FIELD OF INVENTION
The present invention relates to a novel chiral synthesis of N-acyl-(3-substituted)-(8-
substituted)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazines of Formula I, avoiding the use of
protection/deprotection step
BACKGROUND OF INVENTION
The synthesis of N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[l,2,4]triazolo[4,3-
a]pyrazines is disclosed in the literature, comprising a) the synthesis of (3-substituted)-
(8-substituted)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazine intermediates, followed by b)
a classical N-acylation (Scheme 1):
starting
material
Scheme 1: General synthetic scheme for the preparation of N-acyl-(3-substituted)-(8-
substituted)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazines according to the prior art.
Different synthetic approaches that are of general relevance to step a) of the synthesis of
chiral (3-substituted)-(8-substituted)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazine
intermediates are known in the literature. The below examples and experimental
conditions of relevant approaches provided are illustrative only.
In Method A(i) (see Scheme 2), the [l,2,4]triazolopyrazine core IIIa(i) is formed by
acetylation of 2-hydrazidopyrazine (step 1) followed by a cyclodehydration reaction (step
2), using procedures familiar to those skilled in the art. This methodology was initially
developed by Nelson and Potts (J. Org. Chem. 1962, 27, 3243-3248). Subsequent
reduction of the pyrazine ring with H2/Pd affords the [l,2,4]triazolo[4,3-a]piperazine
(step 3). This method is well described in the literature and has been used, for example,
in the Merck synthesis of Sitagliptin (Hansen et al., Org. Process Res. Dev. 2005, 9, 634-
639 and references therein).
la(i) lla(i) llla(i) IVa(i)
Scheme 2: Method A(i).
However, i) perusal of the existing literature indicates that this procedure is generally
used with substrates wherein R1 = H (i.e. non-chiral analogs, cf. Scheme 2), and ii) that
the application of this method to prepare chiral [l,2,4]triazolo[4,3-a]piperazine variant of
general Formula IVa(i) (in Method A(i)) has not been disclosed. The dearth of examples
of pyrazine substrates wherein R1 ¹ H in this methodology may be due to the difficulty
of pyrazine reduction step; noteworthy in this regard is the fact that in the optimized
process scale-up procedure reported by Hansen et a , the pyrazine (R1 = H) reduction
(step 3, Scheme 2) proceeded in merely 51% yield. In addition to the issue of chemical
yield, access to chiral substrates through reduction of [l,2,4]triazolopyrazine substrates
wherein R1 ¹ H would require the additional challenge of efficient asymmetric
hydrogenation conditions (in terms of both yield and chiral purity); this is currently not a
known procedure to the best of Applicant's knowledge. Thus application of Method A(i)
for chiral synthesis of [l,2,4]triazolo[4,3-a]piperazine structures is hitherto unknown.
Method A(ii) (cf. Scheme 3) is a variation on Method A(i) whereby the reduction of R1 ¹
H substituted [l,2,4]triazolopyrazine substrates is circumvented.
la(ii) lla(ii) llla(ii)
IVa(ii) Va(ii)
Scheme 3: Method A(ii).
This method has been reported by the Merck group in their studies related to Sitagliptin
(see, for example, Kowalchick et al., Bioorg. Med. Chem. Lett. 2007, 17, 5934-5939),
wherein Boc-protected intermediates depicted by general Formula IVa(ii) are
deprotonated with a strong base, such as w-butyllithium, in the presence of
tetramethylethylenediamine (TMEDA), followed by treatment of the thus generated
anion with an electrophile such as an alkyl halide (step 4, Scheme 3). The chiral variant
of this methodology has not been reported in the literature.
Inspired by the earlier work by Makino and Kato (JPH06 12826 1(A), 1994), yet another
alternative approach to the synthesis of [l,2,4]triazolo[4,3-a]piperazines was developed
using chloromethyloxadiazoles as a key reagent (Balsells et al., Org. Lett. 2005, 7, 1039-
1042). This methodology (Method B) is depicted in Scheme 4 below.
b Mlb IVb
Scheme 4: Method B.
As reported by Balsells et al., however, this approach proceeds in high yield mainly when
the strong electron-withdrawing R2= CF3 group is present in the chloromethyloxadiazole
reagent. In addition, the mechanism suggested by the said authors would render
application of this strategy unlikely, if not impossible, for a chiral synthesis of IVb
intermediates (cf. Scheme 4). Indeed, in the current literature only racemic or achiral
products are described using such an approach. Thus, application of Method B towards
preparation of chiral [l,2,4]triazolo[4,3-a]piperazine structures has never been disclosed.
Another well-known method for the preparation of [l,2,4]triazolo[4,3-a]piperazine
containing structures is shown in Scheme 5 below (Method C).
lc Mc Mlc iVc
Scheme 5: Method C. The symbol * denotes a well-defined configuration at the carbon
center next to which the said symbol is placed, i.e. the carbon atom to which the R1
group is attached in this scheme.
Addition of acetylhydrazide to piperazinoimidate (step 1) is followed by
cyclodehydration to form the fused triazolo ring (step 2). This method is well documented
in the literature although exemplified only through racemic or achiral structures; e.g.:
McCort and Pascal, Tetrahedron Lett, 1992, 33, 4443-4446; Brockunier et al.
WO 03/082817 A2; Chu-Moyer et al. US 6,414,149 Bl; Banka et al. WO2009/089462
Al. To the best of his knowledge, the Applicant is unaware of any published reports of
the application of this method for obtaining chiral products by starting from chiral
piperazinones (Ic in Scheme 5).
A synthesis of (R )-8-methyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine
compounds through general Method C has been previously described in international
patent application WO201 1/121 137 which is in the name of the Applicant. The
preparation disclosed therein is depicted in Scheme 6:
commercially
available
1.3 1.4 1.5 1.6 1.7
OR
EtOH, microwave (sealed tube)
Scheme 6: Synthesis of (R )-8-methyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine
intermediates according to WO201 1/121 137. Note: Steps 2 and 3 are particularly prone
to racemization despite the graphic depiction of chiral products for each of these steps
in the above scheme. Thus, obtaining intermediates/products in high chiral purity
(>80 ee) is feasible but not in a reproducible fashion.
