Note: Descriptions are shown in the official language in which they were submitted.
2015098
TITLE BA-8800
5PREPARATIvE PROCESS FOR
3-AMINO-2-THIOXO-OXAZOLIDIN-4-ONES
BACKGROUND OF THE INVENTION
3-Amino-2-thioxo-oxazolidin-4-ones are reported
in Z. Naturforsch., ~: Anorg. Chem., Org. Chem.
101983, 38B(8) 1008 (Detlef Geffken), without
suggestion of utility. The method given there for
their preparation is exemplified below for compound ~-
~ ~
Ph ~<OH (~ Ph ~ PhNHNH2 Ph ~
20 ~ c- NOH o Et o
: ~
11 111 ' `
Preparation of compound i requires use of an
expensive N-substituted hydroxylamine. Preparation
of the intermediate ii requires use of the expensive
reagent l,l'-thiocarbonyldiimidazole.
Copending application (Du Pont Case No. BA-8790
describes the antifungal utility of compounds
,
,
~:
~t '` , ' : :; . ' '
.. ~' ' '' ' " ''" ' :, ' .. ' '
r à ~
.
- 201~098
^~ prepared by the method of the present invention, of
which structure iii represents one such compound.
2-Hydroxycarbo~ylic acids can be purchased from
commercial sources, or generally prepared from
ketones or aldehydes by formation of cyanohydrins,
.. .
, then hydrolysis, as is known in the art. For
e~ample, Org. Syn. Coll. Vol. IV, S8 (1968) teaches
the preparation of atrolactic acid from
, acetophenone. Esters can be prepared from the
~, 2-hydro~ycarbo~ylic acids by methods known in the
3 art. The "Dictionary of Organic Compounds~, Vol. 3,
4th ed. (1965), page 1791 (O~ford Univ. Press) lists
atrolactic acid and esters.
'
DESCRIPTIO~ OF THE PROCESS
The process comprises four sequential reactions:
~, (1) reaction of a 2 hydroxycarbo~ylic acid
~, 20 ester with a base;
(2) reaction of the product of reaction (1)
~- with carbon disulfide;
(3) reaction of the product of reaction (2)
with an acylating agent; and
2S (9) reaction of the product of reaction (3)
with a substituted hydrazine.
, This sequence of reactions can be conveniently con-
, ducted in a single reaction vessel without isolation
of chemical intermediates.
The process is represented in Scheme 1 for the
specific case of preparation of compound iii, and in
Scheme 2 for the general case:
.'
--` 2015098
R~ tlon 9t-p~
Ph OH 1. e- 8uOK Ph ~
¦1 10 9ch~ X 3 EtOCOCl Ml~>~ ~NHPh ~ ~
4. PhNMNH~ ~ :
111 ~ ~;
~
:
~:
9che~e 2: X 2 C9 R1 O ~
.~a CO2Z 4. H2NNR3R~ R ~ N~ R
i II (I)
wherein:
Z is alkyl (Cl-cl2); alkenyl (C3-C4);
. cycloalkyl (C3-cl2); cycloalkylalkyl
`~ 30 (C6-c7); alko~yalkyl (C2-C4); benzyl;
l is H; alkyl (Cl-C6); haloalkyl (Cl-c6~
cycloalkyl (C3-c6); alkenyl (C2-C6); alkynyl
(C2-c6); alko~yalkyl (C2-C6); alkyl (Cl-c3)
, substituted with cycloalkyl (C3-c6); phenyl
. 35 or benzyl substituted on the ring with R6;
O
~01~98
'~
R2 is phenyl substituted with R5 and R6;
naphthyl substituted with 1-2 groups
7 5 selected from R6; thienyl substituted with .
~ R5 and R6; furyl substituted with R6;
pyridyl substituted with R6, phenoxy or
phenylthio; alkyl (Cl-C6); alkyl (Cl-C2)
substituted with R6-substituted phenoxy or
1 10 with R6-substituted phenylthio;
! Rl and R2 can be taken together, along with the
carbon atom to which they are attached, to
form a carbocyclic or heterocyclic ring
(containing O, N-R7, or S) of 5-7 ring
7 15 atoms. The heterocylic ring can be fused
7 with an R5-substituted benzene ring or an
R6-substituted thiophene ring, the
heteroatom not being attached to the spiro
center; the carbocyclic ring can be fused
with 1-2 R5-substituted benzene rings or
with an R6-substituted thiophene ring.
