WO 2012/084831 PCT/EP2011/073247 f
PURIFICATION OF PRECURSOR COMPOUND BY CRYSTALLISATION
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 radiolabelled amino acids for use in 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 [ 8F]1-amino-3-fluorocyclobutanecarboxylic acid ([ 8F]-FACBC) have been
designed as novel radiopharmaceuticals. [ F]-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.
EP1 97801 5(A1) provides precursors for the [ F]-FACBC compound and methods to
obtain said precursors. EP1 97801 5(A1) specifically discloses a method to obtain the
precursor syn-1 -(N-(f-butoxycarbonyl)amino)-3-[((trifluoromethyl)sulfonyl)oxy]-
cyclobutane-1-carboxylic acid ethyl ester wherein said method comprises the following
steps:
Step 1 2
1
reflux
3 Step 3 4
Step 2
EP1 97801 5(A1) describes that step 1 of the above reaction scheme comprises
hydrolysis of syn-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
(SOCI2) to yield sy/>1-amino-3-benzyloxycyclobutane-1 -carboxylic acid ethyl ester 3.
Step 3 comprises addition of ferf-butoxycarbonyl (Boc) to the amine function by reaction
of 3 with e -buty dicarbonate (Boc)20 , and the resultant material is purified by
chromatography to obtain syn-1-(A/-(f-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 H2-pressure over the reaction mixture. The
resultant material is purified by chromatography to yield syn-1-( -( -
butoxycarbonyl)amino)-3-benzyloxy-cyclobutane-1 -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/-(f-butoxycarbonyl)amino)-3-
[((trifluoromethyl)sulfonyl)oxy]-cyclobutane-1 -carboxylic acid ethyl ester 6.
The above-described known process is relatively complex, costly and time-consuming,
particularly if applied for large-scale production of the precursor compound. It would be
desirable to have a process that is more straightforward to carry out, more cost
effective, and more amenable to large scale commercial production.
Summary of the Invention
The present invention is a method useful in the preparation of precursor compounds for
[ F]-FACBC and similar compounds that is more amenable to large scale commercial
production than previously-known methods. As compared with the known method, the
method of the present invention permits production of such compounds on a
commercial scale without having to handle large amounts of solvents, and also results
in improved yields.
Detailed Description of the Invention
In one aspect, the present invention relates to a method to obtain a compound of Formula
wherein:
R represents a C 5 straight- or branched-chain alkyl group;
R2 represents an amino protecting group;
v is an integer of 0 to 4; and,
X represents a leaving group selected from a halogen, or the group -0-S0 2-R3
wherein R3 is a halogen, a straight-chain or branched-chain C - 0 alkyl, a straightchain
or branched-chain C1-10 haloalkyl, and a C6 o ary!
wherein said method comprises:
(a) debenzylation of a compound of Formula la:
wherein R1 , R 2 and w are as defined for R , R2 and v of Formula I,
respectively;
crystallisation of the reaction mixture from step (a) to obtain purified
compound of Formula lb:
wherein R2 , R22 and x are as defined for R1, R2 and v of Formula ,
respectively
(c) conversion of purified compound of Formula I obtained in step (b) into a
compound of Formula I by reaction with a suitable form of X wherein X is as
defined for Formula .
The term "alkyl" used alone or in combination means a straight-chain or branched-chain
group having the general formula hH2h+i. The value of n in this general formula is
specified in particular cases. Examples of some preferred alkyl groups include methyl,
ethyl, 1-propyl or isopropyl groups.
By the term "protecting group" is meant a group which inhibits or suppresses undesirable
chemical reactions, but which is designed to be sufficiently reactive that it may be cleaved
from the functional group in question to obtain the desired product under mild enough
conditions that do not modify the rest of the molecule. Protecting groups are well known to
those skilled in the art and are described in 'Protective Groups in Organic Synthesis',
Theorodora W. Greene and Peter G. M. Wuts, (Fourth Edition, John Wiley & Sons, 2007).
