Compound 5b is synthesized by general procedure F from compound 5a in 65% yield (6.5 mmol, 2.07 g).
(158) MS-ESI: 320 (M.sup.++1, 100).
(159) Elementary Analysis:
(160) TABLE-US-00020 Calculated: C 63.94% H 6.63% N 4.39% Determined: C 63.92% H 6.64% N 4.40%
c) Synthesis of (S)-3-[4-(2-Methoxymethoxy-ethoxy)-phenyl]-2-(methyl-prop-2-ynyl-amino)-propan-1-ol (5c)
(161) Compound 5c is synthesized by general procedure Q from compound 5b in 74% yield (3.7 mmol, 1.14 g).
(162) MS-ESI: 308 (M.sup.++1, 100).
(163) Elementary Analysis:
(164) TABLE-US-00021 Calculated: C 66.43% H 8.20% N 4.56% Determined: C 66.46% H 8.21% N 4.55%
d) Synthesis of {(R)-2-[4-(2-Methoxymethoxy-ethoxy)-phenyl]-1-methyl-ethyl}-methyl-prop-2-ynyl-amine (5d)
(165) Compound 5d is synthesized by general sequential procedure I (at 5-fold scale) and U from compound 5c in 81% yield over two steps (2.02 mmol, 589 mg).
(166) MS-ESI: 292 (M.sup.++1, 100).
(167) Elementary Analysis:
(168) TABLE-US-00022 Calculated: C 70.07% H 8.65% N 4.81% Determined: C 70.11% H 8.63% N 4.82%
e) Synthesis of 2-{4-[(R)-2-(Methyl-prop-2-ynyl-amino)-propyl]phenoxy}-ethanol (5e)
(169) Compound 5e is synthesized by general sequential procedure N (at 4-fold scale) from compound 5d in 88% yield (1.76 mmol, 436 mg).
(170) MS-ESI: 248 (M.sup.++1, 100).
(171) Elementary Analysis:
(172) TABLE-US-00023 Calculated: C 72.84% H 8.56% N 5.66% Determined: C 72.81% H 8.55% N 5.67%
f) Methanesulfonic acid 2-{4-[(R)-2-(methyl-prop-2-ynyl-amino)-propyl]-phenoxy}-ethyl ester (5f)
(173) Compound 5f is synthesized by general sequential procedure I from compound 5e in 93% yield (0.47 mmol, 153 mg).
(174) MS-ESI: 326 (M.sup.++1, 100).
(175) Elementary Analysis:
(176) TABLE-US-00024 Calculated: C 59.05% H 7.12% N 4.30% Determined: C 59.07% H 7.11% N 4.30%
g) Synthesis of {(R)-2-[4-(2-Fluoro-ethoxy)-phenyl]-1-methyl-ethyl}-methyl-prop-2-ynyl-amine (5g)
(177) Compound 5g is synthesized by general procedure A from compound 5f in 61% yield (0.153 mmol, 38 mg).
(178) MS-ESI: 250 (M.sup.++1, 100).
(179) Elementary Analysis:
(180) TABLE-US-00025 Calculated: C 72.26% H 8.09% N 5.62% Determined: C 72.22% H 8.07% N 5.60%
h) Synthesis of [F-18]{(R)-2-[4-(2-Fluoro-ethoxy)-phenyl]-1-methyl-ethyl}-methyl-prop-2-ynyl-amine (5h)
(181) Compound 5h is synthesized by general procedure B from compound 5f (isolated 210 MBq from 1.41 GBq).
Example 6
a) Synthesis of ((R)-1-methyl-2-phenyl-ethyl)-prop-2-ynyl-amine (6a)
(182) 840 mg (4 mmol) ((R)-1-methyl-2-phenyl-ethyl)-prop-2-ynyl-ammonium hydrochloride (Sigma) is dissolved in 10 ml dichloromethane and 1M aqueous sodium carbonate. The organic phase is separated. The aqueous phase is extracted three times with 10 ml dichloromethane. The combined organic phases are washed with brine and dried with magnesium sulfate. The crude product 6a is used without further purification.
b) (2-Fluoro-ethyl)-((R)-1-methyl-2-phenyl-ethyl)-prop-2-ynyl-amine (6b)
(183) Compound 6b is synthesized by general procedure H from compound 6a in 60% yield (1.2 mmol, 262 mg).
