Preparation of N-Monofluoroalkyl Compounds.
Field of the Invention.
The present invention relates to an improved synthesis of N-monofluoroalkyl tropanes
using fluoroalkyl iodides or fluoroalkyl sulfonate esters. The invention also provides
the use of such method to prepare the non-radioactive tropane intermediate FP-CIT,
and its subsequent conversion to the 123~-labelleradd iopharmaceutical D ~ T S C A N ~ ~
(1231-ioflupane)A. lso provided is the use of fluoroalkyl iodides or fluoroalkyl
lo sulfonate esters in the alkylation method of the invention.
Background to the Invention.
DaTSCANT M (1 23I -ioflupane or 1 2 3F~P -CIT) is prepared as follows [Neumeyer et al,
J.Med.Chem., 37, 1558-1561 (1994)l:
SnFP-CT [12311 loflupane
The trialkyltin non-radioactive precursor SnFP-CT is prepared from nor-beta-CIT as
follows [Neumeyer et 01, J.Med.Chem., 37, 1558-1 561 (1 994)l:
FP-CIT
Chi et a1 [J. Org. Chem., 2, 658-664 (1 987)] describe a method for the Nfluoroalkylation
of amides and amines. The chemistry described is non-radioactive,
but is designed to be suitable for adaptation to the synthesis of the corresponding I8Flabelled
analogues. Spiperone was used as the model amide for amide N-alkylation,
and phenylpiperazine as the model amine for amine N-alkylation. The route uses the
steps:
5 (i) fluoride ion displacement of a haloalkyl triflate (i.e.
trifluoromethanesulfonate) to give a fluoroalkyl halide;
(ii) N-alkylation of an amidelamine by the fluoroalkyl halide from step (i).
Chi et a1 use only fluoroalkyl bromides for amine N-alkylation.
10 Shiue et a1 [J.Lab.Comp.Radiophann.,2 ,55-64( 1987)l describe the synthesis of
[18~]-fluoroalkylhalideass follows:
Hal-(CH,),-Hal t Hal-(CH,),-l8F
Kryptofix 2.2.2
n = 2 o r 3
Hal = Br or I.
15 The ['8~]-fluoroalkylhalides prepared were used to N-alkylate spiroperidol,
normetazocine and lorazepam.
Teng et crl [Nucl. Med. Biol., l7(8), 81 1-8 17 (1990)l describe the synthesis of the
SCH analogues shown:
R = -(CH2)3F compound 2a
R = -(CH~)~c'o~mFp ound 2b.
Compound 2a of Teng is the non-radioactive (19F) derivative, and is prepared by Nalkylation
of the R = H compound with 1-bromo-3-fluoropropane. Compound 2b of
25 Teng is the radioactive (18~d)e rivative, and is prepared by N-alkylation of the R = H
compound with 3-['s~]fluoro-1 - iodo-propane.
Lannoye et a1 [J.Med.Chem., 33,2430-2437 (1990)l prepare N-fluoroalkyl analogues
of the dopamine D-2 receptor antagonist raclopride. The alkylating agents used were
1-bromo-3-fluoropropane and 1-bromo-2-fluoroethane. Halldin et a1 [Nucl.Med.Biol.,
18(8), 87 1-88 1 (1 991)] disclose the preparation of N-- fluoroalkyl salicylamides, such
5 as raclopride and eticlopride, having N-(CH2)?F substituents, where n is 2 or 3 and y
is 18 or 19. The synthesis uses N-alkylation of the secondary amine substituent with
the bromo-fluoroalkane Br-(CH2)2F.
Swahn et a1 [J.Lab.Comp.Radiopharm.3,8 ,675-685 (1996)l describe the synthesis of
10 FP-CIT, and the corresponding N-(2-fluoroethyl) analogue (CIT-FE) via N-alkylation
of nor-beta-CIT using 1-brorno-3-fluoropropane and I-bromo-2-fluoroethane
respectively.
Lundkvist et a1 [Nucl.Med.Biol., 24,62 1-627 (1 997)] prepare the "F-labelled
15 analogue of '23~-ioflupanew, here the "F radiolabel is located in the N-fluoropropyl
group, via N-alkylation of nor-beta-CIT using '*F-(CH~)~-B~.