Suitable amino protecting groups are well-known in the art. A suitable amino protecting
group R2 is a carbamate. Preferably R2 is selected from; ie/f-butyl carbamate (BOC), 9-
fluoroenylmethyl carbamate (Fmoc), methyl carbamate, ethyl carbamate, 2-chloro-3-
indenylmethyl carbamate (Climoc), benz[f]inden-3-ylmethyl carbamate (Bimoc), 2,2,2-
trichloroethyl carbamate (Troc), 2-chloroethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl
carbamate (DB-f-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), benzyl
carbamate (Cbz) and diphenylmethyl carbamate. Most preferably R2 is te -butyl
carbamate, to provide a N-ferf-butoxycarbonyl.
The term "leaving group " refers to a moiety suitable for nucleophilic substitution and is a
molecular fragment that departs with a pair of electrons in heterolytic bond cleavage.
The term "halogen " or "halo-" used alone or in combination refers to a substituent selected
from fluorine, chlorine, bromine or iodine.
The term " haloalkyl " refers to an alkyl group as defined above comprising between 1-
10 carbon atoms wherein at least one hydrogen is replaced with a halogen, wherein
halogen is as defined above.
The term "C ary!" refers to a monovalent aromatic hydrocarbon having a single ring (i.e.
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 substituentfrom a compound.
The term "benzyl" refers to a group with chemical structure C6H5CH2- . Debenzvlation is a
method well-known in the art and is generally carried out by "catalytic hvdroqenation ",
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 invention include glass sinter
funnel or glass fiber 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
crystallisation 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 "crystallisation " generally refers to the process of formation of solid crystals
precipitating from a solution. Crystallisation can be used as a purification method due to
the fact that well-formed crystals are expected to be pure because each molecule or ion
must fit perfectly into the lattice as it leaves the solution. For crystallisation to occur from a
solution it must be supersaturated. This means that the solution has to contain more
solute entities dissolved than it would contain under the equilibrium (saturated solution).
This can be achieved by various methods, including solvent evaporation, solution cooling,
addition of a second solvent to reduce the solubility of the solute (technique known as
antisolvent or drown-out), chemical reaction and change in pH. In the method of the
invention, a solution of the reactants following step (a) is made. This solution is made
using a first solvent in which the reactants easily dissolve.
The term "a suitable form of X" means X as defined herein in a form that can displace the
hydroxyl function in a substitution reaction.
Compounds of Formula la may be obtained by following or adapting the methods
described in EP1 97801 5(A1). For example, compound 4 as specifically described in
EP1 97801 5(A1 ) is a compound of Formula la suitable for use in the method of the present
invention. The method described in EP1 97801 5(A1) to obtain said compound 4 is
illustrated in Scheme 1 below
Step 2 Step 3
McConathy et al (Appl Ra Isotop 2003; 58: 657-666) also describe methods to obtain
compound of Formula la. In Figure 2 of McConathy e al compound 6 is a compound of
Formula la. The method described by McConathy ei al to obtain said compound 6 is
illustrated in Scheme 2 below.
H3C0 2C
OBn
Boc-NH Scheme 2
6
Hydantoin 1 was treated with 3N aqueous sodium hydroxide at 180°C followed by ditertbutyl
dicarbonate to provide the A/-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 antienantiomers.
There is no need for actively separating enantiomers, at any stage of the
process. Indeed, a slight enrichment of the syn- isomer in the crystalline product has been
achieved, as described in Example 2 herein. Such enrichment was observed more
pronounced at earlier stages of the crystallization during the introductory experiments. At
some lower total yield, the syn/(syn+anti) ratio over 90% was registered. The method of
the invention therefore has the further advantage that it can separate the isomers.
Preferably, R1 is methyl or ethyl and is most preferably ethyl. This preferred definition of R
equally applies to R1 and R2 .
R2 is preferably a carbonate ester protecting group wherein the term "carbonate ester"
refers to a functional group consisting of a carbonyl group flanked by two aikoxy groups
having general structure RO(C=0)OR . R is most preferably a f-butoxycarbonyl group.
This preferred definition of R2 equally applies to R 2 and R22.
Preferably, v is 0 or 1 and is most preferably 0. This preferred definition of v equally
applies to w and x.
A particularly preferred compound of Formula I is:
Compound 1
A particularly preferred compound of Formula la is:
Compound 1a
A particularly preferred compound of Formula lb is:
Compound 1b
For the above Compounds 1, 1a and 1b, Et stands for ethyl, OTf for
trifluoromethanesulfonic acid and Boc for fert-Butyloxycarbonyl.
