U.S. patent application number 10/592820 was filed with the patent office on 2008-06-05 for process for the preparation of diazine derivatives.
Invention is credited to Markus Ege, Wolfgang Jenni, Thomas Von Hirschheydt, Edgar Voss.
Application Number | 20080132699 10/592820 |
Document ID | / |
Family ID | 34924554 |
Filed Date | 2008-06-05 |
United States Patent
Application |
20080132699 |
Kind Code |
A1 |
Ege; Markus ; et
al. |
June 5, 2008 |
Process For the Preparation of Diazine Derivatives
Abstract
The invention relates to a new process for the preparation of
pyrazine derivatives of formula (I), which are useful as
intermediates for the preparation of liquid crystalline media
components or of pharmaceutically active substances.
Inventors: |
Ege; Markus; (Muenchen,
DE) ; Jenni; Wolfgang; (Muenchen, DE) ; Von
Hirschheydt; Thomas; (Penzberg, DE) ; Voss;
Edgar; (Bichl, DE) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.;PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
US
|
Family ID: |
34924554 |
Appl. No.: |
10/592820 |
Filed: |
March 31, 2005 |
PCT Filed: |
March 31, 2005 |
PCT NO: |
PCT/EP05/03346 |
371 Date: |
September 13, 2006 |
Current U.S.
Class: |
544/238 ;
544/333; 544/405 |
Current CPC
Class: |
A61P 35/00 20180101;
C07D 413/14 20130101; A61P 43/00 20180101 |
Class at
Publication: |
544/238 ;
544/405; 544/333 |
International
Class: |
C07D 237/02 20060101
C07D237/02; C07D 241/02 20060101 C07D241/02; C07D 239/02 20060101
C07D239/02 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 2, 2004 |
EP |
04008130.9 |
Claims
1-10. (canceled)
11. A process for the preparation of diazine derivatives of formula
I: ##STR00022## wherein: (1) X is fluorine, chlorine or bromine;
(2) ring A is: ##STR00023## (3) W is --CH.sub.2--CH.sub.2-- or
--CH.dbd.CH--; (4) n is 1 to 10; and (5) R.sup.1 is cycloalkyl,
aryl, heterocyclyl or heteroaryl; comprising the steps of: (a)
coupling a diazine of formula II: ##STR00024## wherein: (1) Y is
iodine or bromine; (2) X and ring A are defined as in formula I;
and (3) X and Y are not both bromine; with a compound of formula
IV: HC.dbd.C--(CH.sub.2).sub.n--R.sup.1 formula IV, wherein R.sup.1
is defined as in formula I; to obtain the compounds of formula V:
##STR00025## wherein X, ring A and R.sup.1 are defined as in
formula I; and (b) hydrogenating the compounds of formula V with
hydrogen in the presence of a catalyst; to obtain the compounds of
formula I.
12. A process according to claim 11, comprising the step of
hydrogenating the compounds of formula IV: ##STR00026## wherein X,
ring A and R' are defined as in formula I of claim 11, with
hydrogen in the presence of a catalyst, to obtain the compounds of
formula I.
13. A process according to claim 11 wherein: (1) X is chlorine or
bromine; (2) n is 1 to 4; and (3) R.sup.1 is cycloalkyl, aryl,
heterocyclyl or heteroaryl.
14. A process according to claim 11 wherein R.sup.1 is
heteroaryl.
15. A process according to claim 11 wherein W is --CH.dbd.CH--.
16. A process according to claim 11 wherein W is --CH.dbd.CH--.
17. A process according to claim 15 wherein the catalyst in the
hydrogenation step is Pd/C or PtO.sub.2
18. A process according to claim 15 wherein the catalyst in the
hydrogenation step is PtO.sub.2.
19. A process according to claim 15 wherein the catalyst in the
hydrogenation step is Pd/CaCO.sub.3.
20. A process according to claim 16 wherein the catalyst in the
hydrogenation step is Pd/CaCO.sub.3.
21. A process according to claim 16 wherein the catalyst in the
hydrogenation step is Pd/Pb/CaCO.sub.3.
Description
[0001] The invention relates to a new process for the preparation
of diazine derivatives of formula I:
##STR00001## [0002] wherein [0003] X is fluorine, chlorine or
bromine; [0004] A is
[0004] ##STR00002## [0005] W is --CH.sub.2--CH.sub.2-- or
--CH.dbd.CH--; [0006] n is 1 to 10 [0007] R.sup.1 is cycloalkyl,
aryl, heterocyclyl or heteroaryl;
[0008] Compounds of formula I can be utilized as intermediates for
the preparation of e.g. liquid crystalline media components as
described in EP 0 606 090; or as intermediates of pharmaceutically
active substances according to formula I-A,
##STR00003## [0009] wherein [0010] R.sup.1 is halogen; [0011]
--O-alkyl; [0012] --S-alkyl; --S(O)-alkyl; --S(O).sub.2-alkyl,
[0013] --SF.sub.5, [0014] --NH-alkyl; or [0015] alkyl, all alkyl
groups being optionally once or several times substituted with
halogen; and [0016] R.sup.2 is hydrogen; or [0017] halogen; and
[0018] R.sup.3 is hydrogen; or alternatively [0019] R.sup.1 and
R.sup.3 are adjacent and together with the carbon atoms of the
phenyl ring to which they are attached form a 5 or 6 membered
heterocyclic ring; and [0020] A is
[0020] ##STR00004## [0021] W is --CH.sub.2--CH.sub.2-- or
--CH.dbd.CH--.