~ R3 is phenyl substituted with R5 and R6; benzyl
:~ substituted on the benzylic carbon with R7 :~
] and or the phenyl ring with R6; naphthyl
.l 25 substituted with R6; thienyl substituted
with R6; furyl substituted with R6; pyridyl
substituted with R6; pyrazyl substituted
, with R6; pyridazyl substituted with R6;
pyrimidyl substituted with R6; alkyl
(C2-C10); cycloalkyl (C5-C7);
~ R4 is ~; formyl; alkylcarbonyl (C2-C4);
, haloalkylcarbonyl (C2-C4); alkoxyalkyl-
' carbonyl (C2-C4); alkoxycarbonyl (C2-C4);
`~ alkylaminocarbonyl (C2-C5); alkylsulfonyl
7 35 (Cl-C4); alkyl (Cl-C6); alkenyl (C3-C4);
. ~.,::
.. .
.; :
.~
- .
`: ::
r ~ : 7~
-" 201~098
`
: 5
: ~ .
alkynyl (C3-C4); cycloalkyl (C4-C6); benzyl
3 substituted or phenyl with R6 or on the
benzylic carbon with R7; phenylaminocarbonyl ~:
wherein the phenyl is substituted with R6; ~ :
R3 and R4 can be taken together, along with the --
~ nitrogen atom to which they are attached, to ~-
i form a pyrrolidino, piperidino or
hexamethyleneimino ring, which rings can be
fused to an R6-substituted benzene ring;
R5 is H; halogen; alkyl (Cl-C6); haloalkyl
' (Cl-C4); alkoxy (Cl-C6); alkenyloxy (C3-C4);
alkylthio (Cl-C5); haloalkylthio (Cl-C4);
haloalkoxy (C1-C4); alkylsulfonyl (Cl-C4);
haloalkylsulfonyl (Cl-C4); nitro; phenyl
' substituted with R6; pheno~y substituted
with R6; phenylthio substituted with R6;
~:` cyano; alkynyloxy (C3-C4); alkoxyalkyl
(C2-C6); alkoxyalkyloxy (C2-C6);
I phenoxymethyl with phenyl substituted by R6;
:~, benzyloxy with phenyl substituted by R6;
.~ phenethyloxy with phenyl substituted by R6;
; benzyl with phenyl substituted by R6;
' 25 phenethyl with phenyl substituted by R6;
;' carboalkoxy (C2-C6); cycloalkyl (C5-C6);
.. i R6 is H; halogen (1-2); methyl; trifluoro-
methyl; alko~y (Cl-C4); methylthio; nitro;
R7 is H; or alkyl (Cl-C4).
Preferred for reasons of ease of synthesis, lower
e~pense or greater utility are compounds of structure
(I), wherein: :~
Z is Cl-C4 alkyl;
Rl is methyl;
; 35 R2 is phenyl substituted with R5 and R6;
. R3 is phenyl substituted with R6; and
R4 is hydrogen.
, ~
.:
201~098
In each of the reaction steps of Scheme 2 it
will be understood by those skilled in the art that
the optimum combination of reaction time, reaction
temperature, stoichiometry, solvent(s), and the like
will depend on the exact product being prepared, as
well as on the relative importance of these factors
and the results to the individual operator. For
example:
The reaction time should be sufficient to
effect the desired reaction; the reaction
temperature should be sufficient to effect the
desired reaction in the desired time without
undue decomposition or side reactions; the
stoichiometry of reactants should generally be
the theoretical values, in the interest of
economy, with variations as needed to
compensate for evaporative or other losses; and
solvent(s) can be selected, e.g., so that
reaction ingredients have a substantial
solubility, in the interest of obtaining
relatively fast reaction rates.
In Reaction Step 1 - Usable bases are those
capable of deprotonation of the hydroxy group without
unacceptable side reactions. Included are the alkali
metal tertiary alkoxides, hydrides, and hydroxides.
