U.S. patent application number 11/693757 was filed with the patent office on 2007-10-04 for process for preparing heterocyclic derivatives.
Invention is credited to Sergio Bacchi.
Application Number | 20070232808 11/693757 |
Document ID | / |
Family ID | 36581002 |
Filed Date | 2007-10-04 |
United States Patent
Application |
20070232808 |
Kind Code |
A1 |
Bacchi; Sergio |
October 4, 2007 |
PROCESS FOR PREPARING HETEROCYCLIC DERIVATIVES
Abstract
The present invention relates to a novel process, useful for
preparing key intermediates of formula (I) in the synthesis of
various compounds, among them compounds which are potent and
specific antagonists of D3 receptors, ##STR00001## in which X may
be Nitrogen or Sulfur; Het means aryl or heteroaryl; each of which
may be substituted by 1 to 4 groups J selected from: halogen, C1-C6
alkyl C1-C6 alkoxy, halo C1-C6 alkyl C2-C6 alkenyl, C2-C6 alkynyl,
halo C1-C6 alkoxy, --C(O)R.sub.1, nitro, hydroxy,
--NR.sub.2R.sub.3, cyano or a group Z; R.sub.1 is a C1-C4 alkyl
--OR.sub.3 or --NR.sub.3R.sub.4; R.sub.2 is hydrogen or C1-C6
alkyl; R.sub.3 is hydrogen or C1-C6 alkyl; R is H, C1-C6 alkyl
aryl, benzyl; each of which may be substituted by 1 to 4 groups J;
according to the following Scheme 1: ##STR00002## in which step a
means a reaction in basic conditions of compounds (IIA) with
3-thiosemicarbazide derivatives, followed by a treatment with an
inorganic base and n-propane phosphonic cyclic anhydride and final
pH adjustment with inorganic acids to give compounds of formula
(II).
Inventors: |
Bacchi; Sergio; (Verona,
IT) |
Correspondence
Address: |
GLAXOSMITHKLINE;Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Family ID: |
36581002 |
Appl. No.: |
11/693757 |
Filed: |
March 30, 2007 |
Current U.S.
Class: |
548/136 ;
548/263.2 |
Current CPC
Class: |
C07D 401/04 20130101;
C07D 417/04 20130101; C07D 403/04 20130101; C07D 413/04
20130101 |
Class at
Publication: |
548/136 ;
548/263.2 |
International
Class: |
C07D 417/02 20060101
C07D417/02; C07D 403/04 20060101 C07D403/04 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 3, 2006 |
GB |
0607899.2 |
Claims
1. Process for preparing thiazole or triazole derivatives of
formula (I) ##STR00013## in which X may be Nitrogen or Sulfur; Het
means aryl or heteroaryl; each of which may be substituted by 1 to
4 groups J selected from: halogen, C1-C6 alkyl C1-C6 alkoxy, halo
C1-C6 alkyl C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy,
--C(O)R.sub.1, nitro, hydroxy, --NR.sub.2R.sub.3, cyano or a group
Z; R.sub.1 is a C1-C4 alkyl --OR.sub.3 or --NR.sub.3R.sub.4;
R.sub.2 is hydrogen or C1-C6 alkyl; R.sub.3 is hydrogen or C1-C6
alkyl; R is H, C1-C6 alkyl aryl, benzyl; each of which may be
substituted by 1 to 4 groups J; according to the following Scheme
1: ##STR00014## in which step a means a reaction in basic
conditions of compounds (IIA) with 3-thiosemicarbazide derivatives,
followed by a treatment with an inorganic base and n-propane
phosphonic cyclic anhydride and finally pH adjustment with
inorganic acids to give compounds of formula (II).
Description
[0001] The present invention relates to a novel process, useful for
preparing key intermediates in the synthesis of various compounds,
among them compounds which are potent and specific antagonists of
D3 receptors.
[0002] The present invention relates to a novel process for
preparing thiazole or triazole derivatives of formula (I)
##STR00003##
in which [0003] X may be Nitrogen or Sulfur; [0004] Het means aryl
or heteroaryl; each of which may be substituted by 1 to 4 groups J
selected from: [0005] halogen, C1-C6 alkyl C1-C6 alkoxy, halo C1-C6
alkyl C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy,
--C(O)R.sub.1, nitro, hydroxy, --NR.sub.2R3, cyano or a group Z;
[0006] R1 is a C1-C4 alkyl --OR.sub.3 or --NR3R.sub.4; [0007]
R.sub.2 is hydrogen or C1-C6 alkyl; [0008] R.sub.3 is hydrogen or
C1-C6 alkyl; [0009] R is H, C1-C6 alkyl aryl, benzyl; each of which
may be substituted by 1 to 4 groups J; [0010] according to the
following Scheme 1:
##STR00004##
[0010] in which [0011] step a means a reaction in basic conditions
of compounds (IIA) with 3-thiosemicarbazide derivatives, followed
by a treatment with an inorganic base and n-propane phosphonic
cyclic anhydride and final pH adjustment with inorganic acids to
give compounds of formula (II).