[0022] The term "cycloalkyl" means a monocyclic saturated
hydrocarbon ring with 3 to 7, preferably 3 to 6, ring atoms.
Examples of such saturated carbocyclic groups are cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
[0023] The term "heterocyclyl" means a saturated, monocyclic ring
with 5 to 6 ring atoms which contains up to 3, preferably 1 or 2
heteroatoms selected independently from N, O or S and the remaining
ring atoms being carbon atoms. Such saturated heterocyclic group
can be optionally substituted one to three, preferably one or two
times by alkyl, which is defined as above, preferably by methyl.
Examples of such saturated heterocyclic groups are pyrrolidinyl,
morpholinyl, piperazinyl, N-methyl-piperazinyl, piperidyl and the
like.
[0024] The term "aryl" means a mono- or bicyclic aromatic ring with
6 to 10 ring carbon atoms. Examples of such aryl groups are phenyl
and naphthyl, preferably phenyl. Such aryl groups are optionally
substituted one to three, preferably one to two times by halogen,
amino, hydroxy, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
halogenated (C.sub.1-C.sub.4)alkyl or halogenated
(C.sub.1-C.sub.4)alkoxy.
[0025] The term "heteroaryl" means a mono- or bicyclic aromatic
ring with 5 to 10, preferably 5 to 6, ring atoms, which contains up
to 3, preferably 1 or 2 heteroatoms selected independently from N,
O or S and the remaining ring atoms being carbon atoms. Examples of
such heteroaryl groups are e.g. triazolyl, imidazolyl, pyrazolyl,
tetrazolyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidyl,
pyrazinyl, pyridazinyl, benzimidazolyl, indolyl, benzothiophenyl,
benzofuranyl, quinolyl, quinazolinyl and the like, preferably
triazolyl and imidazolyl and especially triazolyl. Such heteroaryl
groups are optionally substituted one to two times, preferably one
time, by (C.sub.1-C.sub.4)alkyl.
[0026] The term "alkyl" as used herein means a saturated,
straight-chain or branched-chain hydrocarbon containing from 1 to
6, preferably 1 to 4, carbon atoms, such as methyl, ethyl,
n-propyl, isopropyl, n-butyl, 2-butyl, t-butyl, n-pentyl,
n-hexyl.
[0027] The term "alkoxy" as used herein means an alkyl-O-- group
wherein the alkyl is defined as above.
[0028] The term "halogenated alkyl" as used herein means an alkyl
group as defined above which is substituted one or several times,
preferably one to six and especially one to three times, by
halogen, preferably by fluorine or chlorine, especially by
fluorine. Examples are difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, perfluoroethyl, and the like, especially
trifluoromethyl.
[0029] The term "halogenated alkoxy" as used herein means an alkoxy
group as defined above which is substituted one or several times by
halogen, preferably by fluorine or chlorine, especially fluorine.
Examples are difluoromethoxy, trifluoromethoxy,
2,2,2-trifluoroethoxy, perfluoroethoxy and the like, especially
trifluoromethoxy.
[0030] The term "halogen" means fluorine, chlorine, bromine and
iodine, preferably fluorine, chlorine or bromine and especially
fluorine and chlorine.
[0031] The invention is thus concerned with a new process for the
preparation of compounds of formula I according to Scheme 1
##STR00005##
[0032] In scheme 1, X, ring A, W and R.sup.1 have the significance
given above and Y is iodine or bromine and not both X and Y are
bromine. The synthesis of the compounds of formula I starts from
the corresponding dihalodiazines of formula III. The preparation of
these dihalodiazines of formula III is described in the
accompanying examples or in e.g. WO 2004/000811, Pieterse, K., et
al., Chemistry-A European Journal 9 (2003) 5597-5604 and Sato, N.,
J. Heterocyclic Chem., 19 (1982) 673-674, Draper, T. L., et al., J.
Org. Chem. 60 (1995) 748-50; Goodman, A. J., Tetrahedron 55 (1999)
15067-15070; WO 2004/006922; Vlad, G., et al., J. Org. Chem. 67
(2002) 6550-6552; Zhang, Y., et al., J. Med. Chem., 47 (2004)
2453-2465; EP 0 742 212 and Gacek, M., et al., Acta Chem. Scand.
B39 (1985) 691-696.
[0033] In Step 1, scheme 1 the dihalodiazines of formula III are
reacted with alkyne derivatives of formula IV in a Sonogashira
cross-coupling reaction in the presence of catalytic amounts of
copper iodide and a palladium complex, e.g. Pd(PPh.sub.3).sub.4,
Pd(PPh.sub.3).sub.2Cl.sub.2 or the like. The reaction is carried
out in the presence of a base like triethyl amine, diisopropyl
amine, isopropyl amine, piperidine, morpholine or pyrrolidine and
in solvents like tetrahydrofuran, N,N-dimethylformamide or mixtures
thereof at temperatures varying from 20.degree. C. to 120.degree.
C. yielding derivatives of formula V.
[0034] When the synthesis is proceeded by the reduction Step 2 the
compounds of formula I wherein W is --HC.dbd.CH-- are obtained.