Boc-protected ketopiperazine 1.2 was prepared and then converted to iminoether 1.3 by
using the Meerwein reagent (e.g. Et30BF 4) . Cyclodehydration reaction between the acyl
hydrazide 1.4 and the iminoether aforementioned was conducted either under forcing
thermal reflux conditions, or by applying excessive microwave irradiation in a sealed tube
typically for rather protracted reaction times (often days). When using microwave
irradiation, N-Boc deprotection occurred during the said cyclodehydration step; thus, a
deprotection step was typically not necessary to conduct (i.e., 1.3 + 1.4 ® 1.6 in Scheme
6). However, when thermal cyclodehydration conditions were applied, Boc-deprotection
step was required (i.e., 1.3 + 1.4 ® 1.5 ® 1.6).
As noted in Scheme 6 above, steps 2 and 3 have shortcomings that significantly limit the
application of the said procedure for uses wherein generation of chiral intermediates or
products are required in a reproducible fashion, as with the preparation of
pharmaceutically active ingredient, for instance. Step 2 is the piperazinoimidate
formation (i.e., 1.2 ® 1.3) and step 3 is the cyclodehydration step between the said
imidate and acetylhydrazide (i.e., 1.3 + 1.4 ® 1.5).
An important disadvantage of the Scheme 6 procedure is that racemization of the
stereogenic carbon center occurred frequently in steps 2-3. Consequently, the said
procedure furnished final products that were only infrequently of acceptable chiral purity;
in fact, much more frequently, the Scheme 6 procedures produced final products
represented by the general Formula 1.7 in what is considered essentially racemic by those
skilled in the art. As such, said method cannot be used in practice to prepare a
pharmaceutically active ingredient as this method does not reliably furnish chiral
intermediates (1.3, 1.5, 1.6; Scheme 6) and thus cannot be reliably used for obtaining
chiral products represented by the general Formula 1.7.
Another disadvantage of the Scheme 6 procedure is the excessively protracted reaction
time required for the cyclodehydration step (Scheme 6, 1.3 + 1.4 ® 1.5). Up to several
days (under forcing reaction conditions - see below) were always required with substrates
represented by the general Formula lie (Scheme 5) wherein R ¹ H, i.e. the more sterically
congested analogs, unlike the case with achiral substrates represented by the general
Formula lie (Scheme 5) wherein R = H. Such significantly protracted reaction times
(several days) are not practical for such cases as a cGMP scale-up synthesis required to
prepare a pharmaceutically active ingredient for clinical studies.
As adumbrated in the above paragraph, in the Scheme 6 procedure, the cyclodehydration
step required extremely forcing conditions. Thus, use of elevated temperatures at reflux
(for protracted durations), or additionally with application of essentially maximally
feasible (within margin of experimental safety) microwave irradiation (sealed vessel)
were often required.
Applicant resorted to a racemic synthesis from racemic 5,6,7,(8-methyl)-tetrahydro-
[l,2,4]triazolo[4,3-a]pyrazine followed by an additional chiral preparative HPLC
purification step after forming the final product of interest depicted by the general
Formula 1.7 in Scheme 6. While feasible on small scale for the initial research and
development phase, such an approach poses the problems of scalability in terms of time,
cost and general applicability to such needs as cGMP scale-up of a pharmaceutically
active ingredients, for instance.
An improved chiral synthesis of 5,6,7,(8-substituted)-tetrahydro-[l,2,4]triazolo[4,3-
a]pyrazine intermediates has then been described in international patent application
WO2013/050424 which is in the name of the Applicant.
This method is a variation on the method depicted in Scheme 6: the Boc protective group
of Scheme 6, which is a N-Csp2 protective group, was replaced by a N-Csp3 protective
group, preferably a benzylic protective group such as DMB, PMB or TMB.
The use of such a N-Csp3 protective group was observed to provide 5,6,7,(8-substituted)-
tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine chiral intermediates with a good enantiomeric
excess and in a reproducible fashion. Retention of stereochemistry was observed with
minimal if any racemization.
Even though the method described in WO2013/050424 enables chiral synthesis of Nacyl-(
3-substituted)-(8-substituted)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazines, the
Applicant conducted research to further improve the process, especially its scalability in
terms of time, cost, number of steps, while minimizing racemization. This is all the more
important as these compounds are useful as selective antagonists to neurokinin 3 receptor
(NK-3) thereby making such improved synthetic procedure of practical utility towards
development of such products as pharmaceutical active ingredients.
In contrast to all previously described methods, the new chiral synthetic procedure of the
present invention first involves an N-acylation step followed by the building of the
[l,2,4]triazolo[4,3-a]pyrazine core (Scheme 7):
Scheme 7: General synthetic scheme for the preparation of N-acyl-(3-substituted)-(8-
substituted)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazines of the invention.
This strategy, while described for the synthesis of non-chiral substrates (i.e. R1 = H) by
Glaxo Group Limited (WO 2010/125102 Al), was never applied to the chiral synthesis
of N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazines. As
explained above for the method of Scheme 6, protection of the amine nitrogen atom with
Boc N-Csp2 protective group (such as N-Boc) frequently resulted in impractically high
levels of racemization under the previously reported conditions. Despite the aforesaid
earlier findings, further efforts revealed that with more rigorously controlled milder
experimental conditions (lower temperature and shorter reaction time), presence of
specific N-Csp2 groups, such as N-Boc protective group or N-benzoyl substitution, can
still result in final products with acceptably low (<5 ) racemization. However these latter
findings were also contingent upon the nature of the 5-membered heterocyclic ring in
such a way that it can be of practical value to the target structures of interest by the
Applicant as antagonists to the neurokinin-3 receptor. Collectively the aforementioned
results are unexpected for those skilled in the art.
Therefore, the new synthetic procedure of the present invention presents the distinct
advantage of furnishing final desired targets with very high chiral purity while obviating
the need of additional protection/deprotection steps that will advantageously impact
production costs.