Stehouwer et a1 [J.Med.Chem., 48, 7080-7083 (2005)l prepare N-fluoroalkyl furansubstituted
tropanes as follows:
Br(CH,),F
-0 NE1,
P
CHCI,
Yu et a1 [Bioorg.Med.Chem., Mi, 6145-61 55 (2008)l prepare N-fluoroalkyl
isoquinoline carboxamide derivatives, via N-alkylation of a secondary amide using
25 sodium hydride and 1-bromo-3-fluoropropane or 1-bromo-2-fluoroethane.
Export or import of 1-bromo-3-fluoropropane (BFP) and related chemicals are,
however, now prohibited worldwide due to their ozone-depleting properties. There is
therefore a need for alternative viable syntheses of drugs and imaging agents which
30 comprise N-fluoroalkyl substituents.
The Present Invention.
The conventional synthetic route to N-monofluoroalkyl tropanes employs bromofluoroalkanes
of formula Br-(CH2),YF, where n is 2 or 3, and y is 18 or 19. There
appears to be a bias in the art towards using such bromo compounds, rather than the
5 iodo analogues. The logic is believed to be that, for simple alkylations (e.g. of
sterically unhindered primary amines), there is tendency to form overalkylated
products (e.g. quaternary ammonium salts) when using a reactive alkylating agent
such as an iodoalkane. Thus, there is a bias toward using bromoalkanes in simple
alkylations, as the lower reactivity of the bromoalkane affords improved control over
10 the degree of alkylation.
The problem with such bromo-fluoroalkanes is that they are recognized to be ozonedepleting.
They are therefore increasingly less acceptable to use by the relevant
Regulatory authorities, and of course would not be used by environmentally-
15 conscious drug or chemical manufacturers. Consequently, their commercial
availability is being discontinued, and their continued use is no longer appropriate.
There are, however, drug and/or imaging agent products which comprise such Nmonofluoroalkyl
tropanes.
20 The present invention provides a solution to the continued manufacture of such
desirable drug andlor imaging agent products, which avoids the use of such ozonedepleting
chemicals. Thus, BFP is a class 1 ozone depleter with an 0.02 - 0.7 ODP
(relative to CFC-1 I which has a reference value of 1). 3-Fluoro-1-iodo-propane (FIP)
has a boiling point of 127 OC [J.Org.Chem., 121,748-749 (1956)], so is less volatile
25 than BFP (boiling point 98- 10 1 OC). The list of ozone depleting agents in the
Montreal Protocol (which deals with reduced use of ozone depleting agents) includes
organic molecules, usually alkyl halides, containing fluorine, chlorine or bromine.
The most important process (regarding ozone depletion) is the catalytic destruction of
ozone by atomic chlorine and bromine. The main source of these elements are CFC
30 compounds (Freons) and halons (bromofluoro compounds). There are, however, no
iodine-containing compounds listed - which is an advantage for the iodine-containing
alkylating agents of the present invention.
The alkylating agents and methods of the present invention are expected to permit
faster N-allylation than with the bromoalkanes of the prior art. In addition, the less
prone an amine is to undergo alkylation, the more likely it is that the method of the
present invention will provide an improvement.
5
Detailed Description of the Invention.
In a first aspect, the present invention provides a method of preparation of an Nmonofluoroalkyl
tropane of Formula (IIIA):
10 (IIIA)
which method comprises:
(i) provision of a precursor which comprises an amine of Formula (111):
(ii) alkylation of said precursor with an alkylating agent of formula
F-(CH2)111Xin the presence of a base and optionally in the presence of an
iodide salt, in a suitable solvent, to give the N-monofluoroalkyl tropane of
Formula (IIIA),
wherein:
m is 2,3 or 4; and
X is 1 or -OS02Ra, where Ra is CI4 alkyl, C14 perfluoroalkyl or C5-8 aryl.
The precursor of Formula (111) is known in the art as N-nor-beta-CIT.
25
The term "base" has its conventional chemical meaning. A preferred such base is an
organic base. A preferred organic basis is triethylamine.
