WO2012084794A1 - Process simplification for precursor compound - Google Patents

Process simplification for precursor compound Download PDF

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Publication number
WO2012084794A1
WO2012084794A1 PCT/EP2011/073204 EP2011073204W WO2012084794A1 WO 2012084794 A1 WO2012084794 A1 WO 2012084794A1 EP 2011073204 W EP2011073204 W EP 2011073204W WO 2012084794 A1 WO2012084794 A1 WO 2012084794A1
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Prior art keywords
compound
reaction
acid
amino
mixture
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PCT/EP2011/073204
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French (fr)
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Tom Christian Berg
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Ge Healthcare Limited
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Priority to JP2013543829A priority Critical patent/JP6047100B2/en
Priority to EP11802366.2A priority patent/EP2655320A1/en
Priority to AU2011347636A priority patent/AU2011347636B2/en
Priority to MX2013007188A priority patent/MX340407B/en
Priority to CA2819088A priority patent/CA2819088A1/en
Priority to BR112013015002A priority patent/BR112013015002A2/en
Priority to CN201180061527XA priority patent/CN103261152A/en
Priority to KR1020137019139A priority patent/KR20130133248A/en
Priority to RU2013126497/04A priority patent/RU2593372C2/en
Priority to US13/994,781 priority patent/US9238596B2/en
Publication of WO2012084794A1 publication Critical patent/WO2012084794A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a method to obtain radiopharmaceutical precursors, and in particular to protected amino acid derivatives which are used as precursors for production of radiolabeled amino acids for use in in vivo imaging procedures such as positron emission tomography (PET).
  • PET positron emission tomography
  • the invention further includes a method to obtain said radiolabelled amino acids.
  • EP1978015(A1) specifically discloses a method to obtain the precursor l-(N-(t- butoxycarbonyl)amino)-3-[((trifluoromethyl)sulfonyl)oxy]-cyclobutane-l-carboxylic acid ethyl ester wherein said method comprises the following steps:
  • step 1 of the above reaction scheme comprises hydrolysis of s w-5-(3-benzyloxycyclobutane)hydantoin 1 by addition of barium hydroxide Ba(OH) 2 to the solution and refluxing the mixture at 114°C for 24 hours or longer.
  • step 2 syn- 1 -amino-3-benzyloxycyclobutane- 1 - carboxylic acid 2 is dissolved in ethanol (EtOH) and reacted with thionyl chloride (SOCl 2 ) to yield syn- 1 -annno-3-benzyloxycyclobutane- 1 -carboxylic acid ethyl ester 3.
  • Step 3 comprises addition of fc/7-buto.xycarbonyl (Boc) to the amine function by reaction of 3 with tert-butyl dicarbonate (Boc) 2 0, and the resultant material is purified by chromatography to obtain 5 ⁇ -l -(N-(/-butoxycarbonyl)amino)-3-benzyloxy- cyclobutane- 1 -carboxylic acid ethyl ester 4.
  • the benzyl -protected intermediate 4 is then deprotected in step 4 by dissolving compound 4 in ethanol (EtOH), adding palladium on activated carbon (Pd/C) and applying a small positive 3 ⁇ 4-pressure over the reaction mixture.
  • step 5 The resultant material is purified by chromatography to yield syn- ⁇ -(N-(t- butoxycarbonyl)amino)-3-benzyloxy-cyclobutane- l -carboxylic acid ethyl ester 5 for use in step 5, which comprises reaction of 5 with trifluoromethanesulfonic anhydride (Tf 2 0), followed by chromatographic purification with subsequent re-crystallization of the material in order to obtain syn- 1 -(A-(/-butoxycarbonyl)amino )-3- [((trifiuoromethy])sulfonyl)oxy]-cyclobutane- l -carboxylic acid ethyl ester 6. Similar methods are described in EP2230229 and US201 0016626. In the case of all of these prior art teachings, the methods are suitable for small scale preparation for research purposes.
  • the present invention is a method for the preparation of precursor compounds for [ F]- FACBC and similar compounds that is simplified with respect to known methods.