SUMMARY
The invention relates to a process of preparing chiral N-acyl-(3-substituted)-(8-
substituted)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazine of general Formula I :
or solvates thereof, wherein
R is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, preferably R is methyl, ethyl, npropyl,
hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or fluoromethyl;
more preferably R is methyl;
R2 is alkyl, alkoxyalkyl or haloalkyl, preferably R2 is methyl, ethyl, methoxymethyl,
trifluoromethyl, difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl or 2,2,2-
trifluoroethyl; more preferably R2 is methyl, ethyl, methoxymethyl, trifluoromethyl,
difluoromethyl or fluoromethyl; even more preferably R2 is methyl;
Ar is a phenyl group, optionally substituted by one or more substituent(s) selected from
H, halo, alkyl, alkoxy, haloalkyl, nitrile and thiophen-2-yl; preferably Ar is a phenyl
group, optionally substituted by one or more substituent(s) selected from H, F, CI, methyl,
methoxy, trifluoromethyl, nitrile and thiophen-2-yl; more preferably Ar is a phenyl group
substituted by H or F;
X1 is N and X2 is S or O; or X1 is S and X2 is N;
represents a single or a double bound depending on X1 and X2;
said process comprising the following steps:
a) reacting a compound of Formula A:
wherein R is as defined above;
with a compound of Formula B:
wherein Ar is as defined above; and Y is hydroxyl or halo, wherein halo is preferably F
or CI; more preferably Y is hydroxyl or CI, even more preferably Y is CI;
to obtain a compound of Formula C:
b) converting the compound of Formula C with a tri(Cl-C2 alkyl)oxonium salt, a (Cl-
C2)alkylsulfate, a (Cl-C2)chloroformate or PCl5/POCl3/(Cl-C2)hydroxyalkyl, so as to
obtain a compound of Formula D:
wherein Ar and R are as defined above, and R3 is C1-C2 alkyl;
in the presence of a base;
c) reacting the compound of Formula D with a compound of Formula E:
or a salt or solvate thereof, wherein X1, X2 and R2 are as defined above;
so as to obtain a compound of Formula I or solvate thereof.
According to the present invention, the reaction of each step is carried out under
controlled mild experimental conditions. Especially, the reaction is carried out at a
temperature equal to or below boiling point of the organic solvent, preferably at room
temperature.
In one embodiment, the process does not use any protecting group.
In one embodiment, the process proceeds with the retention of stereochemistry with
respect to the starting material.
The process according to the present invention preferably provides the R j-enantiomer of
compounds of Formula I .
The invention also refers to synthesis of chiral intermediates.
In one embodiment, the process provides chiral compounds of Formula C:
or solvates thereof, wherein R and Ar are as defined above.
In one preferred embodiment, compound C has Formula C-b2:
The invention also refers to compounds of Formula D:
or solvates thereof, wherein R , R3 and Ar are as defined above.
In one preferred embodiment, compound D has Formula D-l:
Preferred compounds of Formula C and Formula D are those wherein the stereoisomer
obtained is the Rj-enantiomer.
The invention also relates to the use of the compounds provided by the process or solvate
thereof, for the manufacture of a medicament, a pharmaceutical composition or a
pharmaceutically active ingredient.
DETAILED DESCRIPTION
Process
The invention relates to a novel chiral synthesis ofN-acyl-(3-substituted)-(8-substituted)-
5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazine compounds avoiding use of
protection/deprotection steps and thus, allowing achieving high chiral purity while
improving cost-effectiveness. Especially, the invention relates to a process of preparing
N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazine
compounds of Formula I :
(I)
or solvates thereof, wherein
R is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, preferably R is methyl, ethyl,
w-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or
fluoromethyl; more preferably R is methyl;
R2 is alkyl, alkoxyalkyl or haloalkyl, preferably R2 is methyl, ethyl,
methoxymethyl, trifluoromethyl, difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-
difluoroethyl or 2,2,2-trifluoroethyl; more preferably R2 is methyl, ethyl,
methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl; even more
preferably R2 is methyl;
Ar is a phenyl group, optionally substituted by one or more substituent(s) selected
from H, halo, alkyl, alkoxy, haloalkyl, nitrile and thiophen-2-yl; preferably Ar is a
phenyl group, optionally substituted by one or more substituent(s) selected from H,
F, CI, methyl, methoxy, trifluoromethyl, nitrile and thiophen-2-yl; more preferably
Ar is a phenyl group substituted by H or F;
X1 is N and X2 is S or O; or X1 is S and X2 is N;
represents a single or a double bound depending on X1 and X2;
said process comprising the following steps:
a) reacting a compound of Formula A:
wherein R is as defined above;
with a compound of Formula B:
wherein Ar is as defined above; and Y is hydroxyl or halo, wherein halo is
preferably F or CI; more preferably Y is hydroxyl or CI, even more preferably Y is
CI;
to obtain a compound of Formula C:
b) converting the compound of Formula C with a tri(Cl-C2 alkyl)oxonium salt, a (Cl-
C2)alkylsulfate, a (Cl-C2)chloroformate or PCl5/POCl3/(Cl-C2)hydroxyalkyl, so as to
obtain a compound of Formula D:
wherein Ar and R are as defined above, and R3 is C1-C2 alkyl;
in the presence of a base;
c) reacting the compound of Formula D with a compound of Formula E:
or a salt or solvate thereof, wherein X1, X2 and R2 are as defined above;
so as to obtain a compound of Formula I or solvate thereof.
The below description of the process of the invention applies to the process of the
invention as defined above, including all embodiments described.
According to a first embodiment, the process is carried out under controlled mild
experimental conditions.
Amide coupling step a) of the process as defined above is advantageously carried out in
an organic, preferably anhydrous, solvent, selected from dichloromethane, acetonitrile
preferably in dichloromethane.
The reaction is advantageously carried out at a temperature equal to or below boiling
point of the organic solvent, preferably at room temperature.
The term "room temperature" as used herein means a temperature comprised between
10 °C and 30 °C, preferably 20+5 °C.
In the case of compounds of Formula B wherein Y is a halo, the reaction is carried out in
the presence of a base selected from the group consisting of di- O-propylethylamine, Nmethylmorpholine,
triethylamine, preferably N-methylmorpholine. In the case of
compounds of Formula B wherein Y is a hydroxyl, the reaction is carried out on an
activated anhydride, ester, acylurea derivative of the latter said compounds - formed
through conventional amide bond forming reagent(s) involving the use of so-called
activating groups, such as isobutylchloroformate, DIC, DCC, HOBt, HATU, HBTU,
DEPBT under reaction conditions known to those skilled in the art. According to a
preferred embodiment, Y is a halo in compounds of Formula B and the reaction is carried
out in the presence of a base selected from the group consisting of di-isopropylethylamine,
N-methylmorpholine, triethylamine, preferably N-methylmorpholine.
Intermediates of Formula C may be optionally purified by silica gel flash chromatography
or silica gel chromatography, and/or precipitation, and/or trituration, and/or filtration,
and/or recrystallization.
The second step of the process, step b), is the conversion of the ketopiperazine compounds
of Formula C to iminoether compounds of Formula D.
Step b) proceeds without significant loss of chirality resulting in the corresponding
products of good enantiomeric purity as defined herein.
