U.S. patent application number 14/744673 was filed with the patent office on 2015-10-08 for processes to produce certain 2-(pyridine-3-yl)thiazoles.
This patent application is currently assigned to DOW AGROSCIENCES LLC. The applicant listed for this patent is Dow AgroSciences LLC. Invention is credited to Kim E. Arndt, Carl DeAmicis, Noormohamed M. Niyaz, Ronald Ross, JR., Gary Roth, Scott P. West, Yuanming Zhu.
Application Number | 20150284377 14/744673 |
Document ID | / |
Family ID | 49671038 |
Filed Date | 2015-10-08 |
United States Patent
Application |
20150284377 |
Kind Code |
A1 |
Ross, JR.; Ronald ; et
al. |
October 8, 2015 |
PROCESSES TO PRODUCE CERTAIN 2-(PYRIDINE-3-YL)THIAZOLES
Abstract
The invention disclosed in this document is related to the field
of processes to produce certain 2-(pyridine-3-yl)thiazoles as
intermediates for the synthesis of pesticidal thiazole amides.
Inventors: |
Ross, JR.; Ronald;
(Zionsville, IN) ; DeAmicis; Carl; (Indianapolis,
IN) ; Zhu; Yuanming; (Carmel, IN) ; Niyaz;
Noormohamed M.; (Indianapolis, IN) ; Arndt; Kim
E.; (Carmel, IN) ; West; Scott P.; (Midland,
MI) ; Roth; Gary; (Midland, MI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Dow AgroSciences LLC |
Indianapolis |
IN |
US |
|
|
Assignee: |
DOW AGROSCIENCES LLC
Indianapolis
IN
|
Family ID: |
49671038 |
Appl. No.: |
14/744673 |
Filed: |
June 19, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13905220 |
May 30, 2013 |
9108952 |
|
|
14744673 |
|
|
|
|
61655086 |
Jun 4, 2012 |
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Current U.S.
Class: |
546/270.7 |
Current CPC
Class: |
C07D 417/04 20130101;
C07D 213/83 20130101 |
International
Class: |
C07D 417/04 20060101
C07D417/04 |
Claims
1. A compound having the following structure ##STR00016## wherein
(A) each R.sup.1 is independently selected from H, F, Cl, Br, I,
CN, NO.sub.2, and substituted or unsubstituted
(C.sub.1-C.sub.6)alkyl, wherein each substituted R.sup.1 has one or
more substituents independently selected from F, Cl, Br, I, CN,
NO.sub.2, (C.sub.1-C.sub.6)alkyl, and (C.sub.1-C.sub.6)haloalkyl;
(C) R.sup.3 is selected from H, substituted or unsubstituted
(C.sub.1-C.sub.6)alkyl, substituted or unsubstituted
(C.sub.3-C.sub.10)cycloalkyl, substituted or unsubstituted
(C.sub.1-C.sub.6)alkyl(C.sub.3-C.sub.10)cycloalkyl, substituted or
unsubstituted (C.sub.6-C.sub.20)aryl, and substituted or
unsubstituted (C.sub.1-C.sub.6)alkyl(C.sub.6-C.sub.20)aryl, wherein
each substituted R.sup.3 has one or more substituents independently
selected from F, Cl, Br, and I; and (D) R.sup.4 is selected from H,
substituted or unsubstituted (C.sub.1-C.sub.6)alkyl, substituted or
unsubstituted (C.sub.3-C.sub.10)cycloalkyl, substituted or
unsubstituted (C.sub.1-C.sub.6)alkyl(C.sub.3-C.sub.1o)cycloalkyl,
substituted or unsubstituted (C.sub.6-C.sub.20)aryl, substituted or
unsubstituted (C.sub.1-C.sub.6)alkyl(C.sub.6-C.sub.20)aryl,
substituted or unsubstituted
(C.sub.1-C.sub.6)alkyl(C.sub.2-C.sub.6)alkenyl, and substituted or
unsubstituted (C.sub.1-C.sub.6)alkyl(C.sub.2-C.sub.6)alkynyl,
wherein each said R.sup.4, which is substituted, has one or more
substituents selected from F, Cl, Br, I, CN, NO.sub.2,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyloxy,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.3-C.sub.10)halocycloalkyl,
(C.sub.6-C.sub.20)aryl, and (C.sub.1-C.sub.20)heterocyclyl.
Description
CROSS REFERENCES TO RELATED APPLICATIONS
[0001] This Application is a divisional of U.S. application Ser.
No. 13/905,220 which was filed on May 30, 2013, and which claims
priority from, and benefit of, U.S. provisional application
61/655,086 filed on Jun. 4, 2012. The entire content of these
applications are hereby incorporated by reference into this
Application.
FIELD OF THE DISCLOSURE
[0002] The invention disclosed in this document is related to the
field of processes to produce certain 2-(pyridine-3-yl)thiazoles as
intermediates for the synthesis of pesticidal thiazole amides.
BACKGROUND OF THE DISCLOSURE
[0003] Controlling pest populations is essential to modern
agriculture, food storage, and hygiene. There are more than ten
thousand species of pests that cause losses in agriculture. The
world-wide agricultural losses amount to billions of U.S. dollars
each year. Pests, such as termites, are also known to cause damage
to all kinds of private and public structures resulting in billions
of U.S. dollars in losses each year. Pests also eat and adulterate
stored food, resulting in billions of U.S. dollars in losses each
year, as well as deprivation of food needed for people.
[0004] Certain pests have or are developing resistance to
pesticides in current use. Hundreds of pest species are resistant
to one or more pesticides. Accordingly, there exists a continuous
need for new pesticides and for processes of forming such
pesticides.
[0005] WO 2010/129497 (the entire disclosure of which is
incorporated herein) discloses certain pesticides. However, the
processes of making such pesticides may be both costly and
inefficient. Accordingly, there exists a need for processes of
efficiently forming such pesticides.
DEFINITIONS
[0006] The examples given in the definitions are generally
non-exhaustive and must not be construed as limiting the invention
disclosed in this document. It is understood that a substituent
should comply with chemical bonding rules and steric compatibility
constraints in relation to the particular molecule to which it is
attached.
[0007] "alkenyl" means an acyclic, unsaturated (at least one
carbon-carbon double bond), branched or unbranched, substituent
consisting of carbon and hydrogen, for example, vinyl, allyl,
butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, and
decenyl.
[0008] "alkenyloxy" means an alkenyl further consisting of a
carbon-oxygen single bond, for example, allyloxy, butenyloxy,
pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, nonenyloxy, and
decenyloxy.