  • the method of the invention leaves out one of the purification steps taught by the prior art and as such permits the resultant precursor compounds to be obtained in a more cost- and time-efficient manner.
  • aryl or fused rings (i.e. naphthalene). Unless otherwise defined, such aryl groups typically contain from 6 to 10 carbon ring atoms.
  • debenzylation refers to the cleavage of a benzyl substituent from a compound.
  • benzyl refers to a group with chemical structure Q.HsCH?-.
  • Debenzylation is a method well-known in the art and is generally carried out by "catalytic hydrogenation", which is a reaction whereby a carbon-carbon bond is cleaved or undergoes "lysis” by hydrogen.
  • Hydrogenolysis is usually carried out catalytically, e.g. using palladium on carbon (Pd/C) as a catalyst.
  • Pd/C palladium on carbon
  • filtration refers to the mechanical separation of solids from fluids.
  • suitable filtration means for use in the present invent ion include glass sinter funnel or glass fibre filer in addition to a filter funnel, although other more specialised filter methods are also suitable.
  • the reaction solvent is removed by drying. Drying may be carried out by methods well-known to the person skilled in the art e.g. by evaporation under nitrogen flow and/or vacuum drying.
  • step (a) is carried out with the proviso that the reaction mixture obtained from step (a) is not purified prior to carrying out step (b), and in particular with the proviso that the reaction mixture of step (a) is not purified by chromatography following step (a) and prior to step (b).
  • step (a) is carried out with the proviso that the reaction mixture obtained from step (a) is not purified prior to carrying out step (b), and in particular with the proviso that the reaction mixture of step (a) is not purified by chromatography following step (a) and prior to step (b).
  • the term ' 'chromato graphy' ' is well-known in the art and refers to a laboratory technique for the separation of chemical substances from each other in a mixture of different substances. Chromatographic separation involves passing the mixture dissolved in a mobile phase through a stationary phase, which separates the molecule of interest from other molecules in the mixture based on differential partitioning between the mobile and stationary phases.
  • a suitable form of X means X as defined herein in a form that can displace the hydroxy! function in a substitution reaction.
  • Hydantoin 1 was treated with 3N aqueous sodium hydroxide at 180°C followed by di- tert butyl dicarbonate to provide the N-Boc acid 5.
  • Methyl ester 6 was obtained in high yield by reacting 5 with trimethylsilyl diazomethane.
  • the starting hydantoin compound includes a mixture of the syn- and anti-enantiomers. There is no need for actively separating enantiomers, at any stage of the process.
  • X is the group -0-S0 2 -R 3 . Most preferably when X is -0-S0 2 -R 3 it is selected from the group consisting of tolucnesulfonic acid, nitrobenzenesulfonic acid, bcnzenesulfonic acid, trifluoromethanesulfonic acid, f!uorosulfonic acid, and perfluoroalkylsulfonic acid. In an especially preferred embodiment
  • -O-SO 2 -R is trifluoromethanesulfonic acid.
  • the group -O-SO 2 -R can be added in step (b) of the method of the invention by reaction of the compound of Formula lb with an electrophilic derivative of the desired -O-SO 2 -R 3 group, which is an example of a suitable form of X".
  • the compound of Formula lb can be reacted with trifluoromethanesulfonic anhydride.
  • X is halogen.
  • X is halogen it is most preferably bromo or chloro.
  • Step (b) of the method of the invention wherein X is a halogen may be carried out by methods well known to those skilled in the art.
  • a compound of Formula I wherein X is chloro can be obtained by reaction of the compound o Formula lb with a chloride-containing reagent such as thionyl chloride, phosphorous pentachloride (PC1 5 ), phosphorous trichloride (PC1 3 ), each of which are examples of a "suitable form of X".
  • a compound of Formula I wherein X is bromo can be obtained by reaction of a compound of Formula lb with a brom ine-con tain i ng reagent such as hydrobromic acid (HBr) or phosphorous tribromide (PBn), again, each of which are examples of a "suitable form of X".
