EP1377546A2 - Process for producing thiosemicarbazides - Google Patents

Process for producing thiosemicarbazides

Info

Publication number
EP1377546A2
EP1377546A2 EP02716977A EP02716977A EP1377546A2 EP 1377546 A2 EP1377546 A2 EP 1377546A2 EP 02716977 A EP02716977 A EP 02716977A EP 02716977 A EP02716977 A EP 02716977A EP 1377546 A2 EP1377546 A2 EP 1377546A2
Authority
EP
European Patent Office
Prior art keywords
thiosemicarbazide
producing
diisopropyl
mtsc
dithiocarbamate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02716977A
Other languages
German (de)
French (fr)
Inventor
Colette De Klerk
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Corteva Agriscience LLC
Original Assignee
Dow AgroSciences LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dow AgroSciences LLC filed Critical Dow AgroSciences LLC
Publication of EP1377546A2 publication Critical patent/EP1377546A2/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C337/00—Derivatives of thiocarbonic acids containing functional groups covered by groups C07C333/00 or C07C335/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C337/06—Compounds containing any of the groups, e.g. thiosemicarbazides

Definitions

  • This invention relates to a process for producing thiosemicarbazides.
  • MTSC 4-Methyl-3-thiosemicarbazide
  • BTDA 5- t-butyl-2-methylamino-1 ,3,4-thiadiazole
  • Tebuthiuron has the chemical name 1-(5-tert-butyl- 1 ,3,4-thiadiazol-2-yl)-1 ,3 dimethylurea.
  • the current production process for MTSC entails the hydrazinolysis of ammonium N-methyl-dithiocarbamate.
  • Methyl isothiocyanate (MITC) is believed to be formed in situ from ammonium N-methyldithiocarbamate when heated in the presence of bases. It reacts with hydrazine monohydrate to give MTSC.
  • This process affords MTSC of 93-94% purity.
  • the purity of MTSC is a critical factor in the manufacturing of BTDA of high purity (98 + %) and yield.
  • the MTSC produced by this process is of insufficient 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 tons of effluent are produced for every ton of MTSC produced on plant scale).
  • 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.
  • DIPEA N,N-diisopropylethylamine
  • DIPMA N,N,-diisopropylmethylamine
  • 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:
  • 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.
  • the alkylamine which is used in the process of the invention has the formula alkyl-NH 2 , 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:
  • 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 The reaction of step 1 is highly exothermic and cooling is generally necessary to maintain the temperature of the reaction medium below 30°C.
  • DIPEA DIPEA
  • 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.
  • MTSC in yields of 70 to 76% and purities of 97,5 to 98,5% are attainable.
  • Methylamine (77, 5g; 40% solution) and DIPEA (142, 2g) were charged to a 1 litre reactor equipped with a reflux condenser and a stirrer.
  • CS 2 (76g) was added dropwise with stirring during 30 minutes.
  • the reaction temperature was maintained below 30°C by external cooling during the addition of CS 2 .
  • 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%.
  • Methylamine (38.7g; 40% solution) and DIPEA (82.4g) were charged to a 0,5 litre reactor equipped with a reflux condenser and a stirrer.
  • CS 2 (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 CS 2 .
  • 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%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

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.

Description

PROCESS FOR PRODUCING THIOSEMICARBAZIDES
BACKGROUND OF THE INVENTION
This invention relates to a process for producing thiosemicarbazides.
4-Methyl-3-thiosemicarbazide (MTSC) is an intermediate in the synthesis of 5- t-butyl-2-methylamino-1 ,3,4-thiadiazole (BTDA), the precursor of tebuthiuron, a broad-spectrum herbicide. Tebuthiuron has the chemical name 1-(5-tert-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 as follows:
the reaction of alkyl isothiocyanates with hydrazine, the reaction of hydrazine with reactive thiocarbamic acid derivatives
(acid chlorides, thiuram monosulfides, etc.), and the hydrazinolysis of N-monoalkyl- and N,N-dialkyldithio- carbamates.
The current production process for MTSC entails the hydrazinolysis of ammonium N-methyl-dithiocarbamate. Methyl isothiocyanate (MITC) is believed to be formed in situ from ammonium N-methyldithiocarbamate when heated in the presence of bases. It reacts with hydrazine monohydrate to give MTSC. This process affords MTSC of 93-94% purity. The purity of MTSC is a critical factor in the manufacturing of BTDA of high purity (98+%) and yield. The MTSC produced by this process is of insufficient 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 tons of effluent are produced for every ton of MTSC produced on plant scale). 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:
θ alkyl NH N
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. 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^H-CS-NH-NHz wherein Ri 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 .
CH3 NH_ + CS.
(A)
Step 2
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, 5g; 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, 1g) 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 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 litre reactor equipped with a reflux condenser and a stirrer. CS2 (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 CS2. 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, 1g) 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.