[0009] "alkoxy" means an alkyl further consisting of a
carbon-oxygen single bond, for example, methoxy, ethoxy, propoxy,
isopropoxy, 1-butoxy, 2-butoxy, isobutoxy, tert-butoxy, pentoxy,
2-methylbutoxy, 1,1-dimethylpropoxy, hexoxy, heptoxy, octoxy,
nonoxy, and decoxy.
[0010] "alkyl" means an acyclic, saturated, branched or unbranched,
substituent consisting of carbon and hydrogen, for example, methyl,
ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, tert-butyl,
pentyl, 2-methylbutyl, 1,1-dimethylpropyl, hexyl, heptyl, octyl,
nonyl, and decyl.
[0011] "alkynyl" means an acyclic, unsaturated (at least one
carbon-carbon triple bond, and any double bonds), branched or
unbranched, substituent consisting of carbon and hydrogen, for
example, ethynyl, propargyl, butynyl, pentynyl, hexynyl, heptynyl,
octynyl, nonynyl, and decynyl.
[0012] "alkynyloxy" means an alkynyl further consisting of a
carbon-oxygen single bond, for example, pentynyloxy, hexynyloxy,
heptynyloxy, octynyloxy, nonynyloxy, and decynyloxy.
[0013] "aryl" means a cyclic, aromatic substituent consisting of
hydrogen and carbon, for example, phenyl, naphthyl, and
biphenyl.
[0014] "cycloalkenyl" means a monocyclic or polycyclic, unsaturated
(at least one carbon-carbon double bond) substituent consisting of
carbon and hydrogen, for example, cyclobutenyl, cyclopentenyl,
cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclodecenyl,
norbornenyl, bicyclo[2,2,2]octenyl, tetrahydronaphthyl,
hexahydronaphthyl, and octahydronaphthyl.
[0015] "cycloalkenyloxy" means a cycloalkenyl further consisting of
a carbon-oxygen single bond, for example, cyclobutenyloxy,
cyclopentenyloxy, cyclohexenyloxy, cycloheptenyloxy,
cyclooctenyloxy, cyclodecenyloxy, norbornenyloxy, and
bicyclo[2,2,2]octenyloxy.
[0016] "cycloalkyl" means a monocyclic or polycyclic, saturated
substituent consisting of carbon and hydrogen, for example,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclodecyl, norbornyl, bicyclo[2,2,2]octyl, and
decahydronaphthyl.
[0017] "cycloalkoxy" means a cycloalkyl further consisting of a
carbon-oxygen single bond, for example, cyclopropyloxy,
cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy,
cyclooctyloxy, cyclodecyloxy, norbornyloxy, and
bicyclo[2,2,2]octyloxy.
[0018] "cyclohaloalkyl" means a monocyclic or polycyclic, saturated
substituent consisting of carbon halo, and hydrogen, for example,
1-chlorocyclopropyl, 1-chlorocyclobutyl, and
1-dichlorocyclopentyl.
[0019] "halo" means fluoro, chloro, bromo, and iodo.
[0020] "haloalkyl" means an alkyl further consisting of, from one
to the maximum possible number of, identical or different, halos,
for example, fluoromethyl, difluoromethyl, trifluoromethyl,
1-fluoroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, chloromethyl,
trichloromethyl, and 1,1,2,2-tetrafluoroethyl.
[0021] "heterocyclyl" means a cyclic substituent that may be fully
saturated, partially unsaturated, or fully unsaturated, where the
cyclic structure contains at least one carbon and at least one
heteroatom, where said heteroatom is nitrogen, sulfur, or oxygen,
for example, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl,
benzoxazolyl, benzothienyl, benzothiazolyl cinnolinyl, furanyl,
indazolyl, indolyl, imidazolyl, isoindolyl, isoquinolinyl,
isothiazolyl, isoxazolyl, 1,3,4-oxadiazolyl, oxazolinyl, oxazolyl,
phthalazinyl, pyrazinyl, pyrazolinyl, pyrazolyl, pyridazinyl,
pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,
quinoxalinyl, 1,2,3,4-tetrazolyl, thiazolinyl, thiazolyl, thienyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl,
and 1,2,4-triazolyl.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0022] An embodiment of this invention is illustrated in Scheme
One
##STR00001##
wherein
[0023] (A) each R.sup.1 is independently selected from H, F, Cl,
Br, I, CN, NO.sub.2, and substituted or unsubstituted
(C.sub.1-C.sub.6)alkyl, wherein each substituted R.sup.1 has one or
more substituents independently selected from F, Cl, Br, I, CN,
NO.sub.2, (C.sub.1-C.sub.6)alkyl, and
(C.sub.1-C.sub.6)haloalkyl;
[0024] (B) R.sup.2 is selected from substituted or unsubstituted
(C.sub.1-C.sub.6)alkyl, substituted or unsubstituted
[0025] (C.sub.2-C.sub.6)alkenyl, substituted or unsubstituted
(C.sub.1-C.sub.6)alkoxy, substituted or unsubstituted
(C.sub.2-C.sub.6)alkenyloxy, substituted or unsubstituted
(C.sub.3-C.sub.10)cycloalkyl, substituted or unsubstituted
(C.sub.3-C.sub.10)cycloalkenyl, substituted or unsubstituted
(C.sub.6-C.sub.20)aryl, substituted or unsubstituted
(C.sub.1-C.sub.6)alkyl)(C.sub.6-C.sub.20)aryl, and substituted or
unsubstituted (C.sub.1-C.sub.20)heterocyclyl, wherein each
substituted R.sup.2 has one or more substituents independently
selected from F, Cl, Br, I, CN, NO.sub.2, (C.sub.1-C.sub.6)alkl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.2-C.sub.6)haloalkenyl, (C.sub.1-C.sub.6)haloalkyloxy,
(C.sub.2-C.sub.6)haloalkenyloxy, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.3-C.sub.10)cycloalkenyl, (C.sub.3-C.sub.10)halocycloalkyl,
(C.sub.3-C.sub.10)halocycloalkenyl, (C.sub.6-C.sub.20)aryl, and
(C.sub.1-C.sub.20)heterocyclyl;
[0026] (C) R.sup.3 is selected from H, substituted or unsubstituted
(C.sub.1-C.sub.6)alkyl, substituted or unsubstituted
(C.sub.3-C.sub.10)cycloalkyl, substituted or unsubstituted
(C.sub.1-C.sub.6)alkyl(C.sub.3-C.sub.10)cycloalkyl, substituted or
unsubstituted (C.sub.6-C.sub.20)aryl, and substituted or
unsubstituted (C.sub.1-C.sub.6)alkyl(C.sub.6-C.sub.20)aryl, wherein
each substituted R.sup.3 has one or more substituents independently
selected from F, Cl, Br, and I; and
[0027] (D) R.sup.4 is selected from H, substituted or unsubstituted
(C.sub.1-C.sub.6)alkyl, substituted or unsubstituted
(C.sub.3-C.sub.10)cycloalkyl, substituted or unsubstituted
(C.sub.1-C.sub.6)alkyl(C.sub.3-C.sub.10)cycloalkyl, substituted or
unsubstituted (C.sub.6-C.sub.20)aryl, substituted or unsubstituted
(C.sub.1-C.sub.6)alkyl(C.sub.6-C.sub.20)aryl, substituted or
unsubstituted (C.sub.1-C.sub.6)alkyl(C.sub.2-C.sub.6)alkenyl, and
substituted or unsubstituted
(C.sub.1-C.sub.6)alkyl(C.sub.2-C.sub.6)alkynyl, wherein each said
R.sup.4, which is substituted, has one or more substituents
selected from F, Cl, Br, I, CN, NO.sub.2, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyloxy,
(C.sub.1-C.sub.6)haloalkyloxy, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.3-C.sub.10)halocycloalkyl, (C.sub.6-C.sub.20)aryl, and
(C.sub.1-C.sub.20)heterocyclyl.