  • a brom ine-con tain i ng reagent such as hydrobromic acid (HBr) or phosphorous tribromide (PBn), again, each of which are examples of a "suitable form of X".
  • R 1 is methyl or ethyl and is most preferably ethyl. This preferred definition of R 1 equally applies to R 1 ' and R 21 . COOEt
  • NHBoc Compound 2a wherein Et is ethyl and Boc is tert-Butyloxycarbonyl.
  • steps (c) and (d) are carried out on an automated synthesiser.
  • [ F] -radiotracers are now often conveniently prepared on an automated radiosynthesis apparatus.
  • Such apparatus commonly comprises a “cassette ' ", often disposable, in which the radiochemistry is performed, which is fitted to the apparatus in order to perform a radiosynthesis.
  • the cassette normally includes fluid pathways, a reaction vessel, and ports for receiving reagent vials as well as any solid-phase extraction cartridges used in post-radiosynthetic clean up steps.
  • a typical cassette for automated synthesis of a compound of Formula 11 includes:
  • Example 1 describes the synthesis of 5-(3-benzyloxycyclobutane)hydantoin.
  • Example 2 describes the synthesis of l-amino-3-(benzyloxy)cyclobutanecarboxylic acid.
  • Example 3 describes the synthesis of l -Arnino-3-benzyloxy-cyclobutanecarboxylic acid
  • the reaction mixture was extracted with Et 2 0 ( 1 50 ml), the water phase discarded, the organic phase washed with HC1 (75 ml, 1 M), brine (75 ml sat.aq.) and dried over Na 2 S04.
  • the mixture was filtered through a glass sinter filter and the filtrate evaporated in vacuo at ⁇ 30°C to afford crude Compound 1 .
  • the crude product was re-dissolved in dichloromethane (40 ml) and adsorbed onto Si0 2 (9.5 g).

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Abstract

The invention relates to a process for preparation of radiopharmaceutical precursors, and in particular protected amino acid derivatives which are used as precursors for production of radiolabelled amino acids for use in in vivo imaging procedures such as positron emission tomography (PET). Particularly, the invention relates to a process for preparation of a precursor useful in the preparation of the [18F]-1-amino-3- fluorocyclobutanecarboxyiic acid ([18F] FACBC) PET tracer.

Description

PROCESS SIMPLIFICATION FOR PRECURSOR COMPOUND
Technical Field of the Invention
The present invention relates to a method to obtain radiopharmaceutical precursors, and in particular to protected amino acid derivatives which are used as precursors for production of radiolabeled amino acids for use in in vivo imaging procedures such as positron emission tomography (PET). The invention further includes a method to obtain said radiolabelled amino acids.
Description of Related Art
In recent years, a series of radioactive halogen-labelled amino acid compounds including [18F]l -amino-3-fluorocyclobutanecarboxylic acid ([I 8F]-FACBC) have been designed as novel radiopharmaceuticals. [! 8F]-FACBC is considered to be effective as a diagnostic agent for highly proliferative tumours, because it has a property of being taken up specifically by amino acid transporters. EP1978015(A1) provides precursors for the [, 8F]-FACBC compound and methods to obtain said precursors.