Preferred among these in the interest of higher
solubility, reactivity, ease or safety of use, higher
yields, or economy are the potassium tertiary
alkoxides such as potassium tert.-butoxide and
potassium tert.-amylate. Especially preferred is
potassium tert.-butoxide.
.. . .
:
,
. . .
~.. , ,- . ' :
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Usable solvents are the 2-hydroxycarbo~ylic
acid ester itself and generally the non-hydroxylic
solvents, including ethers (e.g. diethyl ether,
tetrahydrofuran, dio~ane, 1,2-dimetho~yethane),
esters (e.g. methyl and ethyl acetate), amides (e.g.
N N-dimethylformamide, N,N-dimethylacetamide,
l-methyl-2-pyrrolidone), nitriles (e.g.
acetonitrile), and the like, and mi~tures containing
one or more of these solvents. Preferred among these
solvents are those in which the reactants have
substantial solubility.
The temperature can vary from about -80C to
about ~100C, with about -20C to +80C preferred,
and with about -5C to +50C more preferred. Ambient
temperature is a convenient temperature at which to
conduct the reaction.
The needed reaction time is short with soluble
reactants. No more than a few minutes are required
i at ice to ambient temperatures, e.g. 0.5 to 15
minutes.
Preferred groups Z are Cl-C4 alkyl.
In Reaction Step 2, carbon disulfide (CS2) is
, 25 contacted with the product of Step 1 at about -20C
to l100C, preferably -10C to ~50C, for about 5
seconds to about 24 hrs., preferably for about 5 to
` 30 min. The reaction is rapid for soluble
reactants. Ambient temperature is a convenient
temperature at which to conduct the reaction.
In Reaction Step 3 an acylating agent capable
of forming a mixed-anhydride with the product of
Reaction Step 2 is contacted with the product of
Reaction Step 2. Such acylating agents include
chloroformates, e.g. methyl chloroformate, ethyl
chloroformate, propyl chloroformate, butyl
i~
,..... : . ~ . :
.,,~.. . .
^`` 2015098
chloroformate, and benzyl chloroformate, and other
acylating agents. Preferred acylating agents are
methyl and ethyl chloroformate. The reaction is
rapid, and is complete in about 5 seconds to an hour
with soluble reactants. Most reactions are complete
in about 1 to 30 minutes. The temperature can range
from about -20C to +50C. The preferred range is
from about -10C to +25C. Ice to ambient
temperatures is a convenient temperature range for
conducting this reaction.
In Reaction Step 4 the substituted hydrazine
reactant is contacted with the product of Reaction
Step 3. The substituted hydrazine can be used as the
free base or as a mixture of its acid salt with a
free-basing agent such as a tertiary amine base ~e.g.
triethylamine, N,N-diisopropyl-N-ethylamine). The
reaction is rapid, re~uiring no more than a few
minutes for completion with soluble reactants.
Reaction times may be 10 seconds to about 1 day,
preferably about 1 minute to 8 hrs. Reaction
temperatures can range from about -20C to ~100C.
Ice to ambient temperatures is a convenient range at
which to conduct the reaction.
The product of Step 4 can be isolated by
evaporation of the reaction solvent, and it can be
purified if desired by washing in a water-immiscible
solvent (e.g. carbon tetrachloride, butyl chloride,
ether) with water, mineral acid, and base, followed
~ by drying and evaporation of solvent, in turn
`` follcwed by crystallization or chromatography as
desired.
. :
:
,.~
-" 201~098
The compounds that can be made by the process
of this invention are described in the E~amples and
Tables which follow, and are intended to be only
exemplary.
EXAMPLE 1
Preparation of S-Methyl-5-phenyl-3-
(phenylamino)-2-thio~o-oxazolidin-4-one
[Compound iii]
A solution of methyl atrolactate (7.64 g,
0.0424 mole) in tetrahydrofuran (80 ml) was stirred
and cooled in an ice bath, and potassium
tert.-buto~ide (4.76 9, 0.0424 mole) was added. The
ice bath was removed, and the mixture was stirred for
10 minutes. This procedure provided a clear, yellow
solution at 21C.