[0028] In another embodiment of this invention each R.sup.1 is
independently selected from H, F, and Cl.
[0029] In another embodiment of this invention R.sup.1 is H.
[0030] In another embodiment of this invention R.sup.3 is selected
from H, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, and
(C.sub.6-C.sub.20)aryl.
[0031] In another embodiment of this invention R.sup.3 is selected
from H, CF.sub.3, CH.sub.2F, CHF.sub.2, CH.sub.3, CH.sub.2CH.sub.3,
CH(CH.sub.3).sub.2, and phenyl.
[0032] In another embodiment of this invention R.sup.3 is selected
from H and CH.sub.3.
[0033] In another embodiment of this invention R.sup.4 is
(C.sub.1-C.sub.6)alkyl(C.sub.3-C.sub.10)cyclohaloalkyl.
[0034] In another embodiment of this invention R.sup.4 is selected
from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl(C.sub.6-C.sub.20)aryl,
(C.sub.1-C.sub.6)haloalkyl,
(C.sub.1-C.sub.6)alkyl(C.sub.3-C.sub.10)cycloalkyl,
(C.sub.3-C.sub.10)cycloalkyl--O--(C.sub.1-C.sub.6)alkyl, and
(C.sub.3-C.sub.10)cyclohaloalkyl.
[0035] In another embodiment of this invention R.sup.4 is selected
from H, CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH(CH.sub.3).sub.2, cyclopropyl, (C.sub.6-C.sub.20)aryl,
CH.sub.2-phenyl, CH.sub.2-phenyl-OCH.sub.3,
CH.sub.2OCH.sub.2-phenyl, CH.sub.2CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2F, CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2cyclopropyl,
and cyclopropyl--O--CH.sub.2CH.sub.3.
[0036] In another embodiment of this invention R.sup.4 is selected
from H, CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3, cyclopropyl,
CH.sub.2cyclopropyl, and CH.sub.2CH=CH.sub.2,
CH.sub.2C.ident.CH.
[0037] In another embodiment of this invention molecules having a
structure according to compound (III) are disclosed as
intermediates useful for the synthesis of pesticidal thiazole
amides.
[0038] In general, S-R.sup.2 is a leaving group wherein R.sup.2 is
part of the leaving group that does not substantially and adversely
affect the desired reaction. It is desirable that R.sup.2 is a
group that beneficially affects the volatility of the thio
by-product of the reaction.
[0039] In step a, compounds (I) and (II) are reacted to produce
compound (III). The reaction can be conducted at room temperature
and under ambient pressure, but higher or lower temperatures and
pressures can be used, if desired. The reaction is conducted in a
polar protic solvent. Examples of such solvents include, but are
not limited to, formic acid, n-butanol, isopropanol, n-propanol,
ethanol, methanol, acetic acid, and water. Currently, methanol is
preferred.
[0040] In step b, compound (III) is cyclized using a dehydrating
agent. Examples of such dehydrating agents include, but are not
limited to, POCl.sub.3, H.sub.2SO.sub.4, SOCl.sub.2,
P.sub.2O.sub.5, polyphosphoric acid, p-toluene sulfonic acid, and
trifluoroacetic anhydride. The reaction can be conducted at room
temperature and under ambient pressure, but higher or lower
temperatures and pressures can be used, if desired. Currently, it
is preferred if a temperature higher than room temperature is used,
preferably, up to and including the boiling point of the solution,
for example, a temperature from about 60.degree. C. to about
120.degree. C. can be used. The reaction is conducted in a polar
protic solvent. Currently, acetonitrile is preferred.
[0041] One advantage of steps a and b over the art is that compound
(III) and (IV) are generally produced as substantially pure solids
that do not need additional purification procedures. Another
advantage with these processes is that in compound (IV)-if R.sup.3
is H, it can be halogenated. Consequently, at this point R.sup.3
additionally now includes F, Cl, Br, and I (see Scheme Two).
##STR00002##
[0042] In step c, any halogenating agent can be used, for example,
1-chloropyrrolidine-2,5-dione, N-bromosuccinimide, and
1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2,2,2]octane
bis(tetrafluoroborate). Polar solvents can be used such as
dichloromethane, tetrahydrofuran, ethyl acetate, acetone,
dimethylformamide, acetonitrile, and dimethyl sulfoxide. Currently,
dichloromethane is preferred. The reaction can be conducted are
room temperature and pressure, but higher or lower temperatures and
pressures can be used, if desired. Currently, temperatures from
about 0.degree. C. to about ambient are preferred.
[0043] In another embodiment of this invention R.sup.3 is
preferably Cl.
[0044] Compound (IV) or compound (V) can be further reacted to form
certain pesticides disclosed in WO 2010/129497 (the entire
disclosure of which is incorporated herein by reference).
EXAMPLES
[0045] The examples are for illustration purposes and are not to be
construed as limiting the invention disclosed in this document to
only the embodiments disclosed in these examples.