The method of the present invention shortens process time and reduces cost of goods
in comparison to the prior art methods. In particular for the production of commercialscale
batches of compounds of Formula I, the prior art method using a flash
chromatography step to purify the compound of Formula lb would require a large silica
column and large amounts of solvent. By using crystallisation instead of flash
chromatography the use of large amounts of solvents is avoided, which provides a
benefit both in terms of cost and operator safety.
In a preferred embodiment, X is the group -0-S0 2-R3. Most preferably when X is -OS0
2- 3, X is selected from the group consisting of toluenesulfonic acid,
nitrobenzenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid,
fluorosulfonic acid, and perfluoroalkylsulfonic acid. In an especially preferred
embodiment -0-S0 2-R3 is trifluoromethanesulfonic acid. The group -0-S0 2-R3 can be
added in step (c) of the method of the invention by reaction of the compound of
Formula I with an electrophilic derivative of the desired -0-S0 2-R3 group, which is an
example of a "suitable form of X" . For example, where it is desired to add
trifluoromethanesulfonic 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 (c) 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 lb
wherein X is chloro can be obtained by reaction of the compound of Formula I with a
chloride-containing reagent such as thionyl chloride, phosphorous pentachloride (PCI5),
phosphorous trichloride (PCI3) , each of which are examples of a "suitable form of X" . A
compound of Formula lb wherein X is bromo can be obtained by reaction of a compound
of Formula I with a bromine-containing reagent such as hydrobromic acid (HBr) or
phosphorous tnbromide (PBr3) , again, each of which are examples of a "suitable form of
X".
The compound of Formula I is a useful precursor compound in the radiosynthesis of
certain 18 F-labelled compounds. Therefore, the present invention also provides a
radiosynthetic method to obtain a compound of Formula II:
wherein y is as defined for v of Formula I, wherein said method comprises;
(i) providing a compound of Formula I according to the method as defined
herein;
(ii) reaction of said compound of Formula I with a suitable source of 18Ffluoride
to obtain a compound of Formula lla:
wherein R3 , R32 and z are as defined for R , R2 and v of Formula I ,
respectively; and,
(iii) deprotection of the compound of Formula lla obtained in step (ii) to remove
R3 and R32.
[ 8F]-Fluoride ion is typically obtained as an aqueous solution which is a product of the
irradiation of an [ sO]-water target. Commonly, certain steps are carried out in order to
convert [ 8 F]-fluoride into a reactive nucleophilic reagent, before its use in nucleophilic
radiolabelling reactions. As with non-radioactive fluoridations, these steps include the
elimination of water from [ F]-fluoride ion and the provision of a suitable counterion
(Handbook of Radiopharmaceuticals 2003 Welch & Redvanly eds. Chapter 6 pp 195-227).
The radiofluorination reaction is then carried out using anhydrous solvents (Aigbirhio e a/
1995 J Fluor Chem; 70: pp 279-87).
To improve the reactivity of [ F]-fluoride ion for fluoridation reactions a cationic counterion
is added prior to the removal of water. The counterion should possess sufficient solubility
within the anhydrous reaction solvent to maintain the solubility of the [ 8 F]-fluoride ion.
Therefore, counterions that have been used include large but soft metal ions such as
rubidium or caesium, potassium complexed with a cryptand such as Kryptofix™, or
tetraalkylammonium salts. A preferred counterion for fluoridation reactions is potassium
complexed with a cryptand such as Kryptofix™ because of its good solubility in anhydrous
solvents and enhanced fluoride reactivity.
Deprotection step (iii) is carried out by methods that are well-known to those of skill in the
art. A wide range of protecting groups as well as methods for their removal are described
in 'Protective Groups in Organic Synthesis', Theorodora W. Greene and Peter G. M. Wuts,
(Fourth Edition, John Wiley & Sons, 2007). In a preferred embodiment, the carboxy
protecting group R3 is removed prior to the amino protecting group R32 . For example,
where R3 is Et it may be removed by basic hydrolysis and where R32 is Boc it may be
subsequently removed by acidic hydrolysis.
The range of suitable and preferred definitions of v as provided above for Formula I equally
apply to y and z of Formulae II and lla, respectively.