[0012] The term C1-C6 alkyl as used herein as a group or a part of
the group refers to a linear or branched alkyl group containing
from 1 to 6 carbon atoms; examples of such groups include methyl,
ethyl, propyl, isopropyl, n-butyl, isobutyl, tert butyl, pentyl or
hexyl.
[0013] The term halogen refers to a fluorine, chlorine, bromine or
iodine atom.
[0014] The term halo C1-C6 alkyl, means an alkyl group having one
or more carbon atoms and wherein at least one hydrogen atom is
replaced with halogen such as for example a trifluoromethyl group
and the like.
[0015] The term C1-C6 thioalkyl may be a linear or a branched chain
thioalkyl group, for example thiomethyl, thioethyl, thiopropyl,
thioisopropyl, thiobutyl, thiosec-butyl, thiotert-butyl and the
like.
[0016] The term C2-C6 alkenyl defines straight or branched chain
hydrocarbon radicals containing one or more double bond and having
from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl,
3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl or
3-hexenyl and the like.
[0017] The term C1-C6 alkoxy group may be a linear or a branched
chain alkoxy group, for example methoxy, ethoxy, propoxy,
prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy and the like.
[0018] The term halo C1-C6 alkoxy group may be a C1-C6 alkoxy group
as defined before substituted with at least one halogen, preferably
fluorine, such as OCHF.sub.2, or OCF.sub.3.
[0019] The term C2-C6 alkynyl defines straight or branched chain
hydrocarbon radicals containing one or more triple bond and having
from 2 to 6 carbon atoms including acetylenyl, propynyl, 1-butynyl,
1-pentynyl, 3-methyl-1-butynyl and the like.
[0020] The term aryl means an aromatic carbocyclic moiety such as
phenyl, biphenyl or naphthyl.
[0021] The term heteroaryl means an aromatic heterocycle ring of 5
to 10 members and having at least one heteroatom selected from
nitrogen, oxygen and sulfur, and containing at least 1 carbon atom,
including both mono-and bicyclic ring systems.
[0022] Representative heteroaryls include (but are not limited to)
furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl,
indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl,
isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl,
imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl,
isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
cinnolinyl, phthalazinyl, triazolyl, tetrazolyl, quinazolinyl, and
benzodioxolyl.
[0023] The term 5-6 membered heterocycle means, according to the
above definition, a 5-6 monocyclic heterocyclic ring which is
either saturated, unsaturated or aromatic, and which contains from
1 to 4 heteroatoms independently selected from nitrogen, oxygen and
sulfur, and wherein the nitrogen and sulfur heteroatoms may be
optionally oxidized, and the nitrogen heteroatom may be optionally
quaternized. Heterocycles include heteroaryls as defined above. The
heterocycle may be attached via any heteroatom or carbon atom.
Thus, the term includes (but is not limited to) morpholinyl,
pyridinyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, imidazolyl,
oxadiazolyl, oxazolyl, isoxazolyl, pyrrolidinonyl, pyrrolidinyl,
piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,
tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl,
tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl,
and the like.
[0024] Compounds of formula (II) can be useful, but are not limited
to, for the preparation of D3 antagonists of formula (IA), as
disclosed in WO2005/080382:
##STR00005##
wherein [0025] G is selected from a group consisting of: phenyl,
pyridyl, benzothiazolyl, indazolyl; [0026] p is an integer ranging
from 0 to 5; [0027] R.sub.1 is independently selected from a group
consisting of: halogen, hydroxy, cyano, C.sub.1-4alkyl,
haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, C1-4alkanoyl; or
corresponds to a group R5; [0028] R.sub.2 is hydrogen or
C.sub.1-4alkyl; [0029] R.sub.3 is C.sub.1-4alkyl; [0030] R.sub.4 is
hydrogen, or a phenyl group, a heterocyclyl group, a 5- or
6-membered heteroaromatic group, or a 8- to 11-membered bicyclic
group, any of which groups is optionally substituted by 1, 2, 3 or
4 substituents selected from the group consisting of: halogen,
cyano, C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy,
C.sub.1-4alkanoyl; [0031] R.sub.5 is a moiety selected from the
group consisting of: isoxazolyl, --CH.sub.2--N-pyrrolyl,
1,1-dioxido-2-isothiazolidinyl, thienyl, thiazolyl, pyridyl,
2-pyrrolidinonyl, and such a group is optionally substituted by one
or two substituents selected from: halogen, cyano, C.sub.1-4alkyl,
haloC.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4alkanoyl; and when
R.sub.1 is chlorine and p is 1, such R.sub.1 is not present in the
ortho position with respect to the linking bond to the rest of the
molecule; and when R.sub.1 corresponds to R.sub.5, p is 1.