[0046] Starting materials, reagents and solvents which were
obtained from commercial sources were used without further
purification. Anhydrous solvents were purchased as Sure/Seal.TM.
from Aldrich and were used as received. Melting points were
obtained on a Thomas Hoover Unimelt capillary melting point
apparatus or an OptiMelt Automated Melting Point System from
Stanford Research Systems and are uncorrected. Molecules are given
their known names, named according to naming programs within ISIS
Draw, ChemDraw or ACD Name Pro. If such programs are unable to name
a molecule, the molecule is named using conventional naming rules.
All NMR are in ppm (.delta.) and were recorded at 300, 400, or 600
MHz unless otherwise stated.
Example 1
[0047] Preparation of
N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-2-methyl-3-(methylthio)-
propanamide:
##STR00003##
[0048] Step 1: Preparation of
N-ethyl-2-(pyridin-3-carbothioamido)acetamide:
##STR00004##
[0049] To a dry 3 L round bottom flask equipped with mechanical
stirrer, nitrogen inlet, three-stage sequential mercaptan scrubber
(bleach, 30% sodium hydroxide, and saturated potassium hydroxide),
thermometer, and addition funnel, was charged
2-amino-N-ethylacetamide hydrochloride (SPECS, Catalog #AS-787,
68.8 g, 500 mmol) and methanol (500 mL). The reaction was cooled to
5 .degree. C. and triethylamine (50.6 g, 500 mmol) in methanol (50
mL) was added dropwise (note: slightly exothermic to 10 .degree.
C.). To this mixture was added methyl pyridine-3-carbodithiolate
(85.0 g, 500 mmol) in methanol (100 mL) dropwise and the resulting
mixture stirred at 5-10 .degree. C. for 2 hours. The reaction
mixture was allowed to warm to 25 .degree. C. and stirred under
nitrogen for 2 hours. The reaction mixture was cooled to 5.degree.
C. and water (1 L) was added until a solid precipitated from the
solution. The solid was collected by vacuum filtration, washed with
water (3 L), hexanes (500 mL), and air dried for 16 hours to give
N-ethyl-2-(pyridin-3-carbothioamido)acetamide as a yellow fluffy
solid (free of any mercaptan odor) which was dried in vacuo at
40.degree. C. for 6 hours. This gave a yellow solid (77.7 g, 70%
yield): mp 143-145.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.02 (dd, J=2.4, 0.7 Hz, 1H), 8.86 (s, 1H), 8.70 (dd,
J=4.8, 1.6 Hz, 1H), 8.15 (ddd, J=8.0, 2.4, 1.7 Hz, 1H), 7.35 (ddd,
J=8.0, 4.8, 0.8 Hz, 1H), 6.05 (s, 1H), 4.43 (d, J=4.5 Hz, 2H), 3.38
(dd, J=13.0, 6.4 Hz, 2H), 1.20 (t, J=7.3 Hz, 3H);.sup.13C-NMR (101
MHz, CDCl.sub.3) .delta. 195.66, 166.90, 152.00, 147.20, 136.32,
134.96, 123.24, 49.45, 34.92, 14.75; Anal. Calcd. for
C.sub.10H.sub.13N.sub.3OS: C, 53.79; H, 5.87; N, 18.82; S, 14.36.
Found: C, 53.77: H, 5.79; N, 18.87; S, 14.52.
[0050] Step 2: Preparation of
N-ethyl-2-(pyridin-3-yl)thiazol-5-amine:
##STR00005##
[0051] To a dry 1 L round bottom flask equipped with mechanical
stirrer, addition funnel and reflux condenser was charged
N-ethyl-2-(pyridine-3-carbothioamido)acetamide (50.0 g, 224 mmol)
and acetonitrile (400 mL). To this mixture was added phosphorus
oxychloride (103 g, 672 mmol) dropwise, and the reaction stirred at
ambient temperature for 20 minutes. The reaction mixture was heated
to 55.degree. C. and the course of the reaction was monitored by
HPLC (YMC AQ column 5% acetonitrile ("ACN") 95% water-0.05%
trifluoroacetic acid ("TFA") to 95% ACN 5% water with 0.05% TFA
over 20 Min @ 1.0 ml/min) After 2 hours, the reaction was
essentially complete. The reaction was cooled to 25.degree. C. and
the solvent removed by rotary evaporation to give a thick yellow
syrup. The thick yellow syrup was carefully poured into saturated
aqueous sodium bicarbonate solution (1.5 L) with rapid stirring.
The pH of the resulting yellow solution was adjusted with solid
sodium bicarbonate until slightly basic (pH=8), and a yellow solid
precipitated from solution. Additional cold water (1 L) was added
to the mixture and stirred for an additional 20 minutes. The
precipitate was collected by vacuum filtration, and rinsed with
water (1 L) and hexanes (500 mL). The collected solid was dried in
vacuo at 40.degree. C. for 16 hours to give
N-ethyl-2-(pyridin-3-yl)thiazol-5-amine as a yellow solid (36.7 g,
80%): mp 97-98.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 6 8.98
(dd, J=2.3, 0.8 Hz, 1H), 8.53 (dd, J=4.8, 1.6 Hz, 1H), 8.07 (ddd,
J=8.0, 2.3, 1.6 Hz, 1H), 7.31 (ddd, J=8.0, 4.8, 0.8 Hz, 2H), 6.98
(s, 1H), 3.96 (s, 1H), 3.24 (q, J=5.8 Hz, 2H), 1.31 (t, J=7.2 Hz,
3H); .sup.13C NMR (101 MHz, CDC1.sub.3) 6 152.00, 149.21, 149.21,
146.61, 132.17, 130.44, 123.62, 121.84, 43.09, 14.80. Anal. Calc'd.
for C.sub.10H.sub.11N.sub.3S: C, 58.51; H, 5.40; N, 20.47. Found:
C, 58.34: H, 5.40; N, 20.38; ESIMS m/z 205 ([M+H].sup.+).
[0052] Step 3: Preparation of
4-chloro-N-ethyl-2-(pyridin-3-yl)thiazol-5-amine hydrochloride:
##STR00006##
[0053] To a dry 500 ml round bottom flask equipped with magnetic
stirrer, thermometer, and nitrogen inlet was charged
N-ethyl-2-(pyridin-3-yl)thiazol-5-amine (5.1 g, 25 mmol), diethyl
ether (200 mL) and dioxane (5 mL). The resulting suspension (not
all solid dissolved) was cooled to 5.degree. C., and
N-chlorosuccinamide (3.65 g, 27.3 mmol) was added portionwise.
