CA1267905A - Thiophene derivative - Google Patents
Thiophene derivativeInfo
- Publication number
- CA1267905A CA1267905A CA000602707A CA602707A CA1267905A CA 1267905 A CA1267905 A CA 1267905A CA 000602707 A CA000602707 A CA 000602707A CA 602707 A CA602707 A CA 602707A CA 1267905 A CA1267905 A CA 1267905A
- Authority
- CA
- Canada
- Prior art keywords
- amine
- acid
- chloro
- diacetoxythiophene
- percent
- 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.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/32—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Epoxy Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A novel compound, diacetoxythiophene, of the formula:
A novel compound, diacetoxythiophene, of the formula:
Description
3[35 The invention relates to a novel intermediate for use in the production of thiote-tronic acid.
It has been reported that thiotetronic acid may po58e5~ utility as an lntermediate product for the production of (t) thiolactomycin, which is an antibiotic having a broad effective spectrum. Tetrahedron Letters, Vol. 25, No. 46, pp 5243 to 52~6, (1984). From E. BenarY, Chem. Berichte 46, 2103, ~1913), it i5 known to produce thiotetronic acid starting from acetyl thloglycoyl chloride through reaction thereof with sodium malonic ester and subsequent ring closure and water treatment.
D.B. Macierewicz, Rocz. Chem. 47, 1~35, (~973), reproduced the reaction of E. Benary and obtained thiotetronic acid in a yield of 30.3 percent, based on the actyl~hioglycoyl chloride used. Another possibility for syn~hesis is set out in J.Z. Mortensen et al., Tetrahedron Letters, 2~, 3~39 (1971). Startin~ from 2,4-dibromothiophene, the thiotetronic acid is obtained in a yield of 46.2 percent by way of three steps as a result of reaction with butyl lithium and t-butylperbenzoate.
However, in the case of all of the above-identified 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 novel intermediate compound which can be used in the production of thiotetronic acid by a process which is distinguished by high yields and high purity of thiotetron1c acid, 3~ ~avorable educts and simple procedural steps.
Accordin~ly, one aspect of the invention provides 2,4-diacetoxythiophene of the formula:
o 11 ' .
CH3-C-~ ~ 0 ~6~
Another aspect of the lnvention provides a process for preparing 2,4-diacetoxythiophene, which comprlses reactin~ 4-chloro-A-chloromethyloxetan-2~one wlth hydrogen sulfide in the presence of an amine and treating the reaction mixture with ketene.
This application is a divisional of our copendin~ Application Serial No. 499,621, filed January 15, 1986, which describes and claims a process for preparin~ thiotetronic acid, in which 4-chloro-4-0 chloromethyloxetan-2-one is reacted with hydrogen sulfide ln the presence of an amine to form thiotetronic acid directly, or, alternatively, the reaction solution is reacted prior to isolation of the thiotetronic acid with ketene, the resultant diacetoxyth~ophene is separated and the diacetoxythiophene is finally converted into thiotetronic acid using mineral acid.
The 4-chloro-4-chloromethyloxetan-2-one startins material can be produced in a simple manner according to published European Patent Application 60,808 and after ~0 flash distillation can be used for the conversion accordin~ to the invention.
The hydrogen sulfide is conveniently used in ~aseous form.
As suitable amines, advantageously primary, secondary or tertiary amine~, ammonia and also guanidine can be used. Tertiary amines, such as triethylamine, are particularly ad~antageous.
The reaction is conveniently carried out in a solvent or solvents. As compared to the reactive educt, inert solvents such aR halo~enated hydrocarbon~, ether or carboxylic acid esters are used. For example, methylene chloride, chloroform, ethereal solvents, such as tetrahydrofuran, and also acetic acid ester can be used.
Particularly preferred, however, as the solvent i~
tetrahydrofuran.
The educts are used effectively in a mole ratio of 4-chloro-4-chloromethyloxetan-2-one to hydrog0n sulfide ~6~
to amlne of from 1:2:2 to 1:4:3, and preferably between 1:2.5:2 and 1:3.5:2.5.
Preferably the reaction i8 operated at a temperature of from 0 to -40C, more preEerably between -10 and -25C.
Effectively, the method proceeds in such a way that the educt solution is sa-turated 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 oP the thiotetronic acid can take place by ~ tering off the precipitated salt and subsequently concentrating the solution. For the separation of small quantities of dimeric anhydroth~otetronic acid, the residue can be absorbed in ethereal solvents, ~uch as diethyl ether, tetrahydrofuran (THF) or dioxane, preferably in diethyl ether, and can be filtered by way of an absorption agent, such as silica ~el. After renewed concentration by evaporation of the solvent, the thiotetronic acid is obtained in crystalline form and in good yield.
After recrystallization in an aromatlc hydrocarbon, preferably in toluene, -the thiotetronic acid is subjected to additional purification.