By the term "iodide salt" is meant an ionic salt of iodide ion with an alkali metal,
preferably sodium or potassium iodide, or a quaternary ammonium iodide (eg.
tetrabutylammonium iodide). A preferred such salt is sodium or potassium iodide,
most preferably potassium iodide.
5
Suitable solvents for the alkylation reaction of step (ii) are chosen such that the
precursor and alkylating agent are both soluble in the chosen solvent, and that the
solvent is stable in the presence of a base. Preferred such solvents include toluene and
DMF (dimethylformamide), and related solvents or mixtures thereof. Solvents
10 comprising ketone or ester functional groups are least preferred.
When X is -OS02Ra, and Ra is C5-8 aryl, suitable such aryl groups include phenyl
groups having a substituent in the 4-position chosen from methyl (tosylate or -OTs);
bromine (brosylate or -0Bs); and nitro (nosylate or -0Ns).
15
The tropane of Formula (IIIA) and the precursor of Formula (111) are drawn without
stereochemistry. The present formulae are intended to encompass all isomers,
diastereomers and enantiomers of the chemical structures shown.
20 Preferred features.
The precursor of the first aspect is preferably synthetic. The term "synthetic" has the
conventional meaning of the tern, i.e. man-made as opposed to being isolated from
natural sources eg. from the mammalian body. Such compounds have the advantage
that their manufacture and impurity profile can be fully controlled.
25
For the alkylating agents of the first aspect, m is preferably 2 or 3, most preferably 3.
When X is -OS02Ra, Ra is preferably chosen from -CH3 (mesylate -OMS), -CF3
(triflate -OTf) or -C6&CH3 (tosylate or -0Ts). In that case, the alkylating agent is a
mesylate, triflate or tosylate sulfonate ester respectively.
30
The alkylating agent is preferably F-(CH2),1., with the preferred values of m as
. specified above. The most preferred such alkylating agent is therefore F-(CH2)31.
In the prior art alkylation of N-nor-beta-CIT, it is necessary to use potassium iodide to
catalyse the alkylation using l-bromo-3-fluoropropane, together with heating in
toluene. Use of 3-fluoro- 1 -fluoro-propane permits the use of milder reaction
conditions, but still without overalkylation. When X is I, it is preferred to carry out
5 the method of the first aspect in the absence of an iodide salt, which simplifies the
procedure.
In Formula (IIIA), preferred m values are as specified above, and hence m is most
preferably 3. When m = 3, the product of Formula (IIIA) is FP-CIT or Ioflupane.
10 Preferred alkylating agents for preparing the compound of Formula (IIIA) are as
defined above, hence the most preferred alkylating agent is F-(CH2)31.
Nor-beta-CIT can be prepared by the method of Neumeyer et al [J.Med.Chem., 37,
1558-156 1 (1994)l. It is also commercially available from ABX GmbH, Heinrich-
15 Glaeser-Strasse 10- 14 D-0 1454 Radeberg, Germany.
The alkylating agents of formula F-(CH2),X, when X =I are commercially available
from Apollo Scientific (Whitefield Rd, Bredbury, Stockport, Cheshire SK6 2QR,
USA) and SynQuest Laboratories, Inc. (PO Box 309, Alachua, FL 32616-0309,
20 USA). They can also by prepared from the corresponding triflate F-(CH2),0Tf
(where Tf = triflate) by the method of Chi et a1 [J. Org. Chem., 52, 658-664 (1987)l.
The fluorinated alcohols F-(CH2),0H are commercially available from Sigma-
Aldrich, and can readily be converted to the corresponding sulfonate ester by standard
techniques.
25
Several sulfonate ester alkylating agents of formula F-(CH2),0S02Ra are also
commercially available. Such sulfonate esters can also be prepared by standard
methods, see eg. See "March's Advanced Organic Chemistry", fifth edition,
M.B.Smith and John Wiley & Sons 2001), page1687 which summarises such sulfonic
30 acid ester preparation methods in the textbook.
In a second aspect, the present invention provides a method of preparation of a
trialkyltin radioiodination precursor of Formula IV:
(IV)
5 wherein said method comprises:
(i) carrying out the method of the first aspect, to give the N-monofluoroalkyl
amine product of Formula (IIIA);
(ii) reaction of the compound of Formula (IIIA) from step (i) with sn2Rbs in
the presence of a suitable catalyst to give the desired radioiodination precursor
10 of Formula (IV);
where m is as defined in the first aspect, and
each R~ is independently C1-4 alkyl.