Such compounds are named I-a. Preferably, as reduction reaction a
catalytic hydrogenation is performed. The catalysts are usually
used as finely dispersed solids or adsorbed on to an inert support
such as charcoal (C), calcium carbonate (CaCO.sub.3), barium
sulfate (BaSO.sub.4) or alumina (Al). Typical catalyst are e.g.
Pd/Pb/CaCO.sub.3 (Pd--CaCO.sub.3--PbO system wherein the PbO acts
as catalytic poison and tempers the reactivity), Pd/CaCO.sub.3,
Pd/BaSO.sub.4 or Pt/BaSO.sub.4 eventually poisoned with quinoline,
especially Pd/CaCO.sub.3 or Pd/Pb/CaCO.sub.3. Alternatively nickel
boride(Ni.sub.2B) can be used as catalyst. The mol % of catalyst
added can vary between 1 mol % and 50 mol %, preferably between 5
and 25 mol %. Eventually, a catalytic poison like can be used to
slow down the reaction and to prevent further hydrogenation
according to Step 3. The reaction is typically carried out at
temperatures between 0.degree. C. and 50.degree. C., at hydrogen
pressures between 1.times.10.sup.3 and 4.times.10.sup.5 Pa,
preferably between 2.times.10.sup.3 and 15.times.10.sup.4 Pa, in
solvents like ethyl acetate, hexane, tetrahydrofuran or mixtures
thereof. Alternatively sodium or lithium metal in liquid ammonia
(or some pure primary amines like e.g. ethylamine) can be used to
hydrogenate the alkyne group (--C.ident.C--) to an alkene group (W
is --HC.dbd.CH--).
[0035] When the synthesis is proceeded by the reduction step 3 the
compounds of formula I wherein W is --CH.sub.2--CH.sub.2-- are
obtained. Such compounds are named I-b. Preferably, as reduction
reaction a catalytic hydrogenation is performed. Typical catalysts
are e.g. Pt, PtO.sub.2, Pd, Rh, Ru and Ni (late transition
metals)--usually used as finely dispersed solids or adsorbed on to
an inert support such as charcoal (C), calcium carbonate
(CaCO.sub.3) or alumina (Al). Preferably Pd/C, Pd/CaCO.sub.3 or
PtO.sub.2 is used. The mol % of catalyst added can vary between 1
mol % and 50 mol %, preferably between 5 and 25 mol %. The reaction
is typically carried out at temperatures between 0.degree. C. and
50.degree. C., at hydrogen pressures between 1.times.10.sup.3 and
4.times.15 Pa, preferably between 2.times.10.sup.3 and
15.times.10.sup.4 Pa, in solvents like methanol, ethanol,
tetrahydrofuran, acetone, ethyl acetate or mixtures thereof.
Alternatively a variety of homogeneous catalysts are also effective
e.g. Wilkinson's catalyst [(PPh.sub.3).sub.3RhCl].
[0036] In step 4 of scheme 1 the compounds of formula I-a are
converted to the compounds of formula I-b by obtained by a
reduction reaction. Preferably, as reduction reaction a catalytic
hydrogenation is performed. Typical catalysts are e.g. Pt,
PtO.sub.2, Pd, Rh, Ru and Ni (late transition metals)--usually used
as finely dispersed solids or adsorbed on to an inert support such
as charcoal (C), calcium carbonate (CaCO.sub.3) or alumina (Al).
Preferably Pd/C, Pd/CaCO.sub.3 or PtO.sub.2 is used. The mol % of
catalyst added can vary between 1 mol % and 50 mol %, preferably
between 5 and 25 mol %. The reaction is typically carried out at
temperatures between 0.degree. C. and 50.degree. C., at hydrogen
pressures between 1.times.10.sup.3 and 4.times.10.sup.5 Pa,
preferably between 2.times.10.sup.3 and 15.times.10.sup.4 Pa, in
solvents like methanol, ethanol, tetrahydrofuran, acetone, ethyl
acetate or mixtures thereof. Alternatively a variety of homogeneous
catalysts are also effective e.g. Wilkinson's catalyst
[(PPh.sub.3).sub.3RhCl].
[0037] An embodiment of the invention is a process according to
Step 2 or Step 3 of Scheme 1, for the preparation of diazine
derivatives of formula I
##STR00006##
comprising the step of hydrogenating the compounds of formula V
##STR00007##
with hydrogen in the presence of a catalyst, to obtain a compound
of formula I.
[0038] Another embodiment of the invention is a process according
to Step 2 of Scheme 1, for the preparation of diazine derivatives
of formula I-a
##STR00008##
comprising the step of hydrogenating the compounds of formula V
##STR00009##
with hydrogen in the presence of a catalyst, to obtain a compound
of formula I-a.
[0039] Another embodiment of the invention is a process according
to Step 3 of Scheme 1, for the preparation of diazine derivatives
of formula I-b
##STR00010##
comprising the step of hydrogenating the compounds of formula V
##STR00011##
with hydrogen in the presence of a catalyst, to obtain a compound
of formula I-b.
[0040] Another embodiment of the invention is a process according
to Step 4 of Scheme 1, for the preparation of diazine derivatives
of formula I-b
##STR00012##
comprising the step of hydrogenating the compounds of formula
I-a
##STR00013##
with hydrogen in the presence of a catalyst, to obtain a compound
of formula I-b.