The procedure involves a tri(Cl-C2 alkyl)oxonium salt (Meerwein-type reagents), or
(Cl-C2)alkylsulfate, or (Cl-C2)chloroformate, or use of PC15/P0C13/(C1-
C2)hydroxyalkyl, preferably tri(Cl-C2 alkyl)oxonium salt (Meerwein-type reagents), or
(Cl-C2)alkylsulfate, more preferably tri(Cl-C2 alkyl)oxonium salt, and even more
preferably a tri(C2 alkyl)oxonium salt, such as Et3OBF4.
As set out above, step b) is carried out in the presence of a base.
Use of at least 2 equivalents of tri(Cl-C2 alkyl)oxonium salt with respect to the 3-
substituted-piperazin-2-one of Formula C was required to aid towards a more complete
conversion when step b) was carried out without a mild base additive, such as Na2C0 3,
as further discussed hereunder.
Without being bound by any theory, Applicant believes that formation of an acid such as
HBF4 may be a side-product with the use of moisture-sensitive tri(Cl-C2 alkyl)oxonium
salt (Meerwein-type reagents). Interestingly, there exist two literature references (See (a)
Sanchez et al., J. Org. Chem. 2001, 66, 5731-5735; (b) Kende et al., Org. Lett. 2003, 5,
3205-3208) that cite the use of mild bases such as Na2C0 3 in conjunction with the use of
Meerwein reagent although i) without offering any explicit rationale or detailed
experimental conditions. After extensive reaction optimization experiments, Applicant
found that addition of a base, especially Na2C03, with respect to the Meerwein reagent
helped minimize racemization. Applicant further observed that use of a mild base
additive, especially Na2C0 3, appears to also help accelerate the reaction towards
completion that in turn may contribute to minimizing racemization in such reactions.
The base is advantageously selected from the group consisting of sodium carbonate,
sodium bicarbonate, potassium carbonate or cesium carbonate, preferably the base is
sodium carbonate.
In a preferred embodiment, between 1 and 5, preferably about 1.8 mole equivalents with
respect to tri(Cl-C2 alkyl)oxonium salt of base are used.
The tri(Cl-C2 alkyl)oxonium salt is advantageously selected from the group consisting
of trimethyloxonium tetrafluoroborate, triethyloxonium tetrafluoroborate, preferably the
tri(Cl-C2 alkyl) oxonium salt is triethyloxonium tetrafluoroborate. In an advantageous
embodiment, between 1 and 2, preferably about 1.25, mole equivalents of tri(Cl-C2
alkyl)oxonium salt is used, with respect to the 3-substituted-piperazin-2-one.
The iminoether synthesis step b) is advantageously carried out in an organic, preferably
anhydrous, solvent, preferably dichloromethane.
The reaction is advantageously carried out at a temperature equal to or below the boiling
point of the organic solvent; preferably the reaction is carried out at room temperature.
Intermediates of Formula D may optionally be purified by flash or column
chromatography on silica gel.
The third step of the process, step c), is the preparation of triazolopiperazine compounds
of Formula I by condensation between an iminoether of Formula D and an acylhydrazide
of Formula E or a salt or solvate thereof.
Step c) is generally carried out at a temperature comprised between 50°C and 135°C,
preferably between 50°C and 90°C; more preferably the temperature is about 70°C.
Compounds of Formula I may optionally be purified by silica gel flash chromatography
or silica gel chromatography, and/or precipitation, and/or trituration, and/or filtration,
and/or recrystallization.
The process of the invention provides compounds of Formula I or solvate thereof having
good enantiomeric excess of up to 97 % and possibly more in a reproducible fashion.
The process of the invention proceeds with the retention of stereochemistry with respect
to the starting material except to the extent that racemization occurs as a minor sidereaction;
thus the configuration at position 8 of the ring is defined by the configuration of
the aforesaid chiral starting material.
According to an advantageous embodiment, through the use of chiral 3-substitutedpiperazin-
2-one starting material, the process of the invention provides access to N-acyl-
(3-substituted)-(8-substituted)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazines by
minimizing any intervening racemization during the process.
Compounds of Formula I
The process of invention provides compounds of Formula I ; preferably said compounds
are the (R)-enantiomer.
According to the present invention, preferred compounds of Formula I are those of
Formula :
and pharmaceutically acceptable solvates thereof, wherein
R is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, preferably R is methyl, ethyl,
w-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or
fluoromethyl; more preferably R is methyl;
R2 is alkyl, alkoxyalkyl or haloalkyl, preferably R2 is methyl, ethyl,
methoxymethyl, trifluoromethyl, difluoromethyl, fluoromethyl, l-fluoroethyl, 1,1-
difluoroethyl or 2,2,2-trifluoroethyl; more preferably R2 is methyl, ethyl,
methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl; even more
preferably R2 is methyl;
Ra Ra% Rb, Rb' and R represent independently H, halo, alkyl, alkoxy, haloalkyl,
nitrile or thiophen-2-yl; preferably H, F, CI, methyl, methoxy, trifluoromethyl,
nitrile or thiophen-2-yl; more preferably H or F;
X1 is N and X2 is S or O; or X1 is S and X2 is N.
embodiment, preferred compounds of Formula I are those of Formula la:
and pharmaceutically acceptable solvates thereof, wherein R , R2, Ra, Ra', Rb, Rb'
and Rc are as defined above.
In one embodiment, preferred compounds of Formula la are those of Formula la':
and pharmaceutically acceptable solvates thereof, wherein
R is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, preferably R is methyl, ethyl,
w-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or
fluoromethyl; more preferably R is methyl;
R2 is alkyl, alkoxyalkyl or haloalkyl, preferably R2 is methyl, ethyl,
methoxymethyl, trifluoromethyl, difluoromethyl, fluoromethyl, l-fluoroethyl, 1,1-
difluoroethyl or 2,2,2-trifluoroethyl; more preferably R2 is methyl, ethyl,
methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl; even more
preferably R2 is methyl;
Ra Ra% Rb, Rb' and R represent independently H, halo, alkyl, alkoxy, haloalkyl,
nitrile or thiophen-2-yl; preferably H, F, CI, methyl, methoxy, trifluoromethyl,
nitrile or thiophen-2-yl; more preferably H or F.
According to one embodiment, preferred compounds of Formula la and la' and
pharmaceutically acceptable solvates thereof are those wherein:
R is methyl, ethyl, w-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl,
difluoromethyl or fluoromethyl; preferably R is methyl;
R2 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl, fluoromethyl,
l-fluoroethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl; preferably R2 is methyl,
ethyl, methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl; more
preferably R2 is methyl;
Ra is H, F or methyl;
Ra' is H;
Rb is H, F, CI or methoxy;
Rb' is H or F; and
R is H, F, CI, methyl, trifhioromethyl or nitrile.