After all of the chlorinating agent was added, a brown solid
precipitated from solution. The reaction mixture was stirred at
5.degree. C. for 60 minutes, then analyzed by HPLC (YMC AQ column
5% ACN 95% water-0.05% TFA to 95% ACN 5% water with 0.05% TFA over
20 Min @ 1.0 ml/min) HPLC analysis showed no starting material and
one major product consistent with the desired chloride. The brown
suspension was filtered through a pad of Celite.RTM., and the
Celite.RTM. pad rinsed with diethyl ether (.about.20 mL). The
filtrate was cooled to 5.degree. C. and acidified with stirring by
the addition of 6.5 ml of 4M HCl in dioxane. A yellow solid
immediately formed. The solid was collected by vacuum filtration,
rinsed with diethyl ether, and dried in vacuo at 40.degree. C. for
2 hours. This gave 4-chloro-N-ethyl-2-(pyridin-3-yl)thiazol-5-amine
hydrochloride as a yellow solid (6.3 g, 92%): mp 180-182.degree.
C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.07 (d, J=2.0 Hz,
1H), 8.70 (dd, J=5.4, 1.3 Hz, 1H), 8.59-8.42 (m, 1H), 7.86 (dd,
J=8.2, 5.3 Hz, 1H), 5.27 (s, 5H), 3.20 (q, J=7.2 Hz, 2H), 1.23 (t,
J=7.1 Hz, 3H); .sup.13C NMR (101 MHz, DMSO-d.sub.6) .delta. 148.10,
140.19, 138.58, 137.91, 137.01, 132.06, 127.30, 115.89, 43.43,
13.87; Anal. Calcd. for C.sub.10H.sub.11Cl.sub.2N.sub.3S: C, 43.49;
H, 4.01; Cl, 25.67; N, 15.21; S, 11.61. Found: C, 43.42: H, 4.01;
Cl, 25.55; N, 14.99; S, 11.46.
[0054] Step 4: Preparation of
N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-2-methyl-3-(methylthio)-
propanamide:
[0055] Into a 1 L three-necked flask fitted with a J-KEM type-T
temperature probe, overhead stirrer, reflux condenser, and nitrogen
inlet was added 4-chloro-N-ethyl-2-(pyridin-3-yl)thiazol-5-amine
hydrochloride (75.8 g, 274 mmol) and dichloromethane (500 mL). To
the resulting green suspension was added pyridine (55 g, 695 mmol,
2.5 eq) (note: fuming, with exotherm from 20.degree. C. to
26.degree. C.) portionwise over one minute. The reaction turned
into a dark green-black solution. To this solution was added
N,N-dimethylpyridin-4-amine (DMAP, 16.5 g, 135 mmol, 0.5 eq) (note:
no change in reaction appearance or temperature) followed by
2-methyl-3-methylthiopropanoyl chloride (44.3 g, 290 mmol, 1.06
eq), which was added portionwise over one minute. The reaction
exothermed from 17.degree. C. to 29.degree. C. during the addition
of the acid chloride. The reaction was heated to 35.degree. C. for
19 hours and then cooled to 25.degree. C. for 4 hours. Analysis by
HPLC (YMC AQ column 5% acetonitrile ("ACN") 95% water-0.05%
trifluoroacetic acid ("TFA") to 95% ACN 5% water with 0.05% TFA
over 20 Min @ 1.0 ml/min) showed that the reaction was 95%
complete. The black reaction mixture was transferred to a 2 L
separatory funnel and dichloromethane (200 mL) and water (300 mL)
were added. The phases were separated and the aqueous layer (brown)
was extracted with dichloromethane (100 mL) and the dichloromethane
extracts combined. The combined dichloromethane extract was washed
with brine (300 mL), dried over anhydrous sodium sulfate, filtered,
and evaporated (40.degree. C., 40 mmHg, 1 hour). This gave 99.4 g
of a black thick oil. The thick black oil was dissolved into
dichloromethane (100 mL) and vacuum added to the top of a 240 g
solid load cartridge containing 230 g silica gel 60. The solid load
cartridge was attached to an ISCO companion XL and the material
purified on a 1.5 kg Redisep silica prepacked column using a mobile
phase of hexane:ethyl acetate (gradient: 20% ethyl acetate 5 min,
20% -90% ethyl acetate over 70 minutes) with a flow rate of 400
mL/min The desired compound eluted from the column between 30-50
minutes was collected into 500 mL bottles (fractions 2-16).
Fractions 2-9 were pooled (note: fractions 8-9, which were cloudy,
were filtered through paper) and rotary evaporated (40.degree. C.,
40 mmHg, 2 hours). This gave 56.8 g of a dark yellow oil that was
98% pure by HPLC at 254 nm Fraction 10-15 were filtered and pooled
and rotary evaporated (40.degree. C., 40 mmHg, 2 hour) to give a
golden oil (27.51 g). The sample was analyzed by HPLC (YMC AQ
column 5% ACN 95% water-0.05% TFA to 95% ACN 5% water with 0.05%
TFA over 20 Min @ 1.0 ml/min) at 254 nm and showed a purity of 88%
and contained 10% thiazoleamine starting material and 2% of a
unknown faster moving impurity. The golden oil (27.5 g, 88% pure)
was dissolved into ether (50 mL) and a yellow solid precipitated
after 1 minute. The mixture was stirred for 15 minutes at
25.degree. C., then hexane (50 mL) was added and the mixture
stirred for another 15 minutes at 25.degree. C. The solid was
collected by vacuum filtration and the yellow solid washed with
ether/hexane (1:1, 25 mL). This gave 19.23 g of
N-(4-chloro-2-(pyridin-3-yl)
thiazol-5-yl)-N-ethyl-2-methyl-3-(methylthio)propanamide as a
yellow solid. Analysis by HPLC showed the purity was 97% at 254 nm
The 56.8 g sample (golden oil, 98% purity) was dissolved into ether
(100 mL) and after 1 minute a light tan solid precipitated. The
mixture was stirred for 15 minutes at 25.degree. C. and hexane (100
mL) was added. The mixture was stirred for an additional 15
minutes. The solid was collected by vacuum filtration and washed
with ether/hexane (1:1, 2.times.50 mL). This gave 49.67 g light
yellow solid. Analysis by HPLC (YMC AQ column 5% ACN 95%
water-0.05% TFA to 95% ACN 5% water with 0.05% TFA over 20 Min @
1.0 ml/min) at 254 nm showed a purity of >99%. The mother
liquors from both recrystallization were combined and rotary
evaporated (40.degree. C., 40 mmHg, 1 hour). This gave 11.27 g of a
dark yellow oil. The oil was re-dissolved into ether (40 mL) and
stirred for 30 minutes during which time a dark yellow precipitate
formed. Hexane (50 mL) was added and the mixture stirred for 15
minutes. The dark solid was collected by vacuum filtration and
washed with ether/hexane (1:1, 2.times.20 mL). This gave 5.0 g of a
brown solid that assayed to >99% pure by HPLC at 254 nm The
recrystallized samples were all combined and mixed manually to give
N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-2-methyl-3-(methylthio)-
propanamide as a yellow solid (75 g, 85%): mp 80-81.degree. C.;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.12 (d, J=1.9 Hz, 1H),
8.72 (dd, J=4.8, 1.4 Hz, 1H), 8.22 (ddd, J=8.0, 2.2, 1.8 Hz, 1H),
7.43 (ddd, J=8.0, 4.8, 0.6 Hz, 1H), 4.03-3.80 (m, 1H), 3.80-3.59
(m, 1H), 2.97-2.68 (m, 2H), 2.60-2.39 (m, 1H), 2.03 (s, 3H),
1.30-1.16 (m, 6H); .sup.13C NMR (101 MHz, DMSO-d.sub.6) .delta.