For the method of the second aspect, m and preferred aspects thereof are as defined in
15 the first aspect.
The organometallic precursors of Formula IV are useful in the preparation of
radiopharmaceuticals, as described in the third aspect (below).
20 Preferred R~ groups are methyl and butyl, more preferably methyl. Hexamethylditin
is commercially available from Sigma Aldrich. Hexabutylditin is commercially
available from Merck Schuchardt & Chemos. The preparation and use of organotin
precursors for radioiodination has been described by Bolton
[J.Lab.Comp,Radiopharm.4,5 ,485-528 (2002)l and Ali et a1 [Synthesis, 423-445
25 (1996)l.
In Formula (IV), m is preferably 3 and Rb is preferably methyl, such that the
compound of Formula IV is SnFPCT:
5 In a third aspect, the present invention provides the use of a compound of Formula (I)
or Formula (11) as defined in the first aspect as a precursor in the preparation method
of the first aspect.
For the use of the third aspect, compounds of Formula (I) or Formula (11) and
10 preferred aspects thereof are as defined in the first aspect.
In a third aspect, the present invention provides a method of preparation of a
radio iodinated tropane of Formula (IIIB):
(IIIB)
wherein said method comprises:
(a) carrying out the method of the first aspect, to give the Nmonofluoroalkyl
amine product of Formula (IIIA);
(b) carrying out the method of the second aspect, to obtain the
radioiodination precursor of Formula IV;
(c) reacting the trialkyltin precursor of Formula IV from step (b) with a
supply of radioactive iodide ["I]-iodide, in the presence of a suitable
oxidising agent to give the desired product of Formula (IIIB);
where '1' is ' 2 4 ~o r 123~.
Preferred values of m in the third aspect are as defined in the first aspect. In Formula
(IIIB), '1 is preferably '23~m, ore preferably "I is lZ3Ia nd m is 3, such that the
radioiodinated compound of Formula (IIIB) is '23~-ioflupane.
5 The radioiodinated tropane of Formula (IIIB) is preferably provided as a
pharmaceutical composition together with a biocompatible carrier medium. By the
term "biocompatible carrier medium" is a fluid, especially a liquid, in which the
labelled compound is suspended or dissolved, such that the composition is
physiologically tolerable, i.e. can be administered to the mammalian body without
10 toxicity or undue discomfort. The biocompatible carrier medium is suitably an
injectable carrier liquid such as sterile, pyrogen-free water for injection; an aqueous
solution such as saline (which may advantageously be balanced so that the final
product for injection is either isotonic or not hypotonic); an aqueous solution of one or
more tonicity-adjusting substances (eg. salts of plasma cations with biocompatible
15 counterions), sugars (e.g. glucose or sucrose), sugar alcohols (eg. sorbitol or mannitol),
glycols (eg. glycerol), or other non-ionic polyol materials (eg. polyethyleneglycols,
propylene glycols and the like). The biocompatible carrier medium may also
comprise biocompatible organic solvents such as ethanol. Such organic solvents are
useful to solubilise more lipophilic compounds or formulations. Preferably the
20 biocompatible carrier medium is pyrogen-fiee water for injection, isotonic saline or an
aqueous ethanol solution. Such aqueous ethanol solutions may have a range of
compositions, but 5-10% ethanol is preferred for the final composition. As indicated
above, the pH of the biocompatible carrier medium for intravenous injection is
suitably in the range 4.0 to 10.5. For the '23~-labelledra diopharmaceuticals of the
25 present invention, the pH of the biocompatible carrier medium is suitably 4.5 to 8.5,
preferably 4.6 to 8.0, most preferably 5.0 to 7.5.
The radiopharmaceutical compositions of the present invention are suitably supplied in
a clinical grade syringe or a container which is provided with a seal which is suitable
30 for single or multiple puncturing with a hypodermic needle (e.g. a crimped-on septum
seal closure) whilst maintaining sterile integrity. Such containers may contain single
doses (a "unit dose") or multiple patient doses. Suitable containers comprise a sealed
vessel which permits maintenance of sterile integrity and/or radioactive safety, whilst
permitting addition and withdrawal of solutions by syringe. A preferred such container
is a septum-sealed vial, wherein the gas-tight closure is crimped on with an oversea1
(typically of aluminium). Such containers have the additional advantage that the
closure can withstand vacuum if desired eg. to change the headspace gas or degas
solutions.