In order to obtain diacetoxythiophene, after the addition of the amine, without lsolation of crude -thiotetronic acid, the lat-ter i5 treated with solution with ketene at a temperature of -10 to ~5C, advantageously 0C. Based on one mole of 4-chloro-4-chloromethyloxetan-2-one used, ketene is effectively used in a quantity of 2 to 4 moles, preferably 2.5 to 3.5 moles.
The novel intermediate compound 2,4-diacetoxythiophene havin~ the formula:
R~
~r :ll ~2~
wherein each R is CH3b_, results. The 2,4-diacetoxythiophene can be purified by distillation in a simple manner.
By treating the 2,4-diacetoxythiophene with a non-oxidizlng inorganic mineral acid, pure thiotetronic acid is obtained. Hydrochloric acid or sulfuric acid, preferably hydrochloric acid, can be used in aqueous ~olution ln a concentration of 10 to 30 percent. The conversion temperature is generally between 0 and 30C, preferably 15 to 25C. The reaction time can be 2 to 5 hours.
After concentration, preferably using high vacuum, this procedure provides practically colorless thiotetronic acid in high yield with a purlty greater than 96 percent.
As used herein, all parts, percentages, ratios 20 and proportions are on a weight basis unless otherwise stated herein or otherwise obvious herefrom to one skllled in the art.
The following Examples illustrate the invention or are included for reference purposes.
~5 EXAMPLE 1 15.5 g (0.091 mole) of 4-chloro-4-chloromethyl-oxe-tan-2-one was cooled to -20C in 300 ml of tetrahydrofurane and was saturated 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 over a period of one hour. The temperature of the reaction solution was allowed to rise to ambient temperature, the solution was ~iltered off from the salt obtained and the solvent was evaporated on a rotation evaporator. The residue was filtered through a column filled with silica gel, using 300 ml of ether as eluent. 9.0 0 of a yellow colored crystalline product having a melting point of 115C to 11~C was obtained.
The conten-t (HPLC~ amounted to 89.3 percent.
This corresponds to 8.0 g of 100 percent product = 75.~
percent yield. 7.5 g of the crude thiotetronic acid was recrystallized hot from 350 ml of toluene. 6.6 g of pale rose-colored microcrystalline product having a meltiny point of 120C and a content (HPLC) of 96 percent was obtained. This corresponded to 6.3 g of 100 percent product = 94 percent yield or ~1.2 percent based on the oxetanone used.
Thiotetronic acid was produced as described in Example 1. However, the thiotetronic acid was not isolated but the tetrahydrofuran (THF) solutlon was concentrated to 50 ml and over a period of one hour 0.3 mole of ketene was fed into this solution at 0C.
Subsequently, the temperature of the reaction solution was allowed to rise to ambient temperature and the solvent was distilled off usin~ a rotation evaporator. The residue was subjected to high vacuum distillation. 13.7 g of 2,4-diacetoxythiophene was obtained, content 95.6 percent, b-~-o 25 105C, which corresponded to 13.1 g of 100 percent product (yield 65.2 percent).
Spectroscopic data:
H-NMR (300 MHz, CDCL3) ~ 2.24 (s, 3H), 2.30 (s, 3H), ~5 6~5~ ~dr J=2.5 HZ, lH), 6.61 (d, lH).
MS (~OeV) m/z=200 (+, 3), 158 (M~-CH2=C=0, 10), 116 (M+-2 CH2-C=0, 35) 43 (100) l.B1 g of the 2,4-diacetoxythiophene wa~ reacted with 3.5 ~ of 20 percent hydrochloric acid and the mixture ~0 was stirred at ambient temperature for 3 hours. After 1 hour, a clear solution developed from the initial emulsion. This colored solution was evaporated under high vacuum. 1.0 y of practically colorless crystalline product was obtained having a melting point of 119 to 121C. (HPLC content: 96.1 percent), This corresponded to 0.96 ~ of 100 percent thiotetronic acid = 96 percent yield.
It has been reported that thiotetronic acid may po58e5~ utility as an lntermediate product for the production of (t) thiolactomycin, which is an antibiotic having a broad effective spectrum. Tetrahedron Letters, Vol. 25, No. 46, pp 5243 to 52~6, (1984). From E. BenarY, Chem. Berichte 46, 2103, ~1913), it i5 known to produce thiotetronic acid starting from acetyl thloglycoyl chloride through reaction thereof with sodium malonic ester and subsequent ring closure and water treatment.
D.B. Macierewicz, Rocz. Chem. 47, 1~35, (~973), reproduced the reaction of E. Benary and obtained thiotetronic acid in a yield of 30.3 percent, based on the actyl~hioglycoyl chloride used. Another possibility for syn~hesis is set out in J.Z. Mortensen et al., Tetrahedron Letters, 2~, 3~39 (1971). Startin~ from 2,4-dibromothiophene, the thiotetronic acid is obtained in a yield of 46.2 percent by way of three steps as a result of reaction with butyl lithium and t-butylperbenzoate.