[0041] Another embodiment of the invention is a process according
to Scheme 1, for the preparation of diazine derivatives of formula
I, wherein
X is chlorine or bromine. n is 1 to 4
[0042] Another embodiment of the invention is a process according
to Scheme 1, for the preparation of diazine derivatives of formula
I, wherein
X is chlorine or bromine. n is 1 to 4 R.sup.1 is heteroaryl.
[0043] Another embodiment of the invention is a process according
to Scheme 1, for the preparation of diazine derivatives of formula
I, wherein
R.sup.1 is heteroaryl.
[0044] Another embodiment of the invention is a process according
to Scheme 1, for the preparation of diazine derivatives of formula
I, wherein
W is --CH.sub.2--CH.sub.2--.
[0045] Another embodiment of the invention is a process according
to Step 2b of Scheme 1, for the preparation of diazine derivatives
of formula I, wherein
W is --CH.sub.2--CH.sub.2--.
[0046] Another embodiment of the invention is a process according
to Scheme 1, for the preparation of diazine derivatives of formula
I, wherein
W is --CH.dbd.CH--.
[0047] Another embodiment of the invention is a process according
to Step 2a of Scheme 1, for the preparation of diazine derivatives
of formula I, wherein
W is --CH.dbd.CH--.
[0048] Another embodiment of the invention is a process according
to Scheme 1, for the preparation of diazine derivatives of formula
I, wherein
W is --CH.sub.2--CH.sub.2--; and the catalyst in the hydrogenation
step 2 is Pd/C or PtO.sub.2.
[0049] Another embodiment of the invention is a process according
to Scheme 1 for the preparation of diazine derivatives of formula
I, wherein
W is --CH.sub.2--CH.sub.2--; and
[0050] the catalyst in the hydrogenation step 2 is PtO.sub.2.
[0051] Another embodiment of the invention is a process according
to Scheme 1 for the preparation of diazine derivatives of formula
I, wherein
W is --CH.sub.2--CH.sub.2-- or --CH.dbd.CH--; and
[0052] the catalyst in the hydrogenation step 2 is
Pd/CaCO.sub.3.
[0053] Another embodiment of the invention is a process according
to Scheme 1, for the preparation of diazine derivatives of formula
I, wherein
W is --CH.dbd.CH--; and
[0054] the catalyst in the hydrogenation step is Pd/CaCO.sub.3 or
Pd/Pb/CaCO.sub.3.
[0055] Another embodiment of the invention is a process according
to Scheme 1 for the preparation of diazine derivatives of formula
I, wherein ring A is
##STR00014##
[0056] Another embodiment of the invention is a process according
to Scheme 1, for the preparation of diazine derivatives of formula
I, wherein ring A is
##STR00015##
[0057] Another embodiment of the invention is a process according
to Scheme 1, for the preparation of diazine derivatives of formula
I, wherein ring A is
##STR00016##
[0058] Another embodiment of the invention is a process according
to Scheme 1, for the preparation of diazine derivatives of formula
I, wherein ring A is
##STR00017##
[0059] The following examples and references are provided to aid
the understanding of the present invention, the true scope of which
is set forth in the appended claims. It is understood that
modifications can be made in the procedures set forth without
departing from the spirit of the invention.
EXAMPLES
A: Starting Materials
Preparation of 3-Chloro-6-iodo-pyridazine
[0060] To a suspension of 3,6-dichloro-pyridazine (1.0 g, 6.71
mmol) and NaI (1.35 g, 9.0 mmol) in chloroform (2.5 ml) a
Hydroiodic acid (57 wt. %) (2.85 g, 25.6 mmol) is added at
0.degree. C. The mixture is stirred for 20 hours (h) at room
temperature (r.t) and then poured into a mixture of 100 ml ice
water and 20 ml 10N sodium hydroxide (NaOH). Chloroform (50 ml) is
added and the mixture is stirred for 10 minutes (min). The organic
phase is separated, the aqueous layer is extracted with chloroform
(1.times.50 ml) and the combined organic phases dried over
magnesium sulfate (MgSO.sub.4) and concentrated in vacuo to yield
3-chloro-6-iodo-pyridazine as an off-white solid. Yield 1.16 g
(72%)
[0061] MS: M=340.6 (ESI+)
[0062] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.22 (d, J=8.9 Hz, 1H),
7.83 (d, J=8.9 Hz, 1H)
Preparation of 5-Bromo-2-chloro-pyrimidine
[0063] 2-Pyrimidinol hydrochloride (13.26 g, 100 mmol) is dissolved
in 2N NaOH (50 ml) and bromine (17.98 g, 112.5 mmol) is added over
15 min. The mixture is stirred for 45 min at r.t. and then
concentrated in vacuo to yield a brownish solid.