5
When the radiopharmaceutical is supplied in a multiple dose container, preferred such
containers comprise a single bulk vial (e.g. of 10 to 30 cm3 volume) which contains
enough radiopharmaceutical for multiple patient doses. Unit patient doses can thus be
withdrawn into clinical grade syringes at various time intervals during the viable
10 lifetime of the bulk vial preparation to suit the clinical situation.
Radiopharmaceutical syringes designed to contain a single human dose, or "unit dose"
and are therefore preferably a disposable or other syringe suitable for clinical use.
Such syringes may optionally be provided with a syringe shield to protect the operator
15 from radioactive dose. Suitable such radiopharmaceutical syringe shields are known
in the art, and various designs are commercially available, and preferably comprise
either lead or tungsten.
The radiopharmaceutical composition may optionally further comprise additional
20 components such as an antimicrobial preservative, pH-adjusting agent or filler. By the
term "antimicrobial preservative" is meant an agent which inhibits the growth of
potentially harmful micro-organisms such as bacteria, yeasts or moulds. The
antimicrobial preservative may also exhibit some bactericidal properties, depending on
the dose. The main role of the antimicrobial preservative(s) of the present invention is
25 to inhibit the growth of any such micro-organism in the radiopharmaceutical
composition. Suitable antimicrobial preservative(s) include: the parabens, ie. methyl,
ethyl, propyl or butyl paraben or mixtures thereof; benzyl alcohol; phenol; cresol;
cetrimide and thiomersal. Preferred antimicrobial preservative(s) are the parabens.
30 The term "pH-adjusting agent" means a compound or mixture of compounds useful to
ensure that the pH of the radiopharmaceutical composition is within acceptable limits
(approximately pH 4.0 to 8.5) for human or mammalian administration. Suitable such
pH-adjusting agents include pharmaceutically acceptable buffers, such as tricine,
phosphate buffer or TRIS [ie. tris(hydroxymethyl)aminomethane], and
pharmaceutically acceptable bases such as sodium carbonate, sodium bicarbonate or
mixtures thereof. For ' 2 3 ~ - ~a p~ref-err~ed~ bu~ffe,r is phosphate buffer.
5 By the term "filler" is meant a pharmaceutically acceptable bulking agent which may
facilitate material handling during product production. Suitable fillers include
inorganic salts such as sodium chloride, and water soluble sugars or sugar alcohols
such as sucrose, maltose, mannitol or trehalose.
lo The radiopharmaceuticals of the present invention may be prepared under aseptic
manufacture conditions to give the desired sterile, pyrogen-free product. The
radiopharmaceuticals may also be prepared under non-sterile conditions, followed by
terminal sterilisation using e.g. gamma-irradiation; autoclaving; dry heat; membrane
filtration (sometimes called sterile filtration); or chemical treatment (e.i. with ethylene
15 oxide).
In a fourth aspect, the present invention provides the use of a compound of formula
F-(CH2),X as an alkylating agent in the preparation of either:
(i) the compound of Formula (IIIA) as defined in the first aspect;
(ii) the compound of Formula (IV) as defined in the second aspect;
(iii) the compound of Formula (IIIB) as defined in the third aspect;
wherein m and X are as defined in the first aspect.
25 For the use of the fourth aspect, m and X and preferred aspects thereof are as defined
in the first aspect; preferred aspects of the compound of Formula (IV) are as defined
in the second aspect; and preferred aspects of the compound of Formula (IIIB) are as
defined in the third aspect.
30 In the fourth aspect, the compound of formula F-(CH2),X is preferably used as an
alkylating agent in the methods of preparation as described in the first, second and
third aspects.
In a fifth aspect, the present invention provides the use of an amine of Formula (111) as
defined in the first aspect as a precursor in the method of preparation of the first
aspect.