EP1978015(A1) specifically discloses a method to obtain the precursor l-(N-(t- butoxycarbonyl)amino)-3-[((trifluoromethyl)sulfonyl)oxy]-cyclobutane-l-carboxylic acid ethyl ester wherein said method comprises the following steps:
EP 1978015( A 1 ) describes that step 1 of the above reaction scheme comprises hydrolysis of s w-5-(3-benzyloxycyclobutane)hydantoin 1 by addition of barium hydroxide Ba(OH)2 to the solution and refluxing the mixture at 114°C for 24 hours or longer. In the ethyl esterification step 2, syn- 1 -amino-3-benzyloxycyclobutane- 1 - carboxylic acid 2 is dissolved in ethanol (EtOH) and reacted with thionyl chloride (SOCl2) to yield syn- 1 -annno-3-benzyloxycyclobutane- 1 -carboxylic acid ethyl ester 3. Step 3 comprises addition of fc/7-buto.xycarbonyl (Boc) to the amine function by reaction of 3 with tert-butyl dicarbonate (Boc)20, and the resultant material is purified by chromatography to obtain 5 ^-l -(N-(/-butoxycarbonyl)amino)-3-benzyloxy- cyclobutane- 1 -carboxylic acid ethyl ester 4. The benzyl -protected intermediate 4 is then deprotected in step 4 by dissolving compound 4 in ethanol (EtOH), adding palladium on activated carbon (Pd/C) and applying a small positive ¾-pressure over the reaction mixture. The resultant material is purified by chromatography to yield syn-\ -(N-(t- butoxycarbonyl)amino)-3-benzyloxy-cyclobutane- l -carboxylic acid ethyl ester 5 for use in step 5, which comprises reaction of 5 with trifluoromethanesulfonic anhydride (Tf20), followed by chromatographic purification with subsequent re-crystallization of the material in order to obtain syn- 1 -(A-(/-butoxycarbonyl)amino )-3- [((trifiuoromethy])sulfonyl)oxy]-cyclobutane- l -carboxylic acid ethyl ester 6. Similar methods are described in EP2230229 and US201 0016626. In the case of all of these prior art teachings, the methods are suitable for small scale preparation for research purposes.
It would be desirable to reduce the complexity of the above-described multistep chemical reaction in order to reduce process time, use of equipment and chemicals, and to facilitate scale-up.
Summary of the Invention
The present invention is a method for the preparation of precursor compounds for [ F]- FACBC and similar compounds that is simplified with respect to known methods. The method of the invention leaves out one of the purification steps taught by the prior art and as such permits the resultant precursor compounds to be obtained in a more cost- and time-efficient manner.
Figure imgf000004_0001
Figure imgf000005_0001
phenyl) or fused rings (i.e. naphthalene). Unless otherwise defined, such aryl groups typically contain from 6 to 10 carbon ring atoms.
The term "debenzylation" refers to the cleavage of a benzyl substituent from a compound. The term "benzyl" refers to a group with chemical structure Q.HsCH?-. Debenzylation is a method well-known in the art and is generally carried out by "catalytic hydrogenation", which is a reaction whereby a carbon-carbon bond is cleaved or undergoes "lysis" by hydrogen. Hydrogenolysis is usually carried out catalytically, e.g. using palladium on carbon (Pd/C) as a catalyst. When a catalyst such as Pd/C is used in the debenzylation step, the catalyst is removed from the reaction mixture by filtration prior to the next step. The term "filtration" refers to the mechanical separation of solids from fluids. Non-limiting examples of suitable filtration means for use in the present invent ion include glass sinter funnel or glass fibre filer in addition to a filter funnel, although other more specialised filter methods are also suitable. Generally, following the debenzylation step (a) and prior to the conversion step (b), the reaction solvent is removed by drying. Drying may be carried out by methods well-known to the person skilled in the art e.g. by evaporation under nitrogen flow and/or vacuum drying.
The term "obtained directly" refers to the fact that following step (a) and prior to step (b), no purification steps are carried out on the reaction mixture. In particular, the reaction mixture obtained by carrying out step (a ) is not further purified by chromatography prior to carrying out step (b). Alternatively stated, step (a) is carried out with the proviso that the reaction mixture obtained from step (a) is not purified prior to carrying out step (b), and in particular with the proviso that the reaction mixture of step (a) is not purified by chromatography following step (a) and prior to step (b). The term ' 'chromato graphy' ' is well-known in the art and refers to a laboratory technique for the separation of chemical substances from each other in a mixture of different substances. Chromatographic separation involves passing the mixture dissolved in a mobile phase through a stationary phase, which separates the molecule of interest from other molecules in the mixture based on differential partitioning between the mobile and stationary phases.
The term "a suitable form of X" means X as defined herein in a form that can displace the hydroxy! function in a substitution reaction.