In one embodiment, preferred compounds of Formula I are those of Formula Ia-1:
and pharmaceutically acceptable solvates thereof, wherein:
Rc is H, F, CI, methyl, trifluoromethyl or nitrile; preferably R is H, F or CI;
R is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, preferably R is methyl, ethyl,
w-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or
fluoromethyl; more preferably R is methyl; and
R2 is alkyl, alkoxyalkyl or haloalkyl, preferably R2 is methyl, ethyl,
methoxymethyl, trifluoromethyl, difluoromethyl, fluoromethyl, l-fluoroethyl, 1,1-
difluoroethyl or 2,2,2-trifluoroethyl; more preferably R2 is methyl, ethyl,
methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl; even more
preferably R2 is methyl.
In one embodiment, preferred compounds of Formula Ia-1 are those of Formula Ia- :
(Ia-1')
and pharmaceutically acceptable solvates thereof, wherein:
R , R2 and R are as defined in Formula Ia-1.
In one embodiment, preferred compounds of Formula la are those of Formula Ia-2:
and pharmaceutically acceptable solvates thereof, wherein Ra, Ra', R , R ', Rc and R2 are
as defined in Formula .
In one embodiment, preferred compounds of Formula Ia-2 are those of Formula Ia-2'
and pharmaceutically acceptable solvates thereof, wherein Ra, Ra', R , R ', Rc and R2 are
as defined in Formula .
According to one embodiment, preferred compounds of Formula Ia-2 and Ia-2' and
pharmaceutically acceptable solvates thereof are those wherein:
R2 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl, fluoromethyl,
1-fluoroethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl; more preferably R2 is
methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl;
even more preferably R2 is methyl;
Ra is H;
Rb is H;
Rb' is H; and
one embodiment, preferred compounds of Formula la are those of Formula Ia-3
and pharmaceutically acceptable solvates thereof, wherein Ra, Ra', Rb, Rb', Rc and R are
as defined in Formula .
In one embodiment, preferred compounds of Formula Ia-3 are those of Formula Ia-3' :
and pharmaceutically acceptable solvates thereof, wherein Ra, Ra', Rb, Rb', Rc and R are
as defined in Formula .
In one embodiment, preferred compounds of Formula I are those of Formula lb:
and pharmaceutically acceptable solvates thereof, wherein
R is F or thiophen-2-yl; preferably R is F.
R2 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl, fluoromethyl,
1-fluoroethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl, preferably R2 is methyl,
ethyl, trifluoromethyl, difluoromethyl or fluoromethyl, preferably R2 is methyl,
ethyl, 1-fluoroethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl, preferably R2 is
methyl or ethyl, preferably R2 is methyl.
According to one embodiment, compounds of Formula lb do not comprise compound
wherein R is thiophen-2-yl when R2 is methyl.
In one embodiment, preferred compounds of Formula lb are those of Formula lb':
and pharmaceutically acceptable solvates thereof, wherein R and R2 are as defined in
Formula Ib.
In one embodiment, preferred compounds of Formula lb' are those wherein R is F when
R2 is methyl.
In one embodiment, preferred compounds of Formula lb' are those of Formula Ib-1:
and pharmaceutically acceptable solvates thereof, wherein R2 are as defined in Formula
lb.
In one embodiment, preferred compounds of Formula I are those of Formula Ic:
and pharmaceutically acceptable solvates thereof, wherein Ra, Ra', Rb, Rb', Rc, R and R2
are as defined in Formula .
In one embodiment, preferred compounds of Formula Ic are those of Formula Ic' :
and pharmaceutically acceptable solvates thereof, wherein Ra, Ra', Rb, Rb', Rc, R
and R2 are as defined in Formula Ic.
Preferred compounds of Formula Ic and Ic' and pharmaceutically acceptable
solvates thereof are those wherein:
Ra is H, F or methyl;
Rb is H, F, CI or methoxy;
Rb' is H or F;
Rc is H, F, CI, methyl, trifluoromethyl or nitrile;
R is methyl, ethyl, w-propyl or hydroxyethyl;
R2 is methyl, ethyl or trifluoromethyl.
Particularly preferred compounds of Formula I of the invention are those listed in Table
1 hereafter.
TABLE 1

In Table 1, the term "Cpd" means compound.
The compounds of Table 1 were named using ChemBioDraw Ultra version 12.0
(PerkinElmer).
Synthesis intermediates
In another aspect, the invention provides intermediates for the synthesis of compounds of
Formula I, in particular according to the process of the invention.
Especially, the process of the invention provides compounds of general Formula C:
and pharmaceutically acceptable solvates thereof, wherein Ar and R are as defined in
Formula I .
In one embodiment, preferred compounds of Formula C or solvates thereof are those of
Formula C-a:
and pharmaceutically acceptable solvates thereof, wherein
R is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, preferably R is methyl, ethyl,
w-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or
fluoromethyl; more preferably R is methyl;
Ra Ra% Rb, Rb' and R represent independently H, halo, alkyl, alkoxy, haloalkyl,
nitrile or thiophen-2-yl; preferably H, F, CI, methyl, methoxy, trifluoromethyl,
nitrile or thiophen-2-yl; more preferably H or F.
In one preferred embodiment, compound of Formula C is the (R)-enantiomer.
In one embodiment, preferred compounds of Formula C or solvates thereof are those of
Formula C-b:
and pharmaceutically acceptable solvates thereof, wherein, R and R are as defined in
Formula C-a.
In one embodiment, preferred compounds of Formula C and solvates thereof are those of
Formula C-b':
and pharmaceutically acceptable solvates thereof, wherein R and R are as defined in
Formula C-a.
In one embodiment, preferred compounds of Formula C and solvates thereof are those of
Formula C-a-1:
and pharmaceutically acceptable solvates thereof, wherein Ra, Ra R , R ' and R are as
defined in Formula C-a.
In one embodiment, preferred compounds of Formula C and solvates thereof are those of
Formula C-a- :
(C-a-1)
and pharmaceutically acceptable solvates thereof, wherein Ra, Ra R , R ' , and R are as
defined in Formula C-a.
In one embodiment, preferred compounds of Formula C and solvates thereof are those of
Formula C-bl:
and pharmaceutically acceptable solvates thereof, wherein R is as defined in Formula Ca.