The range of suitable and preferred definitions of R1and R2 as provided above for Formula
I equally apply to R3 and R32, respectively of Formulae II and Ha.
In a preferred embodiment said compound of Formula I I is:
Compound 2
and said compound of Formula lla is:
Compound 2a
wherein Et is ethyl and Boc is terf-Butyloxycarbonyl.
In a preferred embodiment, steps (ii) and (iii) 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 Tracerlab™ 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 I I 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 [ 8F]-fluoride as
defined herein.
(iii) an ion-exchange cartridge for removal of excess [ 8F]-fluoride; 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 is a comparative example describing a prior art method to obtain a
compound of Formula I .
Example 2 describes a method to obtain a compound of Formula by means of the
present invention.
List of Abbreviations used in the Examples
aq aqueous
TLC thin layer chromatography
hr hour(s)
mmol millimole(s)
ml milliliter(s)
g gram(s)
w/w weight for weight
Et20 diethyl ether
min minute(s)
sat. saturated
Examples
Example 1: Prior Art Method to Obtain Compound 1
1(a) Synthesis and purification of Compound 1a
3-benzyloxycyclobutan-1-one is prepared according to the method described by
McConathy et al (Appl Radiat Isotop 2003; 58: 657-666). 3-benzyloxycyclobutan-1-one
is reacted with potassium cyanide, ammonium carbonate and ammonium chloride. 5-
(3-benzyloxycyclobutane)hydantoin , is isolated by crystallization from the reaction
mixture and ring-opened in refluxing Ba(OH)2 (sat.). The reaction mixture is
neutralized with H2S0 , precipitating BaS0 4 is filtered off and the amino acid is isolated
by evaporation of the filtrate. 1-Amino-3-benzyloxy-cyclobutanecarboxylic acid is
turned into 1-Amino-3-benzyloxy-cyclobutanecarboxylic acid ethyl ester by SOCI2 and
Et3N in ethanol. Concentration of the reaction mixture in vacuum gives 1-Amino-3-
benzyloxy-cyclobutanecarboxylic acid ethyl ester isolated as a salt mixture. The amino
group is Boc-protected using boc anhydride in Et3N and ethanol. 3-Benzyloxy-1-tertbutoxycarbonylamino-
cyclobutanecarboxylic acid ethyl ester (Compound 1a) is isolated
by extractive work-up, followed by flash chromatography.
1(b) Synthesis and purification of Compound 1b
Compound 1a (prepared according to Example 1(a); 3 1.83 g, 9 1 mmol)was dissolved
in ethanol (600 ml) and acetic acid (8 ml, 139 mmol) under an N2 atmosphere in a
reaction flask connected to an H2-supply. The resulting mixture was added moistened
Pd on carbon (6.28 g, 10% w/w). The N supply was closed and the reaction flask was
gently evacuated and filled with H2, the procedure was repeated twice. Additional H2
was added the reaction mixture when necessary. The reaction mixture was stirred at
ambient temperature for 2 days, until complete conversion (reaction progress
monitored by TLC). The reaction mixture was filtered through a glass fibre filter and the
filter cake was washed with ethanol (160 ml) before the filtrate was evaporated in vacuo
at <40°C to afford crude Compound 1b (24.64 g). Crude Compound 1b was redissolved
in dichloromethane (500 ml), added Si0 2 (65 g) and evaporated in vacuo at
<40°C to afford adsorbat for chromatographic purification.
System for flash chromatography: Si0 2 (360 g) was loaded into a glass column 0=13
cm to an approximate height of 5 cm and conditioned with heptane followed by heptane
added 30% ethyl acetate. The crude compound was loaded on top of the column as
adsorbat, sea sand (88 g) was carefully added on the top of the column. The column
was then eluted with: heptane added 30% ethyl acetate (3 fractions in total 2000 ml),
heptane added 50% ethyl acetate (8 fractions in total 2750 ml) and heptane added 70%
ethyl acetate (8 fractions in total 4000 ml). The product was isolated in fractions 8-19,
these fractions was combined and evaporated in vacuo at 38°C to afford Compound 1b
20.1 g (86%). Purity GC 99.8%.