[0064] The solid is suspended in phosphorus oxychloride (125 ml),
N,N-dimethylaniline (9.35 g, 77 mmol) added and the mixture is
heated to reflux for 3 h. After cooling the reaction mixture is
poured slowly under stirring onto 1 L ice water and the resulting
mixture is extracted with diethyl ether (3.times.200 ml). The
extract is washed with brine, dried over MgSO.sub.4 and
concentrated in vacuo yielding 5-bromo-2-chloro-pyrimidine as a
pale yellow solid. Yield 10.85 g (56%)
[0065] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.70 (s, 2H)
Preparation of 5-Bromo-2-iodo-pyrimidine
[0066] To a suspension of 5-bromo-2-chloro-pyrimidine (5.80 g, 30
mmol) and sodium iodide (7.5 g, 50 mmol) in chloroform (20 ml) a
Hydroiodic acid (57 wt. %) (2.85 g, 25.6 mmol) is added at
0.degree. C. After removing the cooling the reaction mixture is
stirred for 20 h at r.t and then poured into a mixture of 200 ml
ice water and 30 ml 10N NaOH. Chloroform (150 ml) is added and the
mixture is stirred for 10 min. The organic phase is separated, the
aqueous layer is extracted with chloroform (2.times.100 ml) and the
combined organic phases dried over MgSO.sub.4 and concentrated in
vacuo to yielding 5-bromo-2-iodo-pyrimidine as a pale yellow solid.
Yield 6.29 g (84%)
[0067] MS: M=284.8 (ESI+)
[0068] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.54 (s, 2H)
[0069] 7.56 (d, J=16.4 Hz, 1H), 7.59-7.66 (m, 4H).
Preparation of 1-But-3-ynyl-1H-[1,2,3]triazole
[0070] But-3-yn-1-ol (49.57 g, 707.2 mmol) and triethylamine (107.7
mL, 777 mmol, dried over KOH) are dissolved in dry dichloromethane
(500 mL) under a nitrogen atmosphere and cooled to 0.degree. C.
Methanesulfonyl chloride (54.8 mL, 708 mmol), dissolved in 500 mL
of dry dichloromethane is added within 90 min while keeping the
temperature below 5.degree. C. The mixture is stirred for 3.5 hours
at room temperature, then poured onto 2.5 L of ice water. The
organic phase is separated and washed with 2.times.500 mL of water
and 1.times.250 mL of brine and dried over sodium sulfate. The
volatiles are removed to yield 94.18 g of the methane sulfonate
(631.2 mmol, 89.2%) as a yellow liquid.
[0071] A suspension of NaOH (37.86 g, 946.5 mmol), sodium iodide
(94.65 g, 631.5 mmol) and 1H-[1,2,3]triazole (61.03 g, 883.6 mmol)
in 2-methyl-2-butanol (750 mL) is refluxed for 1 h under an inert
atmosphere. After cooling to room temperature the methane sulfonate
(94.18 g, 631.2 mmol) is added within 5 minutes. The resulting
suspension is then heated to reflux for 3 h, cooled to room
temperature and concentrated in vacuo at 45.degree. C.
[0072] Water (500 mL) and dichloro methane (1 L) are added and the
organic phase is separated, dried over sodium sulfate and the
volatiles removed at 30.degree. C. The residue is distilled at 1
mmHg. A forerun is collected at 20-70.degree. C. The main fraction
distilled at 123-129.degree. C. as a colourless, turbid liquid.
After filtration over Celite 1-but-3-ynyl-1H-[1,2,3]triazole is
obtained as a colourless liquid (29.77 g, 38.9%).
[0073] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 2.05 (t, 1H),
2.75 (dt, 2H), 4.5 (t, 2H), 7.65 (s, 1H), 7.7 (s, 1H)
Example 1
3-chloro-6-(4-[1,2,3]triazol-1-yl-butyl)-pyridazine
[0074] 3-Chloro-6-iodo-pyridazine (11.56 g, 48.1 mmol),
1-but-3-ynyl-1H-[1,2,3]triazole (6.99 g, 57.7 mmol) and triethyl
amine (NEt.sub.3) (94 ml) are dissolved in DMF (188 ml) and copper
iodide (CuI) (0.981 g, 5.15 mmol) is added under stirring. After
passing a stream of argon through the mixture for 10 min
tetrakis(triphenylphosphine)palladium(0) (2.836 g, 2.43 mmol) is
added and stirring is continued for 6 h at r.t. Dichloromethane
(300 ml) is added, the mixture is washed with 0.5N hydrochloric
acid (HCl) and brine, dried over Na.sub.2SO.sub.4 and concentrated
in vacuo. The crude product is purified by flash column
chromatography (ethyl acetate) yielding
3-chloro-6-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyridazine as a
colorless solid. Yield 9.52 g (85%).
[0075] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=3.12 (t, 2H,
CH.sub.2--C.ident.), 4.67 (t, 2H, CH.sub.2--N), 7.39 (d, 1H,
pyridazine), 7.45 (d, 1H, pyridazine), 7.70 (s, 1H, triazole), 7.73
(s, 1H, triazole).
[0076] 3-Chloro-6-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyridazine
(2.50 g, 10.7 mmol) is dissolved in ethyl acetate (450 ml) and
hydrogenated at 3.times.10.sup.3 Pa H.sub.2-pressure for 3.5 h at
r.t. in the presence of palladium on charcoal (10%, 2.50 g). The
reaction mixture is filtered and concentrated in vacuo. The residue
was dissolved in THF (10 ml) and added to a solution of benzyl
alcohol (0.94 ml, 9.0 mmol) and sodium tert-butoxide (NaOtBu)
(0.842 g, 8.76 mmol) in THF (80 ml). After stirring for 2 h ethyl
acetate (100 ml) is added, the mixture is washed with saturated
ammonium chloride (NH.sub.4Cl), dried over Na.sub.2SO.sub.4 and
concentrated in vacuo. After flash column chromatography (ethyl
acetate) 3-chloro-6-(4-[1,2,3]triazol-1-yl-butyl)-pyridazine is
obtained as a colorless solid. Yield 1.14 g (45%).