175.66, 162.63, 151.89, 147.14, 138.19, 133.49 133.23, 128.58,
123.90, 44.81, 38.94, 37.93, 18.16, 16.83, 12.90; Anal. Calcd. for
C.sub.15H.sub.18CIN.sub.3OS.sub.2: C, 50.62; H, 5.10; N, 11.81; S,
18.02. Found: C, 50.49: H, 5.21; N, 11.77; S, 17.99.
Example 2
[0056] Preparation of
N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-cyclopropyl-3-(methylthio)pro-
panamide:
##STR00007##
[0057] Step 1: Preparation 2-amino-N-cyclopropylacetamide
hydrochloride:
##STR00008##
[0058] To a solution of 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (7.77
g, 57 1 mmol), 2-(tert-butoxycarbonylamino)acetic acid (10 g, 57.1
mmol), cyclopropanamine (3.91 g, 68 5 mmol) and DMAP (8.37 g, 68 5
mmol) in DMF (28 mL) was added
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrogen chloride salt and the mixture stirred at room temperature
for 16 h. The mixture was diluted with ethyl acetate, washed with
0.1N aqueous HCl, aqueous NaHCO.sub.3 and brine, dried over
MgSO.sub.4, filtered and concentrated in vacuo to give tert-butyl
2-(cyclopropylamino)-2-oxoethylcarbamate (8.90 g, 41.5 mmol, 72.8%)
as a pale yellow oil: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
6.18 (s, 1H), 3.74 (d, J=5.9 Hz, 2H), 2.71 (m, 1H), 1.45 (s, 9H);
0.84-0.7 (m, 2H), 0.56-0.43 (m, 2H); EIMS m/z 214 ([M].sup.+). To a
solution of tert-butyl 2-(cyclopropylamino)-2-oxoethylcarbamate
(8.5 g, 39 7 mmol) in dioxane (20 mL) was added HCl (100 mmol, 25
mL 4 M in dioxane) and the mixture stirred at 10.degree. C. for 3
h. The mixture was diluted with hexanes and filtered under vacuum
to give 2-amino-N-cyclopropylacetamide, HCl salt as a white solid
(5.2 g, 83%): mp 139-142.degree. C.; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.66 (bs, 1H), 8.19 (bs, 3H), 3.46 (s, 2H),
2.73-2.60 (m, 1H), 0.71-0.60 (m, 2H), 0.48-0.36 (m, 2H).
[0059] Step 2: Preparation of
N-cyclopropyl-2-(pyridine-3-carbothioamido)acetamide:
##STR00009##
[0060] To a solution of methyl pyridine-3-carbodithioate (2.97 g,
17.52 mmol) in methanol (10 mL) was added a solution of
2-amino-N-cyclopropylacetamide (2 g, 17.52 mmol) (HCl salt) and
triethylamine (3.55 g, 35.0 mmol). The mixture was stirred at room
temperature for 1 hour and then diluted with ethyl acetate and
washed with saturated aqueous NaHCO.sub.3, brine, dried over
MgSO.sub.4, filtered, and concentrated in vacuo to give
N-cyclopropyl-2-(pyridine-3-carbothioamido)acetamide as a yellow
solid (3.60 g, 83%): mp 152-153.degree. C.; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.60 (s, 1H), 8.91 (ddd, J=7.0, 2.3, 0.7 Hz,
1H), 8.76-8.56 (m, 1H), 8.10 (m, 2H), 7.57-7.32 (m, 1H), 4.26 (m,
2H), 2.73 - 2.57 (m, 1H), 0.77-0.61 (m, 2H), 0.50-0.29 (m, 2H);
ESIMS (m/z) 234 ([M-H].sup.-).
[0061] Step 3: Preparation of
N-cyclopropyl-2-(pyridin-3-yl)thiazol-5-amine:
##STR00010##
[0062] N-Cyclopropyl-2-(pyridine-3-carbothioamido)acetamide (1.00
g, 4.25 mmol) was dissolved in acetonitrile (5 mL) in a dry flask
and phosphoryloxy trichloride (3.26 g, 21.25 mmol) was added,
dropwise. The mixture was warmed to 100.degree. C. and stirred for
1 hour. The mixture was cooled to room temperature and the yellow
solid filtered under vacuum. This solid was washed with
acetonitrile and dried under vacuum to give 0.36 g of
N-cyclopropyl-2-(pyridin-3-yl)thiazol-5-amine HCl salt (LCMS and
.sup.1H-NMR indicated 100% purity). The filtrate was diluted with
ethyl acetate and carefully basified with saturated aqueous
NaHCO.sub.3. The organic phase was separated and washed with brine,
dried over MgSO.sub.4, and concentrated in vacuo to give
N-cyclopropyl-2-(pyridin-3-yl)thiazol-5-amine as a brown oil (0.45
g, 3.47 mmol, 82%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.10
(d, J=2.1 Hz, 1H), 8.68 (dd, J=5.5, 1.2 Hz, 1H), 8.63-8.58 (m, 1H),
7.89 (dd, J=8.1, 5.4Hz, 1H), 7.07 (d, J=7.8, 1H), 2.57 (dt, J=10.0,
3.3 Hz, 1H), 0.85-0.68 (m, 2H), 0.57-0.45 (m, 2H); ESIMS (m/z) 216
([M-H].sup.-).