Carbon disulfide (2.8 ml, 0.046 mole) was
added, and caused the formation of an orange color
and a temperature rise to 32C. The solution was
cooled in an ice bath for 10 minutes, causing the
temperature to fall to 4C.
I Ethyl chloroformate (4.1 ml, 0.043 mole) was
¦ 25 added to the ice-cooled solution, inducing the
formation of a turbid yellow mi~ture and a
temperature rise to 12C. The mi~ture was stirred
with ice-bath cooling for 5 minutes as the
temperature fell to 5C.
Phenylhydrazine (97%, 4.5 ml, 0.044 mole) was
added. The temperature rose to 24C while the
~i cooling bath was applied. ~fter the temperature fell
~ to 20C, the mi~ture was stirred for 10 minutes, then
i evaporated under reduced pressure to an oil.
, 35
.,
'' ~
~ ~s ~
--` 2015098
The oil was mixed with l-chlorobutane and
water, and the layers were separated. The organic
layer was washed with lN HCl, water, and saturated
aq. sodium bicarbonate solution. The organic
' solution was dried (magnesium sulfate), filtered, and
' evaporated under reduced pressure to an oil. The oil
t was crystallized from carbon tetrachloride/hexane
(~40 ml/20 ml), providing the product (7.40 g, 58.5%
of theory) as a light-yellow solid, m.p. 104-105C.
The product was further purified by recrystallization
! from carbon tetrachloride/hexane with 93% recovery.
In another preparation of the same product,
, 15 carbon tetrachloride was used instead of
; l-chlorobutane during the workup. Crystallization
from the carbon tetrachloride solution by dilution
; with hexane p~ovided the product in 54% yield.
Recrystallization from isopropanol/water provided the
product as a white solid, m.p. 108-109C, with 92%
recovery.
EXAMPLE 2
, Preparation of
-; 25 3'-(Phenylamino)-2'-thioxo-spiro(9H-
~ fluorene-9,5'-oxazolidin)-4'-one
.~
;, :
` 30
;~N--NHPh
`'; ~''' ~
~ '
'~ :
201~098
A solution of 9-hydroxy-9-fluorenecarboxylic
acid, methyl ester (8.91 g, 0.0371 mole) in
tetrahydrofuran (89 ml~ was treated with potassium
tert.-buto~ide (4.16 9, 0.0371 mole). After 6
minutes the solution was cooled in an ice bath and
carbon disulfide (2.3 ml, 0.038 mole) was added.
After 7 minutes ethyl chloroformate (3.6 ml, 0.038
mole) was added to the cold solution. After 7
minutes 97% phenylhydrazine (3.9 ml, 0.038 mole) was
added. After 3 minutes, the mixture was evaporated
under reduced pressure to a yellow syrup. The syrup
was treated with l-chlorobutane and water, and the
organic layer was washed with saturated sodium
bicarbonate solution, water, lN HCl, and water. The
dried (magnesium sulfate) solution was filtered and
evaporated under reduced pressure to an oil. The oil
was crystallized from carbon tetrachloride/hexane,
and the solid product further purified by boiling
with isopropanol (without dissolution of all solid),
cooling, and filtering. The product was obtained as
3.56 9 (27% of theoretical) of analytically-pure
white solid, m.p. 187-189C.
Anal. Calcd. for C21H14N2O2S: C, 70.3 ;
3.99; N, 7.82%. Anal. Found: C, 70.28; H, 4.19; N,
7.68%. The infrared spectrum (Nujol*mull) showed
absorption at 3275 cm~l (N-H) and 1770 cm~l (imide
0 C,O).
'
E~AMPLE 3
Preparation of
5-Phenyl-3-(phenylamino)-2-thioxo-o~azolidin-4-one
~.
* trade mark ~ ~
:.
.~, ~.