(184) MS-ESI: 220 (M.sup.++1, 100).
(185) Elementary Analysis:
(186) TABLE-US-00026 Calculated: C 76.68% H 8.27% N 6.39% Determined: C 76.66% H 8.26% N 6.38%
c) [F-18] (2-Fluoro-ethyl)-((R)-1-methyl-2-phenyl-ethyl)-prop-2-ynyl-amine (6c)
(187) Compound 6c is synthesized by general procedure G from compound 6a and [F-18]-2-fluoro-ethyl-bromide (Bioorg. Med. Chem.; 13; 20; 2005; 5779-5786). The desired product 6c is obtained with 178 MBq starting from 1.98 GBq F-18 fluoride (decay corrected).
d) Synthesis of 2-{[(2R)-1-phenylpropan-2-yl](prop-2-yn-1-yl)amino}ethanol (6d)
(188) A mixture of desmethyldeprenyl (Sigma, 150 mg, 0.72 mmol) and NaOH (60 mg, 1.5 mmol), in MeCN (5 ml) was stirred at room temperature for 30 min. To the stirred mixture 1-bromo ethanol (1.0 mmol) was added and the reaction mixture was refluxed for overnight. The reaction mixture was allowed to cool to room temperature and solvent was evaporated under reduced pressure. The residue was partitioned between CH.sub.2Cl.sub.2 (20 ml) and water (10 ml). The organic phase was separated and washed with saturated NaHCO.sub.3 (10 ml) and brine (10 ml). The organic layer was dried over MgSO.sub.4 and filtered. The solvent was removed under reduced pressure to obtain the crude product as a light yellow liquid. The crude product was purified by silica-gel column chromatography (hexane/ether 8:2).
(189) MS-ESI: 218 (M.sup.++1, 100).
(190) Elementary Analysis:
(191) TABLE-US-00027 Calculated: C 77.38% H 8.81% N 6.45% O 7.36% Determined: C 77.35% H 8.79% N 6.43% O 7.35%
e) Synthesis of N-(2-chloroethyl)-N-[(2R)-1-phenylpropan-2-yl]prop-2-yn-1-amine (6e)
(192) A mixture of 2 (150 mg, 0.69 mmol) and triethyl amine (1.5 mmol), in THF (3 ml) was stirred at room temperature for 30 min. To the stirred mixture mesylchloride (1.4 mmol) was added drop wise at 7 C. and the reaction mixture was stirred at room temperature for additional 30 min. Saturated Na.sub.2CO.sub.3 solution (2 mL) was added and stirred for 30 more min. The organic layer was partitioned between CH2Cl2 (20 ml) and water (10 ml). The organic phase was separated and washed with saturated NaHCO.sub.3 (10 ml) and brine (10 ml) and dried over MgSO.sub.4 and filtered. The solvent was removed under reduced pressure to obtain the crude product as light yellow oil. The crude product was purified by silica-gel column chromatography (hexane/et her 3:1).
(193) MS-ESI: 235 (M.sup.+Cl35, 100).
(194) Elementary Analysis:
(195) TABLE-US-00028 Calculated: C 71.33% H 7.70% N 5.94% Determined: C 71.30% H 7.68% N 5.92%
f) Synthesis of N-(2-fluoroethyl)-N-[(2R)-1-phenylpropan-2-yl]prop-2-yn-1-amine (6b)
(196) To a solution of N-[(2R)-1-phenylpropan-2-yl]prop-2-yn-1-aminium chloride (Sigma 100 mg, 0.578 mmol) in dry DMF (2 mL) was added sodium hydride (48.0 mg, 2 mmol). The reaction mixture was stirred at room temperature for 30 min, after which 1-bromo-2-fluoro ethane (0.85 mg, 0.603 mmol) was added. The reaction mixture was stirred over night, diluted with water (10 mL) and extracted with CH.sub.2Cl.sub.2 (315 mL). The organic phase was separated and washed with saturated NaHCO.sub.3 (15 ml) and brine (15 ml) and dried over MgSO.sub.4 and filtered. The solvent was removed under reduced pressure to obtain the crude product as light yellow oil. The crude product was purified by silica-gel column chromatography (hexane/ether 80:20) and analyzed by NMR, HPLC and LC-MS.