5 The invention is illustrated by the non-limiting Examples detailed below. Example I
shows that 3-fluoro-1-iodopropane gives yields at least comparable to l-bromo-3-
fluoropropane in the N-alkylation of N-nor-P-CIT.
10 Example 1: Alternative Synthesis of FP-CIT us in^ 3-Fluoro-1-iodopropane.
N-nor-P-CIT (0.33 mmol, 123 mg) was dissolved in toluene (20 ml/gram, approx. 2
ml). Added to this solution was 3-fluoro-1-iodopropane (0.43 mmol, 81 mg) and
triethylamine (0.45 mmol, 45 mg). The reaction mixture was heated to reflux under
an inert atmosphere (argodnitrogen). The reaction was essentially complete (as
15 verified by Thin Layer Chromatography, silica TLC plates eluted with hexane-diethyl
ether-triethyl amine) after 6 hours. The solvent was removed by in vacuo evaporation,
and the crude was treated with diethyl ether (6 ml) and the ether phase was analysed
by HPLC (reversed phase C 18, gradient acetonitrile-water-phosphate buffer, UV
detection at 230 nm). The crude contained 87% area of the desired FP-CIT.

CLAIMS.
1. A method of preparation of an N-monofluoroalkyl tropane of Formula (IIIA):
(IIIA)
which method comprises:
(i) provision of a precursor which comprises an amine of Formula (111):
(ii) alkylation of said precursor with an alkylating agent of formula
F-(CH2)rnX in the presence of a base and optionally in the presence of an
iodide salt, in a suitable solvent, to give the N-monofluoroalkyl tropane of
Formula (IIIA),
wherein:
m is 2,3 or 4; and
X is I or -OS02Ra, where Ra is Cl4 alkyl, C1-4 perfluoroalkyl or C54
aryl.
20
2. The method of Claim 1, where X is -OS02Ra and Ra is chosen from -CH3,
-CF3 or X6&CH3.
3. The method of Claim 1, where X is I.
25
4. The method of Claim 3, where m is 3 and the alkylating agent is F-(CH2)3-I.
5. A method of preparation of a trialkyltin radioiodination precursor of Formula
IV :
(IV)
wherein said method comprises:
(i) carrying out the method of any one of claims 1 to 4, to give the Nmonofluoroalkyl
amine product of Formula (IIIA);
(ii) reaction of the compound of Formula (IIIA) from step (i) with ~ n 2in~ ~ 6
the presence of a suitable catalyst to give the desired radioiodination precursor
10 of Formula (IV);
where m is as defined in claim 1, and
each R~ is independently C14 alkyl.
6. A method of preparation of a radioiodinated tropane of Formula (IIIB):
(IIIB)
wherein said method comprises:
(a) carrying out the method of any one of claims 1 to 4, to give the Nmonofluoroalkyl
amine product of Formula (IIIA);
(b) carrying out the method of claim 5, to obtain the radioiodination
precursor of Formula IV;
(c) reacting the trialkyltin precursor of Formula IV from step (b) with a
supply of radioactive iodide ["I]-iodide, in the presence of a suitable
oxidising agent to give the desired product of Formula (IIIB);
25 where "I is 1 2 4 o~r 123~.
7. The method of claim 6, where "I is '23~.
8. The method of claim 7 or claim 8, where the radioiodinated tropane of
Formula (IIIB) is provided as a pharmaceutical composition together with a
biocompat ible carrier medium.
5
9. The use of a compound of formula F-(CH2),X as an alkylating agent in the
preparation of either:
(i) the compound of Formula (IIIA) as defined in claim 1;
(ii) the compound of Formula (IV) as defined in claim 5;
(iii) the compound of Formula (IIIB) as defined in claim 6 or claim 7;
wherein m and X are as defined in Claim 1.
10. The use of claim 8, where the alkylating agent is as defined in any one of
Claims 2 to 4.
15
1 1. The use of claim 9 or claim 10,'where the method of preparation is asdefined
in any one of claims 1 to 8.
12 The use of an arnine of Formula (111) as defined in Claim 1 as a precursor in
20 the method of preparation of any one of claims 1 to 8.
Dated this 08/06/20 12
[HRISHIKE q6-bc RAY HA HURY]
ATTORNEY
-