1(c) Synthesis and purification of Compound 1
Compound 1b (20.1 g, 78 mmol) was dissolved in dichloromethane (500 ml) and added
pyridine (19 ml, 235 mmol), resulting solution cooled to <5°C and added triflic anhydride
(19.5 ml, 115 mmol) in portions over 30 min. The reaction temperature was kept <5°C
during the addition, upon complete addition the leaction mixture was stirred on an icebath
for 1 hr (reaction progress monitored by TLC), reaction quenched by addition of
water (500 ml). The mixture was extracted with Et20 (950 ml), water phase discarded,
organic phase washed with HCI (500 ml, 1M), brine (500 ml, sat.aq.) and dried over
Na2S0 (56 g). The crude mixture was filtered through a glass sinter funnel, filter cake
washed with Et20 (100 ml), combined filtrate evaporated in vacuo at <30°C to afford
crude Compound 1 (28.1 1 g). Crude Compound 1 was re-dissolved in dichloromethane
(400 ml), added Si0 2 (80 g) and evaporated in vacuo at <30°C to afford adsorbat for
chromatographic purification.
System for flash chromatography: Si0 2 (330 g) was loaded into a glass column 0=7 cm
to an approximate height of 19 cm and conditioned with pentane: diethyl ether (3:1 ) .
The crude compound was loaded on top of the column as adsorbat, sea sand (50 g)
was carefully added on the top of the column. The column was then eluted with
pentane: diethyl ether (3:1 ) , fraction size 250 ml, product was isolated in fractions 5-12
which was combined and evaporated in vacuo at <30°C to afford Compound 1 2 1.94
g . To this material in an evaporator flask was added diethyl ether (50 ml) and slowly
stirred on an evaporator at <35°C until all solids had dissolved. Heating turned off and
mixture slowly cooled to 25°C over 1 h 5 min, solution stirred slowly for 1 h and 20 min
at ambient temperature for 1 h 20 min. Subsequently the mixture was cooled to <5°C
and kept on this temperature for 20 min, before the mixture was further cooled to <-
20°C during 15 min and stirred at this temperature for 1 h 30 min. T e solution was
added heptane ( 1 10 ml) and stirred for 1 h 20 min. Crystals collected by filtration on a
pre cooled glass sinter funnel, and washed with ice cold heptane (110 ml, <-5°C). The
reaction afforded Compound 1 19.47 g (64 %), NMR purity + 99%.
Example 2: Method of the Invention to Obtain Compound 1
0.5300 g of crude Compound 1b prepared according to the method described in
Example 1(b) (i.e. including hydrogenation, filtration and evaporation but not flash
chromatography) was dissolved in 5 ml absolute ethanol at ambient temperature. The
solution was slowly concentrated up by blowing nitrogen. The crystals nucleated and
grew during the procedure. After about one hour the evaporation was stopped.
Amount of remaining ethanol was 0.3500 g (0.43 ml), and the mixture contained
significant amount of crystals. 1 ml n-heptane was added and the evaporation by
blowing continued. When the solvent mixture was almost evaporated (about 0.2 ml
solvent left), the evaporation was stopped and 1 ml n-heptane added. After 15 min. the
crystals were filtered off and washed with ~3ml n-heptane. The crystals were dried in
vacuum, the filtrate evaporated by blowing nitrogen and then dried in vacuum. The
isolated yield was 0.4873 g crystals (91 .9%), while recovery 92.9%:
The crystals are well filterable, the size can be controlled by evaporation rate and also
by addition rate of n-heptane.
Example 2: Method to Obtain Purified Compound 1b on a Lame Scale
Crude: Crude reaction mixture from hydrogenation of Compound 1a to Compound 1b
as ethanol solution after filtration of the catalyst and wash. Ethanol = 2.5-3.8 litre.
Equipment: Vacuum evaporator, evaporation flask, filtration equipment. The operation
can be performed in a large evaporator flask initially, and transfer into a small flask after
volume reduction. Alternatively, in a small flask of 500 or 1000 ml size, refilling the
content continuously or in small portions.
1. The clear solution is concentrated by evaporation in vacuum flask down to a
100-200 ml total volume. The solution nucleates and the product crystallizes,
forming a thick suspension.