Figure imgf000007_0001
Hydantoin 1 was treated with 3N aqueous sodium hydroxide at 180°C followed by di- tert butyl dicarbonate to provide the N-Boc acid 5. Methyl ester 6 was obtained in high yield by reacting 5 with trimethylsilyl diazomethane.
It is within the ordinary skill in the art to adapt the above-described prior art methods to obtain other compounds of Formula la that fall within the definition of the present invention. Suitably, the starting hydantoin compound includes a mixture of the syn- and anti-enantiomers. There is no need for actively separating enantiomers, at any stage of the process.
In a preferred embodiment of the invention. X is the group -0-S02-R3. Most preferably when X is -0-S02-R3 it is selected from the group consisting of tolucnesulfonic acid, nitrobenzenesulfonic acid, bcnzenesulfonic acid, trifluoromethanesulfonic acid, f!uorosulfonic acid, and perfluoroalkylsulfonic acid. In an especially preferred embodiment
3 3
-O-SO2-R is trifluoromethanesulfonic acid. The group -O-SO2-R can be added in step (b) of the method of the invention by reaction of the compound of Formula lb with an electrophilic derivative of the desired -O-SO2-R3 group, which is an example of a suitable form of X". For example, where it is desired to add tri fiuoromethanesul fon ic acid, the compound of Formula lb can be reacted with trifluoromethanesulfonic anhydride.
In an alternative preferred embodiment, X is halogen. When X is halogen it is most preferably bromo or chloro. Step (b) of the method of the invention wherein X is a halogen may be carried out by methods well known to those skilled in the art. For example, a compound of Formula I wherein X is chloro can be obtained by reaction of the compound o Formula lb with a chloride-containing reagent such as thionyl chloride, phosphorous pentachloride (PC15), phosphorous trichloride (PC13), each of which are examples of a "suitable form of X". A compound of Formula I wherein X is bromo can be obtained by reaction of a compound of Formula lb with a brom ine-con tain i ng reagent such as hydrobromic acid (HBr) or phosphorous tribromide (PBn), again, each of which are examples of a "suitable form of X".
Preferably, R1 is methyl or ethyl and is most preferably ethyl. This preferred definition of R1 equally applies to R1 ' and R21.
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
COOEt
NHBoc Compound 2a wherein Et is ethyl and Boc is tert-Butyloxycarbonyl.
In a preferred embodiment, steps (c) and (d) are carried out on an automated synthesiser.
[ F] -radiotracers are now often conveniently prepared on an automated radiosynthesis apparatus. There are several commercially-available examples of such apparatus, including Traccrlab™ and Fastlab™ (both from GE Healthcare Ltd). Such apparatus commonly comprises a "cassette'", often disposable, in which the radiochemistry is performed, which is fitted to the apparatus in order to perform a radiosynthesis. The cassette normally includes fluid pathways, a reaction vessel, and ports for receiving reagent vials as well as any solid-phase extraction cartridges used in post-radiosynthetic clean up steps.
A typical cassette for automated synthesis of a compound of Formula 11 includes:
(i) a vessel containing a compound of Formula I as defined herein; and
(ii) means for eluting the vessel with a suitable source of [ F] -fluoride as defined herein.
(iii) an ion-exchange cartridge for removal of excess [ F]-f!uoridc; and,
(iv) a cartridge for deprotection of the compound of Formula Ila to form the compound of Formula II.
The invention will now be described by means of the following experimental examples:
Brief Description of the Examples
Example 1 describes the synthesis of 5-(3-benzyloxycyclobutane)hydantoin.
Example 2 describes the synthesis of l-amino-3-(benzyloxy)cyclobutanecarboxylic acid.
Example 3 describes the synthesis of l -Arnino-3-benzyloxy-cyclobutanecarboxylic acid
Figure imgf000013_0001
Figure imgf000014_0001
for 16 hours 10 minutes.
