PROCEDE DE PRODUCTION DE THIOSEMICARBAZIDES

PROCESS FOR PRODUCING THIOSEMICARBAZIDES

Abrégé français

L'invention concerne un procédé de production d'un thiosemicarbazide, consistant à faire réagir une alkylamine avec du sulfure de carbone en présence d'une base, choisie entre la N,N-diisopropyléthylamine et la N,N,-diisopropylméthylamine, pour obtenir un produit intermédiaire, puis à convertir ce produit intermédiaire en thiosemicarbazide. Ce procédé peut être mis en oeuvre en particulier pour produire du 4-méthyl-3-thiosemicarbazide, un produit intermédiaire utile dans la production de l'herbicide à large spectre tebuthiuron.

Abrégé anglais

A process is provided for producing a thiosemicarbazide which includes the
steps of reacting an alkylamine with carbon disulphide in the presence of a
base selected from N,N-diisopropylethylamine and N,N,-diisopropyl-methylamine
to produce an intermediate and converting the intermediate into the
thiosemicarbazide. The process has particular application to producing 4-
methyl-3-thiosemicarbazide, an intermediate useful in producing the broad-
spectrum herbicide tebuthiuron.

Revendications

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CLAIMS
1. A process for producing a thiosemicarbazide includes the steps of reading
an alkylamine with carbon disulphide in the presence of a base selected from
N,N-diisopropylethylamine and N,N,-diisopropyl-methylamine to produce an
intermediate and converting the intermediate into the thiosemicarbazide.
2. A process according to claim 1 wherein the thiosemicarbazide has the
formula:
R1NH-CS-NH-NH2, wherein R1 is alkyl
3. A process according to claim 1 wherein the thiosemicarbazide is 4-methyl-3-
thiosemicarbazide.
4. A process according to any one of the preceding claims wherein the reaction
of the alkylamine with carbon disulphide takes place in the presence of an
excess of the base.
5. A compound selected from N,N-diisopropylethylammonium N-alkyl
dithiocarbamate and N,N-diisopropylmethylammonium N-alkyl dithio-
carbamate.
6. The use of a compound according to claim 6 in producing a
thiosemicarbazide.
7. The use of a compound according to claim 5 in producing 1-(5-tert-butyl-
1,3,4-thiadiazol-2-yl)-1,3 dimethylurea.

Description

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05-05-2003 CA 02446918 2003-10-O1 IB020102~
. . 14:52 F.9~ 011 884 4660 SPOOR & FISHER C~,.,.,
.,
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BACt~GROUND OF ThiE INVENTION
This invention relates to a process for producing ithiosemicarbazides.
4-Methyl-3-thiosemicarbazide (MTSC) is an inten~ediate in the synthesis of 5-t-
butyl-
Z-methylamino-1,3,4-thiadiazole ~(BTDA), the precursor of tebuthiuron, a broad-
spectrum herbicide. Tebuthiuron has the chemical name 1-(5-tent butyl-1,3,4-
thiadiazol-2-yl)-1,3 dimethylurea.
Several syntheses of thiosemicarbazides, substituted in the 4-position, are
described
in literature and may be broadly grouped asfollvuvs:
the reacfion of alkyl isothiocyanates with hydrazine,
~ the reaction of hydrazine with reactive: thivcarbamic acid derivatives (acid
chlorides, thiuram monosutfides, etc.), and
~ the hydrazinolysis of N-monoalkyl- and N.N-dialkytdithio-carbamates.
The current production process for MTSG entails. the hydrazinvlysis of
ammonium N-
methyl-dithiocarbamate, Methyl isothiocyanate (MITC) is believed to be formed
in
situ from ammonium N-methyldithiocatbamate when heated in the presence of
bases. It reacts with hydrazine monohydrate to give MTSC. This process affords
MTSC of 93-94°!o purity. The purify of MTSG is a critical factor in the
manufacturing
of BTDA of high purity (98*°!°) and yield. The MTSC produced by
this process is of ,
insuffcient~ quality to produce high quality BTDA. This process also generates
efFluents containing high concentrations of ammonium salts. The large volume
of ,
effluent produced during this process is a major problem (approximately four
tuns of
effluent are produced far every ton of MTSC produced on plant scale).
EP339964 discloses a process for producing MTSC by reacting methylamine with
carbon disulphide in the presence of a base which is triethylamine. Although
goad
yields of MTSC are obtained (F~cample 1:$O,O~o, Example 3:81,4°!0,
F~cample
4:86,1°!0), it would be a advantageous to use a method for producing
MTSC which
provides a higher purity product, a better recovery of tfie base, and less
effluents.
Empf .~eit:05/fl AMENDED SHEET