In one embodiment, preferred compounds of Formula C and solvates thereof are those of
Formula C-bl':
and pharmaceutically acceptable solvates thereof, wherein R is as defined in Formula Ca.
In one preferred embodiment, preferred compounds of Formula C and solvates thereof
are compound of Formula C-b2:
In one embodiment, preferred compounds of Formula C and solvates thereof are
compound of Formula C-b2' :
and pharmaceutically acceptable solvates thereof.
The process of the invention also provides compounds of general Formula D:
and pharmaceutically acceptable solvates thereof, wherein Ar and R are as defined
above, and R3 is C1-C2 alkyl.
In a preferred embodiment, compound of Formula D is compound of Formula D-1 ((3-
ethoxy-2-methyl-5,6-dihydropyrazin-l(2H)-yl)(4-fluorophenyl)methanone):
In one preferred embodiment, compound of Formula D is the (R )-enantiomer.
DEFINITIONS
In the present invention, the following terms have the following meanings:
The term "about" preceding a figure means plus or less 10% of the value of said figure.
The term "halo" or "halogen" means fluoro, chloro, bromo, or iodo. Preferred halo
groups are fluoro and chloro.
The term "alkyl" by itself or as part of another substituent refers to a hydrocarbyl radical
of Formula CnH2n+i wherein n is a number greater than or equal to 1. "Cx-Cy-alkyl" refer
to alkyl groups which comprise from x to y carbon atoms. Generally, alkyl groups of this
invention comprise from 1 to 4 carbon atoms (C1-C4), preferably from 1 to 3 carbon
atoms (C1-C3), more preferably from 1 to 2 carbon atoms (C1-C2). Alkyl groups may be
linear or branched. Suitable alkyl groups include but are not limited to methyl, ethyl, npropyl,
/-propyl, n-butyl, /-butyl, -butyl and i-butyl.
The term "haloalkyl" alone or in combination, refers to an alkyl radical having the
meaning as defined above wherein one or more hydrogens are replaced with a halogen as
defined above. Non-limiting examples of such haloalkyl radicals include chloromethyl,
1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the
like.
The term "alkoxy" refers to any group -O-alkyl, wherein alkyl is as defined above.
Suitable alkoxy groups include for example methoxy, ethoxy, n-propoxy, isopropoxy, nbutoxy,
f-butoxy, sec-butoxy, and n-pentoxy.
The term "alkoxyalkyl" refers to any group -alkyl-O-alkyl, wherein alkyl is as defined
above.
The term "hydroxyalkyl" refers to any group -alkyl-OH, wherein alkyl is as defined
above. The term "(Cl-C2)hydroxyalkyl" refers to any (Cl-C2)alkyl-OH.
The term "(Cl-C2)alkylsulfate" refers to any (Cl-C2)alkyl-O-SO compound, wherein
alkyl is as defined above.
The term "(Cl-C2)chloroformate" refers to any (Cl-C2)alkyl -0 -COCl compound,
wherein alkyl is as defined above.
The term "tri(Cl-C2 alkyl)oxonium salt" refers to any salt of [Cl-C2)alkyl ]3-0 +,
wherein alkyl is as defined above.
The term "thiophen-2-yl" as used herein means a group of formula
arrow defines the attachment point.
The term "ester" or "esters" as used herein means a group selected the group consisting
of unsubstituted C1-C4 alkyloxycarbonyl, unsubstituted phenyloxycarbonyl or
unsubstituted phenyl(Cl-C2 alkyl)oxycarbonyl. Suitable ester groups include
methyloxycarbonyl, ethyloxycarbonyl, w-propyloxycarbonyl, z-propyloxycarbonyl, nbutyloxycarbonyl,
z-butyloxycarbonyl, s-butyloxycarbonyl, i-butyloxycarbonyl,
phenyloxycarbonyl, benzyloxycarbonyl and phenethyloxycarbonyl, among which
methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, z-propyloxycarbonyl,
phenyloxycarbonyl, and benzyloxycarbonyl are preferred.
The term "protecting group" refers to a suitable organic moiety used to protect a certain
functional group in a chemical synthesis. In the present invention, protecting group refers
to an organic moiety selected from 2,4-dimethoxybenzyl (DMB), 4-methoxybenzyl
(PMB), iert-butoxycarbonyl (Boc), allyl, diphenyl-phosphiramide (DPP) and/or 2-
trimethylsilylethanesulfonyl (SES) .
The numbering scheme for N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-
[l,2,4]triazolo[4,3-a]pyrazines of the invention is shown in the below:
O R
The compounds of Formula I and subformulae thereof contain a stereogenic carbon center
at position 8 and thus may exist as (R)- and (Sj-enantiomers. The use of a solid line to
depict the bond between position 8 of the ring and R1, with a star next to position 8, (i.e.
*) indicates that the individual enantiomers are meant, thus excluding racemic
mixtures thereof.
A solid wedge (— ) for the bond between position 8 of the ring and R1 is used to depict
the (5,)-enantiomer and a dotted wedge ( ) for the bond between position 8 of the ring
and R1 is used to depict the (R )-enantiomer.
The term "solvate" is used herein to describe a compound in this invention that contain
stoechiometric or sub-stoechiometric amounts of one or more pharmaceutically
acceptable solvent molecule such as ethanol. The term "hydrate" refers to when the said
solvent is water.
All references to compounds of Formula I include references to solvates, multicomponent
complexes and liquid crystals thereof.
The compounds of the invention include compounds of Formula I, Formula C and
Formula D as hereinbefore defined, including all polymorphs and crystal habits thereof,
prodrugs and isomers thereof (including tautomeric isomers) and isotopically-labeled
compounds of Formula I .
In addition, with respect to the salts of the compounds of the invention, it should be noted
that the invention in its broadest sense also included salts, which may for example be used
in the isolation and/or purification of the compounds of the invention. For example, salts
formed with optically active acids or bases may be used to form diastereoisomeric salts
that can facilitate the separation of optically active isomers of the compounds of Formula
E above.
EXAMPLES
The present invention will be better understood with reference to the following examples.
These examples are intended to be representative of specific embodiments of the
invention, and are not intended as limiting the scope of the invention.
CHEMISTRY EXAMPLES
Reaction schemes as described in the example section illustrate by way of example
different possible approaches.
All reported temperatures are expressed in degrees Celsius (°C); all reactions were carried
out at room temperature (RT) unless otherwise stated.