~,z-.. , . ~
,~. , . - . .: - -
201~098
.
s ,,,
1 0 ~N~NHPh
A stirred solution of potassium tert.-butoxide
(11.22 9, 0.1 mole) in tetrahydrofuran (100 ml), held
at 0C to -5C, was treated portionwise with a
solution of methyl mandelate (16.62 9, 0.1 mole) in
tetrahydrofuran (70 ml~, providing an orange-red
solution. After ~ minutes carbon disulfide (6.04 ml, -~ -
0.1 mole) was added. After 5 minutes at 0C to -5C,
the orange solution was cooled to -30C and treated
with ethyl chloroformate ~9.S ml, 0.1 mole). After 2
minutes the solution was warmed to -10C. After 5
minutes at -10C, the solution was cooled to -30C
and treated with 97% phenylhydrazine (10.1 ml,
0.1 mole). The yellow solution was warmed to 25C,
and after 10 minutes the mixture was evaporated under
reduced pressure to a turbid oil. The oil was mixed
with water and l-chlorobutane, the layers were
separated, and the organic solution was washed with
lN HCl, water (twice), and saturated sodium
bicarbonate solution. The dried (magnesium sulfate)
solution was evaporated under reduced pressure to a
yellow-orange oil, and the oil was dissolved in -
chloroform. A silica-gel filtration of the
- ,~
:
2015098
chloroform solution followed by evaporation of the
filtrate under reduced pressure provided a green oil
which began to solidify. Further purification was
accomplished by crystalliæation from l-chlorobutane.
This procedure provided the product as 9.9 g (35% of
theoretical) of a white solid, m.p. 140-141C. The
infrared spectrum (Nujol mull) showed the
characteristic absorption at 3295 cm~l (N-H) and 1760
cm~l (imide C~O).
Other compounds that can be prepared according
to the present invention, from the appropriate
2-hydroxycarboxylic acid ester, base, carbon
disulfide, acylating agent, and substituted hydrazine
are illustrated in the Tables which follow. The
Tables are not intended to be all-inclusive.
.
:~0
,.
j ~ ~.
201~98
,
14
R~ o J~
>~ N ( I )
\R4
TA8LE 1
Rl ~ ~
Ethyl Phenyl ~ Phenyl H
¦ 20 ~-He~yl Phenyl Phenyl H
¦ Cyclopropyl Phenyl Phenyl H
, Cyclohe~yl Phenyl Phenyl H
¦ Vinyl Phenyl Phenyl H
i Allyl Phenyl Phenyl H
25 Propargyl Phenyl Phenyl H
Methoxymethyl Phenyl Phenyl H
I Ethosyethyl Phenyl Phenyl H
! Cyclopropylmethyl Phenyl Phenyl H
Cyclohexylmethyl Phenyl Phenyl H
. 30 ~enzyl Phenyl Phenyl H
j Methyl 4-Fluorophenyl Phenyl H
Methyl 2,4-Difluorophenyl Phenyl H
Methyl 4-Metho~yphenyl Phenyl H
Methyl 4-(Trifluoromethyl)phenyl Phenyl H
Methyl 4-(n-Buto~y)phenyl Phenyl H
.
;`
:~
.
2015098
Rl ~ ~ R4
5 Methyl 4-Methylthiophenyl Phenyl H
Methyl 4-Nitrophenyl Phenyl H
Methyl 2-Methylphenyl Phenyl H
Methyl 3-Methylphenyl Phenyl H
Methyl 4-Methylphenyl Phenyl H
10 Methyl 4-Pentyloxyphenyl Phenyl H
jMethyl 4-Hexyloxyphenyl Phenyl H