[0077] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=1.76-1.84 (m, 2H,
CH.sub.2--CH.sub.2--C.dbd.), 1.97-2.05 (m, 2H,
CH.sub.2--CH.sub.2--N), 2.98 (t, 2H, CH.sub.2--C.dbd.), 4.43 (t,
2H, CH.sub.2--N), 7.25 (d, 1H, pyridazine), 7.40 (d, 1H,
pyridazine), 7.52 (s, 1H, triazole), 7.68 (s, 1H, triazole).
Example 2
3-chloro-6-(4-[1,2,3]triazol-1-yl-butyl)-pyridazine starting from
3-chloro-6-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyridazine
3-Chloro-6-(4-[1,2,3]triazol-1-yl-butyl)-pyridazine
[0078] 3-Chloro-6-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyridazine
(0.100 mg, 0.43 mmol) is dissolved in methanol (10 ml) and
hydrogenated at 3.times.10.sup.3 Pa H.sub.2-pressure for 4.5 h at
r.t. in the presence of platinum(IV) oxide.times.H.sub.2O (0.044
mg, 0.18 mmol). The reaction mixture is filtered and concentrated
in vacuo to yield
3-chloro-6-(4-[1,2,3]triazol-1-yl-butyl)-pyridazine as a colorless
solid. Yield 0.059 g (58%).
[0079] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=1.76-1.84 (m, 2H,
CH.sub.2--CH.sub.2--C.dbd.), 1.97-2.05 (m, 2H,
CH.sub.2--CH.sub.2--N), 2.98 (t, 2H, CH.sub.2--C.dbd.), 4.43 (t,
2H, CH.sub.2--N), 7.25 (d, 1H, pyridazine), 7.40 (d, 1H,
pyridazine), 7.52 (s, 1H, triazole), 7.68 (s, 1H, triazole).
Example 3
2-bromo-5-(4-[1,2,3]triazol-1-yl-but-1-enyl)-pyrazine
2-bromo-5-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyrazine
[0080] 2-Bromo-5-iodo-pyrazine (13.69 g, 48.0 mmol),
1-but-3-ynyl-1H-[1,2,3]triazole (7.01 g, 57.9 mmol) and triethyl
amine (NEt.sub.3) (94 ml) are dissolved in DMF (188 ml) and copper
iodide (CuI) (0.984 g, 5.17 mmol) is added under stirring. After
passing a stream of argon through the mixture for 10 min
tetrakis(triphenylphosphine)palladium(0) (2.844 g, 2.46 mmol) is
added and stirring is continued for 5 h at r.t. Dichloromethane
(300 ml) is added; the mixture is washed with 0.5N hydrochloric
acid (HCl) and brine, dried over Na.sub.2SO.sub.4 and concentrated
in vacuo. The crude product is purified by flash column
chromatography (ethyl acetate/hexanes 7:3) yielding
2-bromo-5-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyrazine as a
colorless solid. Yield 9.99 g (75%).
[0081] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=3.10 (t, 2H,
CH.sub.2--C--), 4.66 (t, 2H, CH.sub.2--N), 7.70 (s, 1H, triazole),
7.72 (s, 1H, triazole), 8.31 (d, 1H, pyrazine), 8.60 (d, 1H,
pyrazine).
2-Bromo-5-(4-[1,2,3]triazol-1-yl-but-1-enyl)-pyrazine
[0082] 2-Bromo-5-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyrazine (0.501
mg, 1.80 mmol) is dissolved in ethyl acetate (115 ml) and
hydrogenated at 3.times.10.sup.3 Pa H.sub.2-pressure for 4.5 h at
r.t. in the presence of palladium on calcium carbonate (10%, 0.454
g). The reaction mixture is filtered and concentrated in vacuo to
yield 2-bromo-5-(4-[1,2,3]triazol-1-yl-but-1-enyl)-pyrazine as a
colorless solid. Yield 0.386 g (77%).
[0083] MS: M=280.1, 282.2 (ESI+)
[0084] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=3.33 (dq, 2H,
CH.sub.2--C.dbd.), 4.59 (t, 2H, CH.sub.2--N), 6.04 (dt, 1H,
.dbd.CH--CH.sub.2), 6.47 (d, 1H, .dbd.CH--C.dbd.), 7.57 (s, 1H,
triazole), 7.69 (s, 1H, triazole), 8.19 (d, 1H, pyrazine), 8.64 (d,
1H, pyrazine).
Example 4
2-bromo-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrazine starting from
2-Bromo-5-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyrazine
[0085] 2-Bromo-5-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyrazine (2.50
g, 9.0 mmol) is dissolved in methanol (700 ml) and hydrogenated at
3.times.10.sup.3 Pa H.sub.2-pressure for 2 h at r.t. in the
presence of platinum(IV) oxide.times.H.sub.2O (0.840 g, 3.40 mmol).
The reaction mixture is filtered and concentrated in vacuo to yield
2-bromo-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrazine as a colorless
solid. Yield 1.63 g (64%)
[0086] MS: M=282.1, 284.2 (ESI+)
[0087] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=1.72-1.80 (m, 2H,
CH.sub.2--CH.sub.2--C.dbd.), 1.94-2.01 (m, 2H,
CH.sub.2--CH.sub.2--N), 2.79 (t, 2H, CH.sub.2--C.dbd.), 4.42 (t,
2H, CH.sub.2--N), 7.51 (s, 1H, triazole), 7.69 (s, 1H, triazole),
8.17 (d, 1H, pyrazine), 8.57 (d, 1H, pyrazine).