(197) MS-ESI: 220 (M.sup.++1, 100).
(198) Elementary Analysis:
(199) TABLE-US-00029 Calculated: C 76.68% H 8.27% N 6.39% Determined: C 76.65% H 8.25% N 6.36%
g) Synthesis of N-[2-(18F)fluoroethyl]-N-[(2R)-1-phenylpropan-2-yl]prop-2-yn-1-amine (6c)
(200) The desired product 6c was obtained from 6e according to the general procedure C.
Example 7
a) Synthesis of (1R,2R)-2-[methyl(prop-2-yn-1-yl)amino]-1-phenylpropan-1-ol (7a)
(201) A mixture of (1R,2R)pseudoehedrine 150 mg, 0.72 mmol) and NaOH (60 mg, 1.5 mmol), in MeCN (5 ml) was stirred at room temperature for 30 min. To the stirred mixture propargyl bromide (1.0 mmol) was added and the reaction mixture was refluxed for overnight. The reaction mixture was allowed to cool to room temperature and solvent was evaporated under reduced pressure. The residue was partitioned between CH.sub.2Cl.sub.2 (20 ml) and water (10 ml). The organic phase was separated and washed with saturated NaHCO.sub.3 (10 ml) and brine (10 ml). The organic layer was dried over MgSO.sub.4 and filtered. The solvent was removed under reduced pressure to obtain the crude product as a light yellow liquid. The crude product 7a was purified by silica-gel column chromatography (hexane/ether 8:2).
(202) MS-ESI: 204 (M.sup.++1, 100).
(203) Elementary Analysis:
(204) TABLE-US-00030 Calculated: C 76.81% H 8.43% N 6.89% Determined: C 76.78% H 8.42% N 6.88%
b) Synthesis of N-[(1S,2R)-1-fluoro-1-phenylpropan-2-yl]-N-methylprop-2-yn-1-amine (7b)
(205) To the stirred solution of 7a (150 mg, 0.74 mmol) in dichloromethane (3 mL) DAST (1.0 mmol) was added drop wise at 5 C. and the reaction mixture was stirred for additional 20 min at the same temperature. Saturated sodium carbonate (2.0 mL) was added to quench the untreated DAST. The organic layer was partitioned between CH.sub.2Cl.sup.2 (15 ml) and water (10 ml). The organic phase was separated and washed with brine (10 ml) and dried over MgSO.sub.4 and filtered. The solvent was removed under reduced pressure to obtain the crude product as light yellow oil. The crude product was purified by silica-gel column chromatography (hexane/ether 4:1)
(206) MS-ESI: 206 (M.sup.++1, 100).
(207) Elementary Analysis:
(208) TABLE-US-00031 Calculated: C 76.07% H 7.86% N 6.82% Determined: C 76.02% H 7.85% N 6.81%
c) Synthesis of N-[(1S,2R)-1-chloro-1-phenylpropan-2-yl]-N-methylprop-2-yn-1-amine (7c)
(209) To a stirred solution of 7a (120 mg, 0.54 mmol) in THF (2 ml) triethyl amine (1.0 mmol) was added. The mixture was stirred at room temperature for 30 min. To the stirred mixture mesylchloride (0.60 mmol) was added drop wise at 7 C. and the reaction mixture was stirred at room temperature for additional 30 min. Saturated Na.sub.2CO.sub.3 solution (1 mL) was added and stirred for 30 more min. The organic layer was partitioned between CH.sub.2Cl.sub.2 (15 ml) and water (10 ml). The organic phase was separated and washed with saturated NaHCO.sub.3 (10 ml) and brine (10 ml) and dried over MgSO.sub.4 and filtered. The solvent was removed under reduced pressure to obtain the crude product as light yellow oil. The crude product 7c was purified by silica-gel column chromatography (hexane/ether 3:1).
(210) MS-ESI: 221 (M.sup.+35Cl+1, 70).