[0063] Step 4: Preparation of
4-chloro-N-cyclopropyl-2-(pyridin-3-yl)thiazol-5-amine:
##STR00011##
[0064] To a solution of
N-cyclopropyl-2-(pyridin-3-yl)thiazol-5-amine (1.00 g, 4.60 mmol)
in acetonitrile (2 mL) was added 1-chloropyrrolidine-2,5-dione (645
mg, 4.83 mmol) and the mixture stirred at 0.degree. C. for lh. The
mixture was filtered and the filtrate was treated with excess HCl
(4M in dioxane) to give
4-chloro-N-cyclopropyl-2-(pyridin-3-yl)thiazol-5-amine as a brown
solid: mp 56-60.degree. C.
[0065] Step 5: Preparation of
N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-cyclopropyl-3-(methylthio)pro-
panamide: To a solution of
4-chloro-N-cyclopropyl-2-(pyridin-3-yl)thiazol-5-amine HCl salt
(288 mg, 1 mmol) and DMAP (305 mg, 2.500 mmol) in
CH.sub.2ClCH.sub.2Cl (1 mL) was added 3-(methylthio)propanoyl
chloride (166 mg, 1.200 mmol), and the mixture stirred at room
temperature for 1 h. The mixture was diluted with ethyl acetate,
mixed with aqueous NaHCO.sub.3 (10 mL). The organic phase was
separated, rinsed with brine (2x), dried over MgSO.sub.4 and
concentrated in vacuo to give a yellow gum. This gum was purified
on reverse phase column chromatography (C-18, CH.sub.3CN/H.sub.2O)
to give
N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-cyclopropyl-3-(methylthio)pro-
panamide (82 mg, 22%) as a brown gum: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 9.10 (s, 0.6H), 9.02 (s, 0.4H), 8.71 (s, 6H),
8.61 (d, J=3.4 Hz, 0,4H), 8.21 (d, J=7.6 Hz, 1H), 8.19-8.10 (m,
1H), 7.41 (d, J=5.6, 0.6H), 7.35 (dd, J=8.3, 4.5 Hz, 0.4H), 3.16
(bs, 1H), 2.91 (s, 3H), 2.88-2.72 (m, 2H), 2.11 (m, 2H), 0.85 (m,
4H); ESIMS (m/z) 354.56 ([M+H].sup.+).
Example 3:
[0066] Preparation of
N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N,2-dimethyl-3-(methylthio)prop-
anamide:
##STR00012##
[0067] Step 1: Preparation of
N-methyl-2-(pyridine-3-carbothioamido)acetamide:
##STR00013##
[0068] A 5 liter three-necked round bottom flask was fitted with a
nitrogen inlet over a dropping funnel, a mechanical stirrer, and a
reflux condenser. A tube from the top of the condenser was plumbed
through a 1 liter bump flask and then into a sparge tube in another
5 liter three-neck stirred flask filled with 2.5 liter of 12% pool
bleach. The outlet of the bleach flask was plumbed through an
alligator trap with about 250 mL of 12% bleach solution. The
reactor was charged with 2-amino-N-methylacetamide (160 g, 1.81
mol) and acetonitrile (3 L) to give a cloudy solution. The dropping
funnel was charged with methyl pyridine-3-carbodithioate (307 g,
1.81 mol) and acetonitrile (200 mL). The addition of the dithioate
took about 20 min and the reaction was swept with a good stream of
nitrogen. A slight exotherm was noted upon the addition (about
3.degree. C.). After the addition was complete, the dropping funnel
was rinsed with 550 mL of acetonitrile to bring the total volume of
acetonitrile to 3750 mL. After stirring for about 10 min, the red
solution precipitated to give a cottage cheese-like solid which
would not stir. The dropping funnel was replaced with a 1/4 inch
straight tube to bubble nitrogen into the reactor. The reactor was
heated slowly to about 45-50.degree. C. to form a reddish solution
and then allowed to cool back down slowly to room temperature and
crystallize to a fine yellowish needle-like solid which stirred
easily. The needles were collected by vacuum filtration and washed
with 100 mL of acetonitrile. The solid was dried under vacuum at
40.degree. C. for 16 h to give
N-methyl-2-(pyridine-3-carbothioamido)acetamide (268.6 g, 71%) as a
light yellow solid: mp 135-137.degree. C.; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.65 (s, 1H), 8.95 (dd, J=2.4, 0.7 Hz, 1H),
8.67 (dd, J=4.8, 1.6 Hz, 1H), 8.14 (ddd, J=8.0, 2.3, 1.7 Hz, 1H),
7.95 (d, J=4.3 Hz, 1H), 7.48 (ddd, J=7.9, 4.8, 0.7 Hz, 1H), 4.34
(s, 2H), 2.62 (d, J=4.6 Hz, 3H); .sup.13C NMR (101 MHz,
DMSO-d.sub.6) .delta. 194.98, 165.77, 150.37, 146.40, 135.25,
134.04, 121.51, 47.66, 24.41; Anal. Calcd. for
C.sub.9H.sub.11N.sub.3OS: C, 51.65; H, 5.30; N, 20.08; S, 15.32.
Found: C, 51.47: H, 5.30; N, 20.01; S, 15.53.
[0069] Step 2: Preparation of
N-methyl-2-(pyridin-3-yl)thiazol-5-amine:
##STR00014##
[0070] To a dry 2 L round bottom flask equipped with mechanical
stirrer, addition funnel and reflux condenser was charged
N-methyl-2-(pyridine-3-carbothioamido)acetamide (100 g, 478 mmol)
and acetonitrile (1 L). To this mixture was added phosphorus
oxychloride (256 g, 1672 mmol) portionwise over 10 minutes. The
reaction mixture was stirred at ambient temperature for 10 minutes
during which time a slight exotherm occurred from 22.degree. C. to
34.degree. C. (Note: some solid remained undissolved in the
reaction mixture, and the mixture became thick, but still stirred
reasonably well). The reaction mixture was heated to 85.degree. C.