Example 5
2-bromo-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrazine starting from
2-bromo-5-(4-[1,2,3]triazol-1-yl-but-1-enyl)-pyrazine
2-Bromo-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrazine
[0088] 2-Bromo-5-(4-[1,2,3]triazol-1-yl-but-1-enyl)-pyrazine (0.020
mg, 0.07 mmol) is dissolved in methanol (4 ml) and hydrogenated at
3.times.10.sup.3 Pa H.sub.2-pressure for 1 h at r.t. in the
presence of platinum(IV) oxide.times.H.sub.2O (0.007 mg, 0.03
mmol). The reaction mixture is filtered and concentrated in vacuo
to yield 2-bromo-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrazine and
2-bromo-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrazine at the ratio of
80:20.
[0089] MS: M=282.1, 284.2 (ESI+)
[0090] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=1.72-1.80 (m, 2H,
CH.sub.2--CH.sub.2--C.dbd.), 1.94-2.01 (m, 2H,
CH.sub.2--CH.sub.2--N), 2.79 (t, 2H, CH.sub.2--C.dbd.), 4.42 (t,
2H, CH.sub.2--N), 7.51 (s, 1H, triazole), 7.69 (s, 1H, triazole),
8.17 (d, 1H, pyrazine), 8.57 (d, 1H, pyrazine).
Example 6
5-(4-[1,2,3]Triazol-1-yl-butyl)-2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-
-oxazol-4-ylmethoxy}-pyrimidine
[0091] 5-Bromo-2-chloro-pyrimidine (0.500 g, 2.53 mmol),
1-but-3-ynyl-1H-[1,2,3]triazole (0.368 g, 3.03 mmol) and triethyl
amine (NEt.sub.3) (5.0 ml) are dissolved in DMF (10 ml) and copper
iodide (CuI) (0.052 g, 0.27 mmol) is added under stirring. After
passing a stream of argon through the mixture for 10 min
tetrakis(triphenylphosphine)palladium(0) (0.149 g, 0.13 mmol) is
added and stirring is continued for 4 h at 80.degree. C.
Dichloromethane (125 ml) is added, the mixture is washed with 0.5N
hydrochloric acid (HCl) and brine, dried over Na.sub.2SO.sub.4 and
concentrated in vacuo. The crude product is purified by flash
column chromatography (ethyl acetate/hexanes 4:1) yielding
2-chloro-5-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyrimidine as a
colorless solid. Yield 373 mg (63%).
[0092] MS: M=234 (API+)
[0093] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=3.10 (t, 2H,
CH.sub.2--C.ident.), 4.63 (t, 2H, CH.sub.2--N), 7.64 (s, 1H,
triazole), 7.72 (s, 1H, triazole) 8.54 (s, 2H, pyrimidine).
[0094] 2-Chloro-5-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyrimidine
(2.52 g, 10.8 mmol) is dissolved in ethyl acetate (210 ml) and
hydrogenated at 3.times.10.sup.3 Pa H.sub.2-pressure for 2.5 h at
r.t. in the presence of palladium on calcium carbonate (10%, 2.55
g). The reaction mixture is filtered and concentrated in vacuo to
yield 2-chloro-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine as a
colorless solid. Yield 2.15 g (84%)
[0095] MS: M=236.2, 238.2 (ESI+)
[0096] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=1.60-1.68 (m, 2H,
CH.sub.2--CH.sub.2--C.dbd.), 1.94-2.02 (m, 2H,
CH.sub.2--CH.sub.2--N), 2.62 (t, 2H, CH.sub.2--C.dbd.), 4.42 (t,
2H, CH.sub.2--N), 7.50 (s, 1H, triazole), 7.70 (s, 1H, triazole),
8.41 (s, 2H, pyrimidine).
Example 7
5-Bromo-2-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine
[0097] 5-Bromo-2-iodo-pyrimidine (1.14 g, 4.0 mmol),
1-but-3-ynyl-1H-[1,2,3]triazole (0.533 g, 4.4 mmol) and triethyl
amine (NEt.sub.3) (2 ml) are dissolved in DMF (1 ml) and copper
iodide (CuI) (0.38 g, 0.2 mmol) is added under stirring. After
passing a stream of argon through the mixture for 10 min
bis(triphenylphosphine) palladium(II) dichloride (0.140 g, 0.2
mmol) is added and stirring is continued for 3 h at r.t. Chloroform
(300 ml) is added; the mixture is washed with 1N HCl and water,
dried over MgSO.sub.4 and concentrated in vacuo. The residue is
purified by flash column chromatography (chloroform
(100%)->ethyl acetate (100%)) yielding
5-bromo-2-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyrimidine as a beige
solid.
[0098] Yield 0.96 g (86%).
[0099] MS: M=277.9 (ESI+)
5-Bromo-2-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine
[0100] 5-Bromo-2-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyrimidine
(1.50 g, 5.4 mmol) is dissolved in THF (400 ml) and hydrogenated at
3.times.10.sup.3 Pa H.sub.2-pressure for 8 h at r.t. in the
presence of palladium on calcium carbonate (10%, 1.20 g). The
reaction mixture is filtered and concentrated in vacuo to yield
5-bromo-2-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine as a colorless
solid. Yield 1.34 g (88%).
