Note: Descriptions are shown in the official language in which they were submitted.
The invention relates-to a process for the production of
thiotetronic acid.
It has been reported that thiotetronic acid m~y posess utility
as an intermedlate product Eor the production of l~) thiolact~cin,
whLch is an c~ntibiotic having a broad effective spectnm. T rahedron
Letters, Vol. 25, No. 46, pp 5243-to 5246, (1984). From senary~ Chem.
Berichte 46, 2103, (1913)j it is known to produce thiotetronic
acid star-ting from acetyl thioglycoyl chloride through reac-
tion thereof wlth sodium malonlc ester and subsequent ring
closure and water treatment. D.B. Macierewicz, Rocz. Chem.
47, 1735, (1973), reproduced the reaction of E. Benary and
ob-tained thiotetronic acid in a yield of 30.3 percent, based
on the ace-tyl-thioglycoyl chloride used. Another possibility
~ for synthesis is set out in J.Z.: Mortensen et al., Tetrahedron
.~ 15 Letters) 27, 3839 (1971~. Starting from 2,4-dibromothiophene,
the thiotetronic acid i5 obtained in a yield of 46.2 percent
by way of three s-teps as a result of reaction with bu-tyl
.~ lithium and t-butylperbenzoate.
~; However, in the case of all of the above-identified
~ 20 traditional syntheses, the yields are much too low for a
technical or commercial process. Moreover, the processes
are characterized by cumbersomeness, expensive educts and
~ by reagents that are difficult to handle.
: An object of the invention is to provide a process
for the production of thiotetronic acid which is distinguished
by high yields and high purity of thiotetronic acid, favorable
educts and simple procedural steps.
~ccordingly, the invention provides a process
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for preparing thiote-tronic acid/ in which 4-chloro-4-chloro-
methyloxetan-2-one is reacted with hydrogen sulfidè in the
presence of an amine to form thiotetronic acid directly,
or, alternatively, -the reaction solution is reacted prior
to isola-tion of the thiotetronic acid with ke-tene, the result-
ant diacetoxythiophene i5 separated and the diacetoxythiophene
is flnally converted into thiotetronic acid using mineral
acid.
Another aspect of the invention comprises the
novel in-termediate product diacetoxythiophene, having the
formuIa: CH3-C~
~ O-~-CH
S
-
;~ 15 The 4-chloro-4-chloromethyloxe-tan-2-one starting
material can be produced in a simple manner according to
published European Patent Application 60~808 and after flash
distillation can be used for the conversion according to
the invention.
The hydrogen sulfide is conveniently used in gaseous
.
form.
; As suitable amines, advantageously primary, secondary
or tertiary amines, ammonia and also guanidine can be used.
Tertiary amines, such as triethylamine, are particularly
advantageous.
The reaction is conveniently carried out in a
solvent or solvents. As compared to the reactive educt,
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-- 3
inert solvents such as halogenated hydrocarbons, ether or
carboxylic acid esters are used. For example, methylene
chloride, chloroform, ethereal solvents, such ac, tetra-
hydrofuran, and also acetic acid ester can be used. ParticuS larly preferred, ~lowever, as the solvent is tetrahydrofuran.
The educts are used effectively in a mole ratio
of 4-chloro-4-chloromethyloxetan-2-one -to hydrogen sulfide
to amine of from 1~ 2 to 1:4:3, and preferably between
2.5:2 and 1-3.5:2.5.
Preferably the reaction lS operated at a temperature
of from 0 to -~0C., m~re preferably between -10 and -25C.
Effectively, the method proceeds in such a way
that the educt solution is saturated with the hydrogen
sulfide and the amine is added subsequently over a period
of 30 to 120 minutes.
After complete addition of the amine, the processing
of the -thiotetronic acid can take place by filtering off
the precipitated salt and ~ubsequently concentrating the
solu-tion. For the separation of small quan-tities of dimeric
anhydrothiotetronic acid, the residue can be absorbed in
ethereal solvents, such as diethyl ether, tetrahydrofuran
(THF) or dioxane, preferably in diethyl ether, and can be
filtered by way of an absorption agent, such as silica gel.
After renewed concentration by evaporation of the solvent,
the thiotetronic acid is ob-tained in crys-talline form and
in good yield.
After recrystallization in an aromatic hydrocarbon,
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preferably in toluene, the thiotetronic acid is subjected
-to additional purification.