Claims

1. 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 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:
R^H-CS-NH-NHz, wherein Rj 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-diisopropyl-ethylammonium dithiocarbamate and N,N-diisopropyl-methylammonium dithiocarbamate.
6. The use of a compound according to claim 5 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.
EP02716977A 2001-04-09 2002-04-02 Process for producing thiosemicarbazides Withdrawn EP1377546A2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ZA200102904 2001-04-09
ZA200102904 2001-04-09
PCT/IB2002/001023 WO2002081438A2 (en) 2001-04-09 2002-04-02 Process for producing thiosemicarbazides

Publications (1)

Publication Number Publication Date
EP1377546A2 true EP1377546A2 (en) 2004-01-07

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP02716977A Withdrawn EP1377546A2 (en) 2001-04-09 2002-04-02 Process for producing thiosemicarbazides

Country Status (10)

Country Link
EP (1) EP1377546A2 (en)
JP (1) JP2004536795A (en)
KR (1) KR20030086351A (en)
CN (1) CN1518539A (en)
BR (1) BR0208743A (en)
CA (1) CA2446918A1 (en)
HU (1) HUP0303844A2 (en)
IL (1) IL158288A0 (en)
MX (1) MXPA03009215A (en)
WO (1) WO2002081438A2 (en)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102584661A (en) * 2012-01-19 2012-07-18 中国科学院海洋研究所 Preparation method of substituted phenylthiosemicarbazide compound
CN103709081B (en) * 2013-12-13 2016-01-06 黄河三角洲京博化工研究院有限公司 A kind of preparation method of thiosemicarbazide
CN104860857B (en) * 2015-04-09 2017-03-08 山东华阳农药化工集团有限公司 Methylthiosemicarbazone synthesis technique
CN105772100B (en) * 2016-04-06 2018-05-15 上海应用技术学院 (R) Cr-Anderson types heteropolyacid catalyst thiourea modified -1- (1- (2- naphthyls) ethyl), preparation method and applications
CN105797770B (en) * 2016-04-06 2018-03-30 上海应用技术学院 (S) the thiourea modified Cr Anderson types heteropolyacid catalyst of 1 (phenylpropyl of 3 hydroxyl 1), preparation method and applications
CN105854940B (en) * 2016-04-06 2018-05-15 上海应用技术学院 (R) Cr-Anderson types heteropolyacid catalyst thiourea modified -1- (1- phenethyls), preparation method and applications
CN105772086B (en) * 2016-04-06 2018-03-30 上海应用技术学院 (S) the thiourea modified Mn Anderson types heteropolyacid catalyst of 1 (isopropyl of 1 ethoxy 1), preparation method and applications
CN105833909B (en) * 2016-04-06 2018-05-15 上海应用技术学院 (S) Cr-Anderson types heteropolyacid catalyst thiourea modified -1- (2- hydroxyl -1- phenethyls), preparation method and applications
CN105772101B (en) * 2016-04-06 2018-03-30 上海应用技术学院 The Mn Anderson types heteropolyacid catalyst of 1 Phenethylthiourea modification, preparation method and applications
CN105797769B (en) * 2016-04-06 2018-03-30 上海应用技术学院 (R) the thiourea modified Mn Anderson types heteropolyacid catalyst of 1 (phenethyl of 2 hydroxyl 1), preparation method and applications
CN105772085B (en) * 2016-04-06 2018-04-13 上海应用技术学院 (S) the thiourea modified Cr Anderson types heteropolyacid catalyst of 1 (1 ethoxy, 1 isopropyl), preparation method and applications
CN105854952B (en) * 2016-04-06 2018-05-15 上海应用技术学院 (S) Mn-Anderson types heteropolyacid catalyst thiourea modified -1- (2- hydroxyl -1- phenethyls), preparation method and applications

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA931961A (en) * 1970-04-17 1973-08-14 Gulf Research And Development Company Combating unwanted vegetation with 1,3,4-thiadiazolylureas
BR8901957A (en) * 1988-04-27 1989-12-05 Lilly Co Eli PROCESS TO PREPARE 4-METHYL-3-THEMOSEMICARBAZIDE

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO02081438A2 *

Also Published As

Publication number Publication date
JP2004536795A (en) 2004-12-09
MXPA03009215A (en) 2004-03-10
CA2446918A1 (en) 2002-10-17
WO2002081438A2 (en) 2002-10-17
BR0208743A (en) 2004-06-22
KR20030086351A (en) 2003-11-07
HUP0303844A2 (en) 2004-03-29
WO2002081438A3 (en) 2002-11-28
IL158288A0 (en) 2004-05-12
CN1518539A (en) 2004-08-04

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