[0101] MS: M=282.1, 284.2 (ESI+)
[0102] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=1.83-1.90 (m, 2H,
CH.sub.2--CH.sub.2--C.dbd.), 1.95-2.04 (m, 2H,
CH.sub.2--CH.sub.2--N), 2.97 (t, 2H, CH.sub.2--C.dbd.), 4.44 (t,
2H, CH.sub.2--N), 7.54 (s, 1H, triazole), 7.75 (s, 1H, triazole),
8.70 (s, 2H, pyrimidine).
Example 8
Hydrogenation of Halogen-Diazine-Alkyne-Derivatives with Different
Catalysts
[0103] The different halogen-diazine-alkyne derivatives were
dissolved in the appropriate solvent and hydrogenated in the
presence of a catalyst. The reaction mixture is filtered and
concentrated in vacuo to yield
5-bromo-2-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine as a colorless
solid. The used catalysts and reaction conditions (mol % catalyst,
solvent, reaction temperature, reaction time) are listed in Table
1. The ratios of the obtained alkenes (A) and alkanes (B) were
detected by .sup.1H-NMR (400 MHz, CDCl.sub.3). Where the main
products were isolated the yield is given.
TABLE-US-00001 TABLE 1 Educt: halogen- Main Product: halogen- Main
Product: halogen- alkynyl-diazine alkenyl-diazine = A alkyl-diazine
= B L = --C.ident.C--(CH.sub.2).sub.2-- Catalyst and Ratios/
Catalyst and Ratios/ 1-[1,2,3] triazole Conditions Yields
Conditions Yields ##STR00018## 9 mol % Pd/Pb onCaCO.sub.3 (5%
(w/w)Pd)/8% (w/w) Pb)3 .times. 10.sup.3Pa, ethylacetate
(EtOAc),0.75 h, r,t, A:B.sup.I)92:8 22 mol %Pd/CaCO.sub.3,3 .times.
10.sup.3Pa, EtOAc,2 h, r.t. A:B.sup.I)0:100(NMR)(isolatedYield84%)
##STR00019## 22 mol %Pd/CaCO.sub.3, 3 .times. 10.sup.3Pa, EtOAc, 2
h,r.t. A:B.sup.II)75:25 13 mol % Pd/C(10% (w/w) Pd),~1 .times.
10.sup.5Pa,EtOAc, 2 h, r.t. A:B0:100(isolatedYield82%) 21 mol %
A:B.sup.II) Pd/CaCO.sub.3, 0:100 3 .times. 10.sup.3 Pa, (isolated
tetrahydrofuran Yield (THF), 8 h, r.t. 88%) ##STR00020## 22 mol
%Pd/CaCO.sub.3, 3 .times. 10.sup.3Pa, EtOAc, 2 h,r.t.
A:B.sup.III)94:6 22 mol % Pd/C(10% (w/w) Pd),3 .times. 10.sup.3Pa,
EtOAc,5 h, r.t. A:B.sup.III)13:87(isolatedYield45%) 42 mol %
PtO.sub.2, A:B.sup.III) 3 .times. 10.sup.3Pa, 0:100 methanol
(isolated (MeOH), 4.5 h, Yield r.t. 58%) ##STR00021## 22 mol %
Pd/C(10% Pd), 3 .times. 10.sup.3Pa, EtOAc, 6.5 h,r.t.
A:B.sup.III)65:35 22 mol % Pd/C(10% Pd), 3 .times. 10.sup.3Pa,
EtOAc, 17 h,r.t. A:B.sup.III)61:39(isolatedYield45%) 22 mol %
A:B.sup.IV) 30 mol % PtO.sub.2, A:B.sup.IV) Pd/CaCO.sub.3, 3
.times. 10.sup.3 86:14 3 .times. 10.sup.3Pa, 0:100 Pa, EtOAc, 4.5
h, (isolated MeOH, 1.5 h, r.t. (isolated r.t. Yield Yield 77%)
64%)
[0104] The ratios of the obtained alkenes (A) and alkanes (B) were
detected by .sup.1H-NMR (400 MHz, CDCl.sub.3) according to the
integrals of the following .sup.1H-NMR-signals (underlined):
I) --CH.sub.2--CH.sub.2-triazole II) --CH.sub.2--CH.sub.2-triazole
III) --CH.sub.2--CH.sub.2-triazole; IV)
--CH.sub.2--CH.sub.2-triazole;
LIST OF REFERENCES
[0105] Draper, T. L., et al., J. Org. Chem. 60 (1995) 748-50 [0106]
Gacek, M., et al., Acta Chem. Scand. B39 (1985) 691-696 [0107]
Goodman, A. J., Tetrahedron 55 (1999) 15067-15070 [0108] Pieterse,
K., et al., Chemistry-A European Journal 9 (2003) 5597-5604 [0109]
Sato, N., J. Heterocyclic Chem., 19 (1982) 673-674 [0110] Vlad, G.,
et al., J. Org. Chem. 67 (2002) 6550-6552 [0111] EP 0 606 090
[0112] EP 0 742 212 [0113] WO 2004/006922 [0114] WO 2004/000811
[0115] Zhang, Y., et al., J. Med. Chem., 47 (2004) 2453-2465
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