2. 200 ml n-hexane is added and after 10 min stirring (rolling), the suspension is
concentrating up to about 150 ml volume.
3. A new portion of 200 ml n-heptane is added and Step 2 is repeated.
After 30 min. rolling (ambient temperature or bellow) the suspension is filtered
and the crystals washed by n-heptane.
The crystals are dried in vacuum.
Claims
A method to obtain a compound of Formula I :
wherein:
R represents a C1-5 straight- or branched-chain alkyl group;
R2 represents an amino protecting group;
v is an integer of 0 to 4; and,
X represents a leaving group selected from a halogen, or the group -0-S0 2-R3
wherein R3 is a halogen, a straight-chain or branched-chain C^o alkyl, a straightchain
or branched-chain C1- 0 haloalkyl, and a C6- o aryl
wherein said method comprises:
(a) debenzylation of a compound of Formula la:
wherein R , R12 and w are as defined for R , R2 and v of Formula I,
respectively;
crystallisation of the reaction mixture from step (a) to obtain purified
compound of Formula lb:
and x are as defined for R , R2 and v of Formula I,
(c) conversion of purified compound of Formula I obtained in step (b) into a
compound of Formula I by reaction with a suitable form of X wherein X is as
defined for Formula .
(2) The method as defined in Claim 1 wherein R , R and R2 are ethyl.
(3) The method as defined in either Claim 1 or Claim 2 wherein R2, R 2 and R22 are
selected from the group consisting of a f-butoxycarbonyl group, an allyloxycarbonyl
group, a phthalimide group and N-benzylideneamine substituent.
(4) The method as defined in any one of Claims 1-3 wherein v, w and x are 0 or 1.
(5) The method as defined in Claim 1wherein X is a group represented by the group -
0-S0 2-R3.
(6) The method as defined in Claim 5 wherein R3 is selected from the group consisting
of toluenesulfonic acid, nitrobenzenesulfonic acid, benzenesulfonic acid,
trifluoromethanesulfonic acid, fluorosulfonic acid, perfluoroalkylsulfonic acid,
trimethylstannyl and triethylstannyl.
(7) The method as defined in Claim 6 wherein R3 is trifluoromethanesulfonic acid.
(8) The method as defined in any one of Claims 1-7 wherein said compound of
Formula I is:
said compound of Formula lb is:
and said compound of Formula la is:
wherein Et is ethyl, OTf is trifluoromethanesulfonic acid and Boc is tert-
Butyloxycarbonyl.
(9) The method as defined in Claim 1 wherein X is halogen.
(10) The method as defined in Claim 10 wherein said halogen is bromo or chloro.
( 1 1) A radiosynthetic method to obtain a compound of Formula II:
wherein y is as defined for v in Claim 1, wherein said method comprises;
(i) providing a compound of Formula I according to the method as defined
in Claim 1;
(ii) reaction of said compound of Formula I with a suitable source of 8Ffluoride
to obtain a compound of Formula Ma:
wherein R3 1 , R32 and z are as defined in Claim 1 for R , R2 and v,
respectively; and,
(iii) deprotection of the compound of Formula la obtained in step (ii) to remove
R3 and R32.
(12) The method as defined in Claim 11 wherein said source of F-fluoride is 8Ffluoride
in the presence of a counterion wherein said counterion is selected from,
rubidium, caesium, potassium complexed with a cryptand, or a tetraalkylammonium
salt.
(13) The method as defined in either Claim 11 or Claim 12 wherein said deprotection
comprises removal of R3 followed by removal of R32.
(14) The method as defined in any one of Claims 11-13 wherein y and z are the same
and are 0 or .
The method as defined in any one of Claims 1-14 wherein R3 is ethyl.
The method as defined in any one of Claims 11-15 wherein R32 is a tbutoxycarbonyl
group.
The method as defined in any one of Claims 11-16 wherein said compound of
Formula I I is:
and said compound of Formula Ila is:
wherein Et is ethyl and Boc is te/f-Butyloxycarbonyl.
(18) The method as defined in Claim 17 wherein said deprotection step comprises
removal of Et by basic hydrolysis and removal of Boc by acidic hydrolysis.
( 19) The method as defined in any one of Claims 11-18 wherein steps (ii) and (iii) are
carried out on an automated synthesiser.