Solid material from vacuum drying (257.2g) was dissolved in water-isopropanol ( 15.0 1, 1 : 1). The solution was stirred at ambient temperature for 70 minutes and un-dissolved particles were removed by filtration through a glass sinter filter (pore size 3). Filtrate evaporated in vacuo at 45-49"C to approximately 1/3 of the starting volume. The resulting slurry was cooled to 7.6°C, filtered through a glass sinter filter funnel (pore size 3) and washed with cold water (2.0 1, < 7°C). The filter cake was transferred to a Schott Duran glass bottle and in vacuo at 36°C for 18 h 40 min. Yield: 229.6 g (71 %).
Ή NMR (500 MHz, DMSC ,) δ (ppm): 10.63 (s, 111. Ni l), 8.24 (s, 1H, NH), 7.38- 7.27 (m, 5H, Bz), 4.32 (s, 1H, C¾-Bz), 4.06-3.98 (m, 1H, CH-ring), 2.68-2.61 (m, 2H,
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
dichloromethane (77.5 ml ) and pyridine (2.95 ml. 36.6 mmol), and the resulting solution cooled to <5°C. Triflic anhydride (3.01 ml, 1 7.9 mmol) was added to the mixture in portions over 23 minutes, with the reaction temperature kept at <5°C during the addition. The resulting mixture was stirred on an ice bath for 31 minutes (reaction progress monitored by TLC) and upon complete reaction water (70 ml) was added to quench the reaction.
The reaction mixture was extracted with Et20 ( 1 50 ml), the water phase discarded, the organic phase washed with HC1 (75 ml, 1 M), brine (75 ml sat.aq.) and dried over Na2S04. The mixture was filtered through a glass sinter filter and the filtrate evaporated in vacuo at <30°C to afford crude Compound 1 . The crude product was re-dissolved in dichloromethane (40 ml) and adsorbed onto Si02 (9.5 g).
The crude product was puri fied by flash chromatographic purification using Si02 column, isocratic elution with pentanc: diethyl ether (3 : 1). The product fractions were combined and evaporated in vacuo at <30°C to afford Compound 1 (3.22g).
Compound 1 was further puri lied by re-crystallization by dissolving the material in diethyl ether (7.7 ml) and slowly stirring the mixture at <35°C until all solids had dissolved. The reaction mixture was slowly cooled to 25°C over 45 minutes and further stirred at this temperature for 1 hour 25 minutes. The solution was further cooled to <5°C and gently stirred at this temperature for 54 minutes, then further cooled to <-20°C and stirred at this temperature for 1 hour 4 minutes, ice-cold heptane (25 ml) was added and the solution gently stirred for 1 hour 20 minutes. Formed crystals were collected by filtration using a pre-cooled glass sinter filter and washed with ice cold heptane (25 ml, <-5°C). The reaction afforded Compound 1 2.86 g (61 %).

Claims

Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
PCT/EP2011/073204 2010-12-20 2011-12-19 Process simplification for precursor compound WO2012084794A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
JP2013543829A JP6047100B2 (en) 2010-12-20 2011-12-19 Simplified process for precursor compounds
EP11802366.2A EP2655320A1 (en) 2010-12-20 2011-12-19 Process simplification for precursor compound
AU2011347636A AU2011347636B2 (en) 2010-12-20 2011-12-19 Process simplification for precursor compound
MX2013007188A MX340407B (en) 2010-12-20 2011-12-19 Process simplification for precursor compound.
CA2819088A CA2819088A1 (en) 2010-12-20 2011-12-19 Process simplification for precursor compound
BR112013015002A BR112013015002A2 (en) 2010-12-20 2011-12-19 method to obtain a compound
CN201180061527XA CN103261152A (en) 2010-12-20 2011-12-19 Process simplification for precursor compound
KR1020137019139A KR20130133248A (en) 2010-12-20 2011-12-19 Process simplification for precursor compound
RU2013126497/04A RU2593372C2 (en) 2010-12-20 2011-12-19 Simple method of producing precursor compound
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US9238596B2 (en) 2016-01-19
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