(211) Elementary Analysis:
(212) TABLE-US-00032 Calculated: C 70.42% H 7.27% Cl 15.99% N 6.32% Determined: C 70.39% H 7.25% Cl 15.97% N 6.30%
Example 8
a) Synthesis of (3aS,8aR)-3,3a,8,8a-tetrahydroindeno[1,2-d][1,2,3]oxathiazole 2,2-dioxide (8a)
(213) To a stirred solution of 5 g (33 mmol) commercially available (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol in 200 ml dichloromethane and 9.3 ml (67 mmol) triethyl amine was added 3.25 ml (40 mmol) sulfonylchloride (SO.sub.2Cl.sub.2) in 80 ml dichloromethane at 65 C. The reaction mixture was stirred for 3 h and warmed slowly to room temperature and stirred at this temperature for 18 hours. The precipitate was filtered and the filtrate was washed three times with water and then with brine, dried over magnesium sulphate and concentrated. The residue was diluted in little dichloromethane and recrystallizes in hexane. The product was purified by columns chromatography (ethyl acetate hexane 0:100.fwdarw.100:0) to obtain 2.2 g of the desired product 8a.
(214) MS-ESI: 212 (M.sup.++1)
(215) Elementary Analysis:
(216) TABLE-US-00033 Calculated: C 51.17% H 4.29% N 6.63% Determined: C 57.20% H 4.30% N 6.61%
b) Synthesis of (3aS,8aR)-3-(prop-2-yn-1-yl)-3,3a,8,8a-tetrahydroindeno[1,2-d][1,2,3]oxathiazole 2,2-dioxide (8b)
(217) To a stirred solution of 2.2 g (10.4 mmol) 8a in 120 ml dimethylformamide was added 1.35 ml (22.8 mmol) prop-2-yn-1-ol and 6 g (22.8 mmol) triphenylphosphin and 4.42 ml (22.8 mmol) dipropan-2-yl (E)-diazene-1,2-dicarboxylate. The reaction mixture was stirred for 2 h and concentrated. The residue was purified by two subsequent column chromatographies (ethyl acetate hexane 1:20.fwdarw.2:1) to obtain 970 mg (37%) of the desired product 8b.
(218) MS-ESI: 250 (M.sup.++1)
(219) Elementary Analysis:
(220) TABLE-US-00034 Calculated: C 57.82% H 4.45% N 5.62% Determined: C 57.85% H 4.46% N 5.61%
c) Synthesis of [(1S,2S)-2-fluoro-2,3-dihydro-1H-inden-1-yl]prop-2-yn-1-ylsulfamic acid (8c)
(221) To a stirred solution of 100 mg (0.4 mmol) 8b in 2 ml dry THF was added 139 mg (0.44 mmol) tetrabutylammonium fluoride. The reaction mixture was stirred for 90 min and concentrated. The residue was purified by preparative HPLC. The desired product 8c was obtained in 10% yield containing minor amounts of TBAF.
d) Synthesis of (1S,2S)-2-fluoro-N-(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-amine (8d)
(222) To a stirred solution of 100 mg (0.4 mmol) 8b in 2 ml dry THF was added 139 mg (0.44 mmol) tetrabutylammonium fluoride at 0 C. The reaction mixture was stirred for 90 min and concentrated. 2 ml 3N sulphuric acid was added and the solution was heated in microwave oven for 10 min. The solution was poured into 20 ml ice-cold and vigorously stirred 0.35 N sodium hydroxide solution. The aqueous phase was extracted with dichloromethane-isopropyl alcohol mixture (10:1) and the organic phase was dried over magnesium sulphate and concentrated. The residue was purified by preparative HPLC to obtain the compound 8d as 14 mg amount batch
e) Synthesis of (1S,2S)-2-(18F)fluoro-N-(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-amine (8e)
(223) The desired product 8e was obtained according to the general procedure E
(224) The features of the present invention disclosed in the specification, the claims and/or in the accompanying drawings, may, both separately, and in any combination thereof, be material for realizing the invention in various forms thereof.
(225) Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The preceding preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
(226) In the foregoing and in the examples, all temperatures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indicated.
(227) The entire disclosures of all applications, patents and publications, cited herein and of corresponding European application No. 07021042.2, filed Oct. 26, 2007, are incorporated by reference herein.
(228) The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
(229) From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.