(refluxing gently). After 3 hours, all of the solid had dissolved,
forming a dark amber solution. Analysis of an aliquot by TLC (70%
ethyl acetate: 30% hexanes) after 4 hours indicated that the
reaction was essentially complete. The reaction mixture was allowed
to cool to 25.degree. C. and the solvent removed by rotary
evaporation. The residue was dissolved in water and treated with
solid sodium bicarbonate until slightly basic (pH .about.8) with
continuous stirring (Note: No attempt was made to control the
temperature, and the flask was slightly warm to the touch). A brown
precipitate started to form after a few minutes. The mixture was
continued to stir at 25.degree. C. for 16 hours. The brown solid
was collected by vacuum filtration and washed with water. This gave
a tan solid wet cake (91 g) which was then dried in vacuo at
40.degree. C. to a constant weight. This gave
N-methyl-2-(pyridin-3-yl)thiazol-5-amine as a sand colored solid
(68.5 g, 75%): mp 140-141.degree. C.; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.98 (dd, J=2.3, 0.7 Hz, 1H), 8.53 (dd, J=4.8,
1.6 Hz, 1H), 8.07 (ddd, J=8.0, 2.2, 1.7 Hz, 1H), 7.40-7.21 (m, 1H),
6.96 (s, 1H), 4.18 (s, 1H), 2.96 (s, 3H); .sup.13C NMR (101 MHz,
Chloroform) .delta. 153.23, 149.15, 146.54, 132.23, 130.47, 123.65,
121.20, 34.48; Anal. Calc'd. for C.sub.9H.sub.9N.sub.3S: C, 56.52;
H, 4.74; N, 21.97; S, 16.77. Found: C, 56.31: H, 4.74; N, 21.81; S,
16.96.
[0071] Step 3: Preparation of
4-chloro-N-methyl-2-(pyridin-3-yl)thiazol-5-amine:
##STR00015##
[0072] To a dry 100 ml round bottom flask equipped with magnetic
stirrer, thermometer, and nitrogen inlet was charged
N-methyl-2-(pyridin-3-yl)thiazol-5-amine (0.528 g, 2.76 mmol) and
dichloromethane (50 mL). The resulting solution was cooled to
5.degree. C., followed by the portionwise addition of the solid
N-chlorosuccinamide. After all of the chlorinating agent was added
a dark brown solution formed. The solution was stirred at 5.degree.
C. for 20 minutes, then analyzed an aliquot by HPLC (YMC AQ column
5% ACN 95% water-0.05% TFA to 95% ACN 5% water with 0.05% TFA over
20 Min @ 1.0 ml/min) HPLC analysis showed no starting material and
one major product. The reaction mixture was poured into a
separatory funnel containing dichloromethane (50 mL) and washed
with water (2.times.10 mL) followed by saturated aqueous sodium
chloride solution (10 mL). The organic phase was dried over
anhydrous magnesium sulfate, filtered, and rotary evaporated to
give a powdery brown solid (0.51 g). The solid was purified on an
ISCO Combiflash Rf (silica gel 80 g cartridge, mobile phase
A=hexane, B=ethyl acetate, gradient 0% B to 100% B over 20
minutes). Fractions were collected into 25 mL test tubes. The tubes
containing the desired material were combined and rotary evaporated
to afford 4-chloro-N-methyl-2-(pyridin-3-yl)thiazol-5-amine as a
canary yellow solid (0.32 g, 51%); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.97 (dd, J=2.3, 0.7 Hz, 1H), 8.54 (dd, J=4.8,
1.6 Hz, 1H), 8.07 (ddd, J=8.0, 2.3, 1.6 Hz, 1H), 7.45-7.14 (m, 1H),
4.07 (dd, J=40.5, 38.0 Hz, 1H), 3.03 (d, J=5.3 Hz, 3H); .sup.13C
NMR (101 MHz, CDCl.sub.3) .delta. 149.55, 146.03, 145.60, 145.28,
131.73, 129.71, 123.64, 117.37, 35.75; Anal. Calc'd. for
C.sub.9H.sub.8CIN.sub.3S: C, 49.89; H, 3.57; N, 18.62; S, 14.21.
Found: C, 48.03: H, 3.64; N, 18.42; S, 14.23.
[0073] Step 4: Preparation of
N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N,2-dimethyl-3-(methylthio)prop-
anamide:
[0074] To a dry 500 ml round bottom flask equipped with magnetic
stirrer, thermometer, and nitrogen inlet was added
4-chloro-N-methyl-2-(pyridin-3-yl)thiazol-5-amine (22 g, 97 mmol)
and dichloromethane (250 mL). The suspension was stirred at room
temperature while pyridine (8.48 g, 107 mmol) and DMAP (1.20 g,
9.75 mmol) were added. To this suspension was added
2-methyl-3-(methylthio)propanoyl chloride (17.8 g, 117 mmol) over 5
minutes. During the addition all solids went into solution and the
reaction was exothermic from 20.degree. C. to 30.degree. C. The
reaction was stirred at ambient temperature for 16 h. The mixture
was checked by HPLC (YMC AQ column 5% ACN 95% water-0.05% TFA to
95%ACN 5% water with 0.05% TFA over 20 Min @ 1.0 ml/min) which
showed complete conversion of all starting material. The reaction
mixture was diluted with dichloromethane and water was then added.
The mixture was poured into a separatory funnel with
dichloromethane and water and the layers separated. The organic
phase was washed with brine, dried over anhydrous magnesium
sulfate, filtered, and rotary evaporated to afford 33.6 g of a dark
oil. The oil was purified on an ISCO Combiflash Rf (330 g silica
gel cartridge, mobile phase A=hexane, B=ethyl acetate, gradient 0%
B to 100% B over 20 minutes). The fractions were collected into 25
mL test tubes. The tubes containing the desired product were
combined and the solvent removed by rotary evaporation. This
afforded 22.8 g of a thick yellow liquid in 68.4% isolated yield.
The entire sample crystallized and hexane (200 mL) was added to
give a slurry. The slurry was vacuum filtered and the solid allowed
to air dry. This gave
N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N,2-dimethyl-3-(methy-
lthio)propanamide as an off-white solid; mp 75-80.degree. C.;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.12 (d, J=1.4 Hz, 1H),
8.73 (d, J=3.8 Hz, 1H), 8.34-8.09 (m, 1H), 7.43 (dd, J=7.9, 4.9 Hz,
1H), 3.30 (s, 3H), 3.06-2.70 (m, 2H), 2.49 (d, J=7.4 Hz, 1H), 2.04
(s, 3H), 1.21 (d, J=6.4 Hz, 3H); .sup.13C NMR (101 MHz,
DMSO-d.sub.6) .delta. 175.22, 162.37, 151.91, 146.53, 136.46,
134.64, 133.35, 127.98, 124.27, 37.47, 36.71, 36.47, 17.56, 15.44;
Anal. Calcd. for C.sub.14H.sub.16CIN.sub.3OS.sub.2: C, 49.18; H,
4.72; N, 12.29; S, 18.76. Found: C, 49.04: H, 4.68; N, 12.29; S,
18.68.
* * * * *