In order to obtain a -thio-te-tronic acid of good
quality, -the method can proceed in such a way that, af-ter
the addi-tion of the amine, wi-thout isolation of the crude
thiotetronic acid, the lat-ter is -treat~d in solution with
ketene at a temperature of -lO to +5C., advantageously
0C. Based on one mole of 4-chloro-4-chloromethyloxe-tan-
2-one used, ketene is effectively used in a quantity of
2 to 4 moles, preferably 2.5 to 3.5 moles.
; In the course of the process according to the
invention, the novel intermediate compound 2,4-diacetoxy-
thiophene having the formula: RO
~ O~
', O
wherein each R is CH3C-, results. The 2,4-diacetoxythiophene
can also be purified by distil1ation in a simple manner.
By treatlng the 2,4-diacetoxythiophene with a
non-oxidizing inorganic mineral acidr pure thiotetronic
acid is obtained. Hydrochloric acid or sulfuric acid,
preferably hydrochloric acid, can be used in aqueous solu-tion
in a concentration of lO to 30 percent. The conversion
temperature is generally between 0 ana 30C., preferably
; 25 15 to 25C. The reaction time can be 2 to 5 hours.
After concentration, preferably using high vacuum,
this procedure provides practically colorless thiotetronio
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acid in high yield with a purity greater than 96 percent.
As used herein, all par-ts, percen-tages, ratios
and proportlons are on a weiyht basis unless otherwise s-tated
hereLn or o-therwise obvious herefrom to one skilled in the
art.
The following Examples illustxate the invention.
EXhMPLE i
15~5 g (0.091 mole) of 4-chloro-4-chloromethyloxe-
tan-2-one was co~l~ed to -20C~ in 300 ml of tetrahydrofurane
and was satu~a-ted with gaseous hydrogen sulfide. Subsequently,
a solution of 20~2 g (0.2 mole) of triethylamine in 100
ml of tetrahydrofuran was added dropwise at -15C. ov~
a period of one hour~ The temperature of the reaction solu-
tion was allowed to rise to ambien-t temperature, the solution
; 15 was filtered off from the salt obtained and the solvent
-~ was evaporated on a rotation evaporator. The residue was
flltered thr~ugh a column filled with silica gel, using
300 ml of ether as eluent~ 9~0 g of a yellow colored crystal-
line product having a melting point of I15 to 117C~ was
obtained. The content (HPLC) amounted to 89.3 percent.
This corresponds to 8.0 g of lOO percent product = 75~7
percent yield. 7~5 g of the crude thiotetxonic acid was
recrystallized hot from 350 ml of toluene. 6.6. g of pale
rose-colored microcrystalline product having a melting point
of 120C and a content ~HPLC) of 96 percen-t was ob-tained.
This corresponded to 6.3 g of 100 percent produc-t - 94 percent
yield or 71~2 percent based on the oxe-tanone used~
. ~
~64~
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EXAMPLE 2
Thio-te-tronic acid was produced as described in
Example 1. However, the thiotetronic acid was no-t i.solated
but -the -te-trahydrofuran (THF) solution was concentrated
to 50 ml and over a period of one hour 0.3 mole of ketene
was fed in-to this solu-tion ak O~C. Subsequently,~-the
temperature of the reac-tion so.lution was allowed.to rise
to ambient temperature and the solvent was distilled.off
using a ro-tation evaporator. The residue was subjected
to high vacuum distilla-tion. 13.7 g of 2,4-diacetoxythiophene
was obtained, content 95.6 percent, b.p.o 25 105C., which
corresponded -to 13.1 g of lOO:percent produc-t ~yield 65.2
" percent)~
Spectroscopic data:
H-NMR~300 MHz, CDCL3): ~2.24(s,3H), 2.30(s,3H?, 6.57~d,J=
~ 15 2.5Hz,lH?, 6.61 (d,lH)
- ` MS(70eV) m/2=200(M ,3), 158(M -CH2=C=O,10~ 116 ~M -2
. ~
.. . .
: ~ CH2=C=O,35) 43 (100)
1.81 g of the 2,4-diacetoxythiophene was reacted
with 3~5 g of 20 percent hydrochloric acia and the mixture
~ 20 was stirred at am~ient temperature ~or 3 hours. After 1
: hour, a clear solu~ion developed from the initial emulsion.
- ThiS colored solution~was evaporated under high vacuum.
~ l.O.g of practically colorless crystalline product was
:,
~ obtained hav.tng a melting point of 119 to 121C.. :(HPLC
:~ 25 con-tent: 96.1 percent). This corresponded to 0.96 g of
100.percent -thiotetronlc acid = 96 percent yield.
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By way of summaryl the invention involves a process
for the produc-tion of thiotetronic acid by the reaction
4-chloro-4-chloromethyloxe-tan-2-one and hydrogen sulfide
in the presence of an amine.
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