All reactions were followed by thin layer chromatography (TLC) analysis (TLC plates,
silica gel 60 F254, Merck) was used to monitor reactions, establish silica-gel flash
chromatography conditions. All other TLC developing agents/visualization techniques,
experimental set-up or purification procedures that were used in this invention, when not
described in specific details, are assumed to be known to those conversant in the art and
are described in such standard reference manuals as: i) Gordon, A. J.; Ford, R. A. "The
Chemist's Companion - A Handbook of Practical Data, Techniques, and References",
Wiley: New York, 1972; ii) Vogel's Textbook of Practical Organic Chemistry, Pearson
Prentice Hall: London, 1989.
HPLC-MS spectra were typically obtained on an Agilent LCMS using electropsray
ionization (ESI). The Agilent instrument includes an autosampler 1200, a binary pump
1100, an ultraviolet multi-wavelength detector 1100 and a 6100 single-quad massspectrometer.
The chromatography column used was Sunfire 3.5 mih, C18, 3.0 x 50 mm
in dimensions. Eluent typically used was a mixture of solution A (0.1% TFA in H20 ) and
solution B (0.1% TFA in MeCN). Gradient was applied at a flow rate of 1.3 mL per
minute as follows: gradient A: held the initial conditions of 5% solution B for 0.2 min,
increased linearly to 95% solution B in 6 min, held at 95% during 1.75 min, returned to
initial conditions in 0.25 min and maintained for 2.0 min; gradient B: held the initial
conditions of 5% solution B for 0.2 min, increased linearly to 95% in 2.0 min, held at
95% during 1.75 min, returned to initial conditions in 0.25 min and maintained for 2 min.
Determination of chiral purity was made using chiral HPLC that was performed on an
Agilent 1100 (binary pump and a ultraviolet multi wavelength detector) with manual or
automatic (Autosampler 1100) injection capabilities. Column used is CHIRALPAK IA
5 mih, 4.6 x 250 mm in isocratic mode. Choice of eluent was predicated on the specifics
of each separation. Further details concerning the chiral HPLC methods used are provided
below:
Method A: column CHIRALPAK IA 5 mpi, 4.6 x 250 mm, eluent: DCM/EtOH (98:2 v/v)
plus 0.1% of DEA, flow rate: 1.0 mL per minute; UV detection at 254 nm; column at RT,
eluent was used as sample solvent.
Method B: column CHIRALPAK IA 5mih 4.6 x 250 mm, eluent: MTBE plus 0.1% of
DEA, flow rate: 1.0 mL per minute; UV detection at 254 nm, column at RT, eluent was
used as sample solvent.
(300 MHz), 1 F-NMR (282 MHz) and 1 C NMR (75 MHz) spectra were recorded on
a Bruker Avance ARX 300 instrument. Chemical shifts are expressed in parts per million,
(ppm, d units). Coupling constants are expressed in Hertz (Hz). Abbreviations for
multiplicities observed in NMR spectra are as follows: s (singlet), d (doublet), t (triplet),
q (quadruplet), m (multiplet), br (broad).
Solvents, reagents and starting materials were purchased and used as received from
commercial vendors unless otherwise specified.
The following abbreviations are used:
DCM: Dichloromethane,
DEA: diethylamine,
ee: Enantiomeric excess,
EtOAc: Ethyl acetate,
EtOH: Ethanol,
L: Liter(s),
MeOH: Methanol,
mL: Milliliter(s),
mmol: Millimole(s),
min: Minute(s),
MTBE: methyl tert-butyl ether,
P: UV purity at 254 nm or 215 nm determined by HPLC-MS,
RT: Room temperature.
All compounds disclosed in the present application were named using ChemDraw Ultra
12® purchased from CambridgeSoft (Cambridge, MA, USA).
B C
Scheme 1: General synthetic scheme.
General Method A: Acylation of ketopiperazine A by B to afford C
B
Scheme 2: Acylation of A.
General Method A is illustrated by the synthesis of intermediate (R)-4-(4-fluorobenzoyl)-
3-methylpiperazin-2-one (i.e. compound C wherein Ar is 4-F-Ph and R is (R)-Me).
To a solution of (R )-3-methylpiperazin-2-one (14 g, 123 mmol) in commercial anhydrous
DCM (400 mL) at RT was added 4-methylmorpholine (12.8 mL, 125 mmol) dropwise
over 1 min, followed by 4-fluorobenzoyl chloride (14.5 mL, 123 mmol) dropwise over 5
min. The reaction mixture was stirred at RT for 10 min and then washed with HC1 (1M,
150 mL) and NaOH (1M, 150 mL). The organic layer was dried over MgS0 4, filtered and
evaporated under reduced pressure (1-2 mbar). The residue obtained was solubilized in a
hot mixture of DCM (140 mL) and MTBE (315 mL). Pentane (350 mL) was then added
until a cloudy solution was obtained. After 5 min at RT and 14 h at 4°C (freezer), the
white crystals were filtered off, washed with pentane (140 mL) and dried under vacuum
(1-2 mbar, 40 °C) for 1 hour to afford white needles. Yield: 27.6 g, 95 . HPLC-MS: P
> 99 , tR = 1.8 min, (M+H)+: 237; Chiral HPLC - Method A: ee > 99.9; ^-NMR
(CDC13) : d 7.4 (m, 2H), 7.1 (m, 2H), 6.4 (bs, 1H), 4.8 (m, 1H), 4.3 (m, 1H), 3.5 (m, 1H),
3.3 (m, 2H), 1.5 (d, J = 6.9 Hz, 3H); 19F-NMR (CDCI3): d -97.4 (s, IF).
General Method B : Iminoether D formation from acylated ketopiperazine C
C D
Scheme 3: Iminoether formation.
General Method B is illustrated by the synthesis of intermediate (R )-(3-ethoxy-2-methyl-
5,6-dihydropyrazin-l(2H)-yl)(4-fluorophenyl)methanone (i.e. compound D wherein Ar
is 4-F-Ph and R is (R )-Me).