[0032] The preparation of compounds of formula (II) described in
WO2005/080382 employed 1-hydroxybenzotriazole (HOBt) together with
1,3-dicyclohexylcarbodiimide (DCC).
[0033] The disadvantages of this reagents at an industrial level
may be summarized as follows: HOBt and its by-products have an
explosive nature and DCC and its by-product are always difficult to
fully remove.
[0034] The process solves the above problems by using n-propane
phosphonic cyclic anhydride, T3P, as condensation agent.
##STR00006##
[0035] The T3P was first used in the peptide synthesis in 1980 by
H. Wissmann (Angew. Chem., 1980, 92, 129) and is steadily gaining
importance in organic synthesis because is less toxic and safer
compared to other common condensation agents, such as DCC.
[0036] The reagent does not afford any water insoluble by-product.
T3P is used as 50% solution in ethyl acetate in the process of the
present invention and does not need the isolation of the
intermediate hydrazine-carbothiamide. Similarly, T3P is available
as 50% solution in DMF (dimethylformamide) and may be employed in
the process of the present invention.
[0037] The process of the present invention can be depicted in more
details as follows:
##STR00007##
[0038] The starting material, the heterocyclic carboxylic acid,
generally commercially available or which may be prepared according
to known methods in the literature, in an amount of 1 equivalent
may be conveniently dissolved in the appropriate solvent (for
example dimethylformamdide; ethyl acetate; acetonitrile and
tetrahydrofurane and other polar aprotic solvent) and treated with
a slightly excess of derivatives of 3-thiosemicarbazide (1.10 eq),
such as 4-methyl derivative. Then an organic base (e.g.
triethylamine, diisopropylethylamine and possibly other aliphatic
of aromatic amines) is added at RT.
[0039] N-propane phosphonic cyclic anhydride (50% w/w in ethyl
acetate) may be then added at a temperature ranging from 0 to 40
degrees dropwise. In case the addition is made at about 0.degree.
C., the temperature is then maintained below 15.degree. C. over
20-60 minutes. The resulting mixture was then stirred at 20.degree.
C. for 2-16 hours.
[0040] The mixture is then diluted with an aqueous solution of an
appropriate inorganic base until basic pH was reached. The suitable
base may be selected among: potassium carbonate, sodium carbonate,
sodium hydroxide, potassium hydroxide.
[0041] The resulting bi-phasic mixture (when observed) is then
allowed separating and the upper organic layer discarded. The
aqueous layer is then heated to 50-90.degree. C. (internal
temperature) for half an hour to several hours until reaction
completion.
[0042] After cooling down to 20.degree. C., an appropriate mineral
acid, (e.g. HCl 37%) is then slowly added to adjust the pH as
needed. (4 to 8).
[0043] The suspension is then generally stirred for 2-16 hours,
then the solid was filtered, washed with pure water and dried in a
vacuum oven at 40-60.degree. C. until dryness. The final product is
isolated from the aqueous mixture uncontaminated by phosphorous
derivatives.
EXAMPLES
[0044] In the Examples unless otherwise stated:
[0045] All temperatures refers to .degree. C. Infrared spectra were
measured on a FT-IR instrument. Compounds were analysed by direct
infusion of the sample dissolved in acetonitrile into a mass
spectra operated in positive electro spray (ES.sup.+) ionisation
mode. Proton Magnetic Resonance (.sup.1H-NMR) spectra were recorded
at 400 MHz, chemical shifts are reported in ppm downfield (d) from
Me.sub.4Si, used as internal standard, and are assigned as singlets
(s), broad singlets (bs), doublets (d), doublets of doublets (dd),
triplets (t), quartets (q) or multiplets (m). Column
chromathography was carried out over silica gel (Merck AG
Darmstaadt, Germany). The following abbreviations are used in the
text: T3P=N-propane Phosphonic Cyclic Anhydride, EtOAc=ethyl
acetate, DIPEA=N,N-diisopropylethylamine.