Methyl 4-Allyloxyphenyl Phenyl H
'Methyl 4-Butylthiophenyl Phenyl H
Methyl 4-(Trifluoromethylthio)phenyl Phenyl H
'.15 Methyl 9-(Difluoromethoxy)phenyl Phenyl H
Methyl 4-(Trifluoromethoxy)phenyl Phenyl H
~,Methyl 4-Methylsulfonylphenyl Phenyl H
`, Methyl 4-(Trifluoromethylsulfonyl)phenyl Pheny~ H
! Methyl 4-Phenylphenyl Phenyl H
20 Methyl 4-(4-Chlorophenyl)phenyl Phenyl H
Methyl 4-(4-Methoxyphenyl)phenyl Phenyl H
~Methyl 3-(4-Chlorophenoxy)phenyl Phenyl H
~Methyl 4-(4-Phenylthio)phenyl Phenyl H
'Methyl 4-(4-Chlorophenylthio)phenyl Phenyl H
25 Methyl 4-Cyanophenyl Phenyl H
Methyl 4-Propargyloxyphenyl Phenyl H
Methyl 4-(Methoxymethyl)phenyl Phenyl H
Methyl 4-(2-Methoxyethyl)phenyl Phenyl H
Methyl 4-(2-Ethoxyethyl)phenyl Phenyl H
30 Methyl 4-(Methoxymetho~y)phenyl Phenyl H
Methyl 4-(2-Methoxyethoxy)phenyl Phenyl H
Methyl 4-(Pheno~ymethyl)phenyl Phenyl H
Methyl 4-(Benzyloxy)phenyl Phenyl H
Methyl 3-Pheno~yphenyl Phenyl H
~'35 Methyl 2-Pheno~yphenyl Phenyl H
Methyl 4-(2-Phenethyloxy)phenyl Phenyl H
.~
,,I,j~,'. ~ ,, . : ' ' '
5~
2~15098
16
Bl Bl/B~ B~ ~3
5 Methyl 4-Benzylphenyl Phenyl H
Methyl 4-(2-Phenylethyl)phenyl Phenyl H
Methyl 4-Carbometho~yphenyl Phenyl H
Methyl 2-Naphthyl Phenyl H
Methyl 2-Thienyl Phenyl H
10 Methyl 3-Thienyl Phenyl H
Methyl 2-Furyl Phenyl H
Methyl 3-Furyl Phenyl H
Methyl 2-Pyridyl Phenyl H
Methyl 3-Pyridyl Phenyl H
lS Methyl 4-Pyridyl Phenyl H
Methyl 3-Methyl-2-thienyl Phenyl H
Methyl 5-Methyl-2-furyl Phenyl H
Pentamethylene Phenyl H
Tetramethylene Phenyl H
CH2CH2N(CH3)cH2cH2 Phenyl H
CH2CHzOCH2CH2 Phenyl H
CH2CH2ScH2cH2 Phenyl H
~ H2CH2CH2 Phenyl H
~H2CH2CH2cH2 Phenyl H
~ .
S CH2CH2CH2cH2 Phenyl H
35 4-Fluorophenyl 4-Fluorophenyl Phenyl H
2015098
pl ~ ~ R3~4
Methyl Phenyl 4-Fluorophenyl H
Methyl Phenyl 2-Fluorophenyl H
Methyl Phenyl 3-Fluorophenyl H
Methyl Phenyl 4-Pentyloxy H
Methyl Phenyl 2,6-Dimethylphenyl H
Methyl Phenyl Phenyl Methyl
Methyl Phenyl Phenyl Formyl
Methyl Phenyl Phenyl Acetyl
Methyl Phenyl Phenyl Allyl
Methyl Phenyl Phenyl Methoxyacetyl
Methyl Phenyl (CH2)5
Methyl 4-Chlorophenyl Phenyl H
Methyl Phenyl 3-Chlorophenyl H
H Cyclohexyl Phenyl H
Methyl 4-Cyclohexylphenyl Phenyl H
Methyl Pheno~ymethyl Phenyl H
Methyl Phenylthiomethyl Phenyl H
~` 201~098
18
X I I
C02Z :'
TABLE 2
Bl ~ z
Phenyl Methyl Ethyl
20 Phenyl Methyl Propyl : :
Phenyl Methyl Butyl
Phenyl Methyl Pentyl
Phenyl Methyl Dodecyl
Phenyl Methyl Allyl
25 Phenyl Methyl 2-Methyl-2-propen-1-yl
Phenyl Methyl Cyclopropyl
Phenyl Methyl Cyclohexyl
Phenyl Methyl Cyclododecyl
Phenyl Methyl Cyclopentylmethyl
30 Phenyl Methyl Cyclohe~ylmethyl
Phenyl Methyl Metho~ymethyl
~ Phenyl Methyl Etho~yethyl
il Phenyl Methyl ~enzyl
'~ Methyl 9-Phenoxyphenyl Methyl
~,35 Methyl 3-Fluorophenyl Methyl
Methyl 3-Thienyl Methyl
~, :