To a suspension of sodium carbonate (0.3 g, 2.86 mmol) in DCM (1.3 mL) at 0°C was
added (R )-4-(4-fluorobenzoyl)-3-methylpiperazin-2-one (0.3 g, 1.27 mmol) in one
portion, followed by commercial triethyloxonium tetrafluoroborate (0.3 g, 1.59 mmol) in
one portion. Thereafter the reaction mixture was stirred further at RT for 45 min,
whereupon the reaction mixture was diluted with brine (20 mL). The layers were
separated and the aqueous layer was further extracted with DCM (20 mL). The organic
layers were combined, dried over MgS0 4, filtered and concentrated under reduced
pressure. The crude compound was then purified on silica gel (EtOAc) to afford the
desired product as colorless oil. Yield: 0.16 g, 47 %. HPLC-MS: P = 96 , tR = 1.8 min,
(M+H20+H) +: 283; Chiral HPLC - Method B: ee > 99.9; -NMRn (CDC13) : d 7.4 (m,
2H), 7.1 (m, 2H), 4.9 (m, 1H), 4.1 (m, 2H), 3.5 (m, 3H), 3.1 (m, 1H), 1.4 (m, 3H), 1.2 (m,
3H); 1 F-NMR (CDC13) : d -96.7 (s, IF).
General Method C: Triazolopiperazine I formation from iminoether D
Scheme 4: Triazolopiperazine formation.
General Method C is illustrated by the synthesis of (R )-(4-fluorophenyl)(8-methyl-3-(3-
methyl-l,2,4-thiadiazol-5-yl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-
yl)methanone (i.e. compound I wherein Ar is 4-F-Ph, R is (R )-Me, R2 is Me, X1 = N and
X2 = S - Compound 1).
To (R )-(3-ethoxy-2-methyl-5,6-dihydropyrazin-l(2H)-yl)(4-fluorophenyl) (0.16 g,
0.6 mmol) at RT was added 3-methyl-l,2,4-thiadiazole-5-carbohydrazide (0.10 g,
0.6 mmol) in one portion. The mixture was diluted with commercially anhydrous MeOH
(0.6 mL) and the resulting mixture was heated to 70 °C for 5h.
The reaction mixture was then allowed to reach RT whereupon the solvent was removed
under reduced pressure (1-2 mbar). The crude residue was then dissolved in DCM
(25 mL), and thus-obtained organic phase washed with NaOH (1 M, 25 mL) and HC1
(1 M, 25 mL). The organic layer was then dried over MgS0 4, filtered and concentrated
under reduced pressure (1-2 mbar) to afford the desired product as colorless oil. Yield:
0.10 g, 45 .
Compound 1 : HPLC-MS: P = 94 , tR = 2.1 min, (M+H)+: 359; chiral HPLC: ee =
96.7; -NMRn (CDC13) : d 7.5 (m, 2H), 7.3 (m, 2H), 5.8 (m, IH), 4.9 (m, IH), 4.6 (m,
IH), 4.3 (m, IH), 3.5 (m, IH), 2.7 (s, 3H), 1.7 (d, J = 6.9 Hz, 3H); 19F-NMR (CDC13) : d
-98.4 (s, IF).
The following compound was also prepared from the ad hoc reagents using General
Method C:
Compound 2 : From 3-methyl-l,2,4-oxadiazole-5-carbohydrazide (48h at 60°C, crude
compound purified on silica gel (EtOAc/MeOH 99/1)). Yield: 0.14 g, 53 . HPLC-MS:
P > 98 , tR = 2.0 min, (M+H)+: 343; chiral HPLC: ee = 92.0; -NMRn (CDC13) : d 7.5
(m, 2H), 7.2 (m, 2H), 5.8 (m, IH), 4.9 (dd, J = 3.3, 13.5 Hz, IH), 4.6 (m, IH), 4.3 (td, J
= 4.0, 12.8 Hz, IH), 3.5 (m, IH), 2.5 (s, 3H), 1.7 (d, J = 6.9 Hz, 3H); 19F-NMR (CDC13) :
d -98.3 (s, IF).
CLAIMS
1. A process of preparing chiral N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-
[l,2,4]triazolo[4,3-a]pyrazine of general Formula I :
(I)
or solvates thereof, wherein
R is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl;
R2 is alkyl, alkoxyalkyl or haloalkyl;
Ar is a phenyl group, optionally substituted by one or more substituent(s)
selected from H, halo, alkyl, alkoxy, haloalkyl, nitrile and thiophen-2-yl;
X1 is N and X2 is S or O; or X1 is S and X2 is N;
represents a single or a double bound depending on X1 and X2;
said process comprising the following steps:
a) reacting a compound of Formula A:
wherein R is as defined above;
with a compound of Formula B:
wherein Ar is as defined above; and Y is hydroxyl or halo;
to obtain a compound of Formula C:
b) converting the compound of Formula C with a tri(Cl-C2 alkyl)oxonium salt, a
(Cl-C2)alkylsulfate, a (Cl-C2)chloroformate or PC15/P0C13/(C1-
C2)hydroxyalkyl, so as to obtain a compound of Formula D:
wherein Ar and R are as defined above, and R3 is C1-C2 alkyl;
in the presence of a base;
c) reacting the compound of Formula D with a compound of Formula E
or a salt or solvate thereof, wherein X1, X2 and R2 are as defined above;
so as to obtain a compound of Formula I or solvate thereof.
2. The process according to claim 1 proceeding with the retention of stereochemistry
with respect to the starting material.
3. The process according to anyone of claim 1 and 2, wherein the reaction of each step
is carried out under controlled mild experimental conditions.
4. The process according to anyone of claims 1 to 3, wherein the reaction is carried
out at a temperature equal to or below boiling point of the organic solvent.
5. The process according to anyone of claims 1 to 4, wherein the process does not use
any protecting group.
6. The process according to anyone of claims 1 to 5, wherein the base in step b) is
selected from the group consisting of sodium carbonate, sodium bicarbonate,
potassium carbonate or cesium carbonate.
7. The process according to anyone of claims 1 to 6, wherein the compound of
Formula I is the R j-enantiomer.
8. The process according to anyone of claims 1 to 7, wherein the compound of
Formula I is
9. The process according to anyone of claims 1 to 7, wherein the compound of
Formula I is
A compound of Formula C:
or solvates thereof, wherein
R is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl;
Ar is a phenyl group, optionally substituted by one or more substituent(s) selected
from H, halo, alkyl, alkoxy, haloalkyl, nitrile and thiophen-2-yl;.
The compound of claim 10 having Formula C-b2:
A compound of Formula D:
or solvates thereof, wherein
R is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl;
R3 is C1-C2 alkyl;
Ar is a phenyl group, optionally substituted by one or more substituent(s) selected
from H, halo, alkyl, alkoxy, haloalkyl, nitrile and thiophen-2-yl.
13.The compound of claim 12 having Formula D-1
14.The compound according to anyone of claims 10 to 13, wherein the stereoisomer
obtained is the (R J-enantiomer.