TABLE-US-00001 Column Phenomenex LUNA Detector UV Wavelength 220 nm
Flow 1 mL/min Injection volume 1 .mu.L Temperature 40.degree. C.
Run Time 8 min Mobile Phase A: 0.05% v/v TFA in water/B: 0.05% v/v
TFA in acetonitrile
TABLE-US-00002 Gradient FAST gradient: Step 1:
Time-Reserv.A-Reserv.B Time 0 min 100% A Step 2:
Time-Reserv.A-Reserv.B Time 8 min 5% A Step 3:
Time-Reserv.A-Reserv.B Time 8.01 min 100% A
Example 1
Preparation of
4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thi-
one
##STR00008##
[0047] 4-Methyl-1,3-oxazole-5-carboxylic acid (commercially
available) (12.9 g, 101.5 mmol) was dissolved in DMF (60 mL) and
treated with 4-methyl-3-thiosemicarbazide (11.61 g, 1.10 eq). Then
DIPEA (31.0 mL, 1.75 eq) was added at 20.degree. C. Under ice bath
cooling, T3P 50% w/w in EtOAc (90 mL) was added dropwise,
maintaining the temperature below 15.degree. C. over 20 minutes.
The resulting mixture was then stirred at 20.degree. C. for 6
hours.
[0048] The mixture was diluted with NaOH 4 M (120.0 mL). The
resulting bi-phasic mixture was allowed separating and the upper
organic layer discarded. The aqueous layer (pH=8) was adjusted to
pH=11 with additional NaOH 4 M (60 mL) and then heated to
70.degree. C. (internal temperature) for 30 min. After cooling down
over night, HCl 37% was slowly added until pH=5 was reached.
[0049] The suspension was stirred for 8 hours, then the solid was
filtered and washed with water (60 mL), and it was dried in a
vacuum oven at 40.degree. C. overnight.
[0050] Yield: 10.48 g, 53,4 mmol, 53% th
[0051] 1H NMR (DMSO-d6, 600 MHz, .delta.ppm): 14.11 (bs, 1H), 8.60
(s, 1H), 3.61 (s, 3H), 2.33 (s, 3H)
[0052] MH.sup.+=197
Example 2
Preparation of
5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole--
3-thione
##STR00009##
[0054] 2,4-Dimethyl-1,3-oxazole-5-carboxylic acid (commercially
available) (5 g, 31.8 mmol) and 4-methyl-3-thiosemicarbazide (3.68
g, 1.10 eq) were dissolved in DMF (15 mL). Then DIPEA (10.0 mL,
1.80 eq) was added at 20.degree. C. Under ice bath cooling, T3P 50%
w/w in EtOAc (35 mL, 1.50 eq) was added dropwise, maintaining the
temperature below 10.degree. C. The resulting mixture was then
stirred at 20.degree. C. for 2 h.
[0055] The mixture was diluted with water (20 mL), then NaOH 4 M
was added (20.0 mL). The organic phase was discarded and the
aqueous phase was heated to 70.degree. C. (internal temperature)
for 90 min. After cooling down to 50.degree. C., HCl 37% was slowly
added until pH=6.5 was reached.
[0056] The suspension was cooled to 5.degree. C. and the solid was
filtered and washed with water, and it was then dried in a vacuum
oven at 40.degree. C. overnight.
[0057] Yield: 5.45 g, 24.4 mmol, 77% th
[0058] 1H NMR (DMSO-d6, 400 MHz, .delta. ppm): 14.02 (bs, 1H), 3.39
(s, 3H), 2.69 (s, 3H), 2.34 (s, 3H)
[0059] MH.sup.+=227
Example 3
Preparation of
4-methyl-5-(2-methyl-3-pyridinyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione
##STR00010##
[0061] 2-Methylnicotinic acid (commercially available) (5 g, 36.5
mmol) and 4-methyl-3-thiosemicarbazide (4.22 g, 1.10 eq) were
dissolved in EtOAc (15 mL). Then DIPEA (14.5 mL, 2.28 eq) was added
at 20.degree. C. Under ice bath cooling, T3P 50% w/w in EtOAc (32.5
mL, 1.50 eq) was added drop wise, maintaining the temperature below
15.degree. C. The resulting mixture was then stirred at 20.degree.
C. for 90 min. The mixture was diluted with water (10 mL), then
NaOH 4 M was added (18.5 mL). The organic layer was discarded and
the remaining aqueous layer was heated to 70.degree. C. (internal
temperature) for 2 h 45 min. After cooling down to ambient
temperature, a suspension was obtained, which had a pH of about 7.5
to 8.0.