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SUMMARY OF THE INVENTION
According to a first aspect of the invention, a process for producing a
thiosemicarbazide includes the steps of reacting an alkylamine with carbon
disulphide in the presence of a base selected from N,N-diisopropylethylamine
(DIPEA) and N,N,-diisopropylmethylamine (DIPMA) to produce an intermediate
and converting the intermediate into the thiosemicarbazide. It is preferred
that
the reaction of the alkylamine with the carbon disulphide takes place in the
presence of an excess of the base.
The intermediate is an N,N-diisopropyl-ethylammonium dithiocarbamate or a
N,N-diisopropyl-methylammonium dithiocarbamate. Both intermediates are
believed to be new and form another aspect of the invention. The structure of
N,N-diisopropylethyl ammonium N-alkyl dithiocarbamate is:
/~\~ of
alkyl NH S N H
The invention further provides a method of producing an N,N-diisopropyl-
ethylammonium dithiocarbamate or an N,N-diisopropyl-methylammonium
dithiocarbamate by reacting an alkylamine with carbon disulphide in the
presence of DIPEA or DIPMA.

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DESCRIPTION OF EMBODIMENTS
The alkylamine which is used in the process of the invention has the formula
alkyl-NH2, i.e. a primary alkylamine. The preferred alkyl is methyl.
The thiosemicarbazide which is produced by the process of the invention may
have the formula:
R~NH-CS-NH-NHZ
wherein R, is alkyl.
The invention has particular application to producing MTSC and an
intermediate therefor, N,N-diisopropyl-ethylammonium dithiocarbamate,
following steps 1 and 2 set out hereinafter:
Step 1
\ p
CHI NHZ + CSZ + N ~ CH, NH S N H
(A)
Step 2
s
a ~
/C\6 ~~ ~C\ _ + N + H,S
CHI NH S ~ N H + HZNNHZ.HiO --~ CHI NH HN NHz

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In the above process, it is preferred that an excess of DIPEA is used. This
forces the reaction of step 1 to the right and increases the stability of the
intermediate (A). Typically, an excess of 10% to 30% DIPEA is used.
The reaction of step 1 is highly exothermic and cooling is generally necessary
to maintain the temperature of the reaction medium below 30°C.
Using DIPEA as a base in producing MTSC, reduces substantially the amount
of effluent which is produced. Further, the intermediate (A) has been shown to
have significant stability resulting in a decrease in the formation of by-
products
such as thiocarbohydrazide and dimethylthiourea. Further, MTSC in yields of
70 to 76% and purities of 97,5 to 98,5% are attainable.
Examples of the invention will now be described.
EXAMPLE 1 (10% excess of DIPEA)
Methylamine (77,58; 40% solution) and DIPEA (142,2g) were charged to a 1
litre reactor equipped with a reflux condenser and a stirrer. CS2 (76g) was
added dropwise with stirring during 30 minutes. The reaction temperature was
maintained below 30°C by external cooling during the addition of CS2.
The
mixture was stirred for an additional 3 hours after which distillate (60g)
from a
previous batch was added. The reaction mixture was diluted with water to
obtain a DTC (dithiocarbamate) concentration of 24%.
Hydrazine hydrate (60,1 g) was added to the DIPEA-DTC mixture. The
reaction mixture was heated to 89°C and maintained at 89 to 92°C
under reflux
conditions for 2 hours and 20 minutes. The DIPEA was distilled off
(distillation
is complete when the temperature rises above 95°C), the reaction
mixture
cooled to 15°C while stirring, and the MTSC crystals separated from the

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supernatant layer, providing a 73,8% isolated yield of MTSC. The purity of
MTSC was 98.0%.
EXAMPLE 2 (30% excess of DIPEA)
Methylamine (38.7g; 40% solution) and DIPEA (82.4g) were charged to a 0,5
Titre reactor equipped with a reflux condenser and a stirrer. CSz (38.1g) was
added dropwise with stirring during 30 minutes. The reaction temperature was
maintained below 30°C by external cooling during the addition of CSz.
The
mixture was stirred for an additional 3 hours after which distillate (30g)
from a
previous batch was added. The reaction mixture was diluted with water to
obtain a DTC (dithiocarbamate) concentration of 24%.
Hydrazine hydrate (30,1 g) was added to the DIPEA-DTC mixture. The
reaction mixture was heated to 92°C and maintained at 92°C under
reflux
conditions for 2 hours and 20 minutes. The DIPEA was distilled off
(distillation
is complete when the temperature rises above 95°C), the reaction
mixture
cooled to 15°C while stirring, and the MTSC crystals separated from the
supernatant layer, providing a 75,8% isolated yield of MTSC.
J