[0062] HCl 37% was slowly added until pH=5 was reached.
[0063] The solid was filtered and it was then dried in a vacuum
oven at 40.degree. C. overnight.
[0064] Yield: 7.04 g, 34.1 mmol, 93% th
[0065] 1H NMR (DMSO-d6, 600 MHz, .delta. ppm): 14.01 (bs, 1H), 8.66
(dd, 1H), 7.96 (dd, 1H), 7.42 (dd, 1H), 3.29 (s, 3H), 2.42 (s,
3H)
[0066] MH.sup.+=207
Example 4
Preparation of
4-methyl-5-(4-pyridazinyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione
##STR00011##
[0068] 4-Pyridazinecarboxylic acid (commercially available) (5 g,
40.3 mmol) and 4-methyl-3-thiosemicarbazide (4.66 g, 1.10 eq) were
dissolved in DMF (15 mL). Then DIPEA (12.5 mL, 1.78 eq) was added
at 20.degree. C. Under ice bath cooling, T3P 50% w/w in EtOAc (36
mL, 1.50 eq) was added dropwise, maintaining the temperature below
20.degree. C. The resulting mixture was then stirred at 20.degree.
C. for 30 min. HPLC showed a new peak at 0.6 minutes and at 2.93
min.
[0069] The mixture was diluted with water (20 mL), then NaOH 4 M
was added (20.0 mL). The organic layer was discarted and the
remaining aqueous phase was heated to 70.degree. C. (internal
temperature) for 5 h, until, by HPLC, complete conversion was
observed. After cooling down to ambient temperature, a suspension
was obtained, which had a pH of about 7.5 to 8.0. HCl 37% was
slowly added until pH=5 was reached.
[0070] The solid was filtered and washed with water (3 times with
20 mL), and it was then dried in a vacuum oven at 40.degree. C.
overnight.
[0071] Yield: 6.37 g, 33.0 mmol, 82% th
[0072] 1H NMR (DMSO-d6, 500 MHz, .delta. ppm): 14.29 (bs, 1H), 9.58
(d, 1H), 9.47 (d, 1H), 8.09 (d, 1H), 3.64 (s, 3H)
[0073] MH.sup.+=194
Example 5
Preparation of
5-(2,4-dimethyl-1,3-oxazol-5-yl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-
-thione
##STR00012##
[0075] 4-methyl-3-thiosemicarbazide (4.5 g, 42.8 mmol) was
dissolved in DMF (12.5 mL, 2.5 vol) under stirring. Commercially
available 2,4-dimethyl-1,3-oxazole-5-caboxylic acid (5 g, 35.4
mmol) and DIPEA-diisopropylethylamine-(15.5 mL, 89 mmol) were
added. Mixture was cooled down to 5.degree. C. with an ice-water
bath and a solution of T3P 50% w/w in ethyl acetate (45.5 mL, 76.4
mmol) was added drop wise in 15 minutes maintaining temperature
below 10.degree. C. At the end of the addition, mixture was allowed
to reach ambient temperature and stirred for 2 hours under
nitrogen. The mixture was diluted with 22.5 mL of water and 22.5 mL
of a solution of NaOH 32% w/w under stirring (final pH=12). After
separation, the upper organic layer was discarded while the water
phase was heated to 70.degree. C. (65.degree. C. internal). The pH
of the mixture was checked over time and pH adjusted to 12 if
necessary. The heating was kept for a total amount of 3 hours.
[0076] After cooling down to ambient temperature, 2.5 mL of a
solution of HCl 37% w/w were added until pH was 8. A solid started
precipitating and the suspension was stirred over night.
[0077] The mixture was filtered, the cake washed with 22.5 mL of
water and the collected solid dried under vacuum oven at 40.degree.
C. for 5 hours.
[0078] Yield 4.28 g; 57% theoretical
[0079] 1H-NMR 600 MHz, DMSO-d6: 2.26 (3H, s), 2.48 (3H, s), 3.59
(3H, s), 14.07 (1H, br. s.)
[0080] MH.sup.+ [211]
[0081] All publications, including but not limited to patents and
patent applications, cited in this specification are herein
incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
[0082] It is to be understood that the present invention covers all
combinations of particular and preferred groups described herein
above.
[0083] The application of which this description and claims forms
part may be used as a basis for priority in respect of any
subsequent application. The claims of such subsequent application
may be directed to any feature or combination of features described
herein. They may take the form of product, composition, process, or
use claims and may include, by way of example and without
limitation, the following claims:
* * * * *