However, in the case of all of the above-identified 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 novel intermediate compound which can be used in the production of thiotetronic acid by a process which is distinguished by high yields and high purity of thiotetron1c acid, 3~ ~avorable educts and simple procedural steps.
Accordin~ly, one aspect of the invention provides 2,4-diacetoxythiophene of the formula:
o 11 ' .
CH3-C-~ ~ 0 ~6~
Another aspect of the lnvention provides a process for preparing 2,4-diacetoxythiophene, which comprlses reactin~ 4-chloro-A-chloromethyloxetan-2~one wlth hydrogen sulfide in the presence of an amine and treating the reaction mixture with ketene.
This application is a divisional of our copendin~ Application Serial No. 499,621, filed January 15, 1986, which describes and claims a process for preparin~ thiotetronic acid, in which 4-chloro-4-0 chloromethyloxetan-2-one is reacted with hydrogen sulfide ln the presence of an amine to form thiotetronic acid directly, or, alternatively, the reaction solution is reacted prior to isolation of the thiotetronic acid with ketene, the resultant diacetoxyth~ophene is separated and the diacetoxythiophene is finally converted into thiotetronic acid using mineral acid.
The 4-chloro-4-chloromethyloxetan-2-one startins material can be produced in a simple manner according to published European Patent Application 60,808 and after ~0 flash distillation can be used for the conversion accordin~ to the invention.
The hydrogen sulfide is conveniently used in ~aseous form.
As suitable amines, advantageously primary, secondary or tertiary amine~, ammonia and also guanidine can be used. Tertiary amines, such as triethylamine, are particularly ad~antageous.
The reaction is conveniently carried out in a solvent or solvents. As compared to the reactive educt, inert solvents such aR halo~enated hydrocarbon~, ether or carboxylic acid esters are used. For example, methylene chloride, chloroform, ethereal solvents, such as tetrahydrofuran, and also acetic acid ester can be used.
Particularly preferred, however, as the solvent i~
tetrahydrofuran.
The educts are used effectively in a mole ratio of 4-chloro-4-chloromethyloxetan-2-one to hydrog0n sulfide ~6~
to amlne of from 1:2:2 to 1:4:3, and preferably between 1:2.5:2 and 1:3.5:2.5.
Preferably the reaction i8 operated at a temperature of from 0 to -40C, more preEerably between -10 and -25C.
Effectively, the method proceeds in such a way that the educt solution is sa-turated 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 oP the thiotetronic acid can take place by ~ tering off the precipitated salt and subsequently concentrating the solution. For the separation of small quantities of dimeric anhydroth~otetronic acid, the residue can be absorbed in ethereal solvents, ~uch as diethyl ether, tetrahydrofuran (THF) or dioxane, preferably in diethyl ether, and can be filtered by way of an absorption agent, such as silica ~el. After renewed concentration by evaporation of the solvent, the thiotetronic acid is obtained in crystalline form and in good yield.
After recrystallization in an aromatlc hydrocarbon, preferably in toluene, -the thiotetronic acid is subjected to additional purification.
In order to obtain diacetoxythiophene, after the addition of the amine, without lsolation of crude -thiotetronic acid, the lat-ter i5 treated with solution with ketene at a temperature of -10 to ~5C, advantageously 0C. Based on one mole of 4-chloro-4-chloromethyloxetan-2-one used, ketene is effectively used in a quantity of 2 to 4 moles, preferably 2.5 to 3.5 moles.
The novel intermediate compound 2,4-diacetoxythiophene havin~ the formula:
R~
~r :ll ~2~
wherein each R is CH3b_, results. The 2,4-diacetoxythiophene can be purified by distillation in a simple manner.
By treating the 2,4-diacetoxythiophene with a non-oxidizlng inorganic mineral acid, pure thiotetronic acid is obtained. Hydrochloric acid or sulfuric acid, preferably hydrochloric acid, can be used in aqueous ~olution ln a concentration of 10 to 30 percent. The conversion temperature is generally between 0 and 30C, preferably 15 to 25C. The reaction time can be 2 to 5 hours.
After concentration, preferably using high vacuum, this procedure provides practically colorless thiotetronic acid in high yield with a purlty greater than 96 percent.
As used herein, all parts, percentages, ratios 20 and proportions are on a weight basis unless otherwise stated herein or otherwise obvious herefrom to one skllled in the art.
The following Examples illustrate the invention or are included for reference purposes.
~5 EXAMPLE 1 15.5 g (0.091 mole) of 4-chloro-4-chloromethyl-oxe-tan-2-one was cooled to -20C in 300 ml of tetrahydrofurane and was saturated 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 over a period of one hour. The temperature of the reaction solution was allowed to rise to ambient temperature, the solution was ~iltered off from the salt obtained and the solvent was evaporated on a rotation evaporator. The residue was filtered through a column filled with silica gel, using 300 ml of ether as eluent. 9.0 0 of a yellow colored crystalline product having a melting point of 115C to 11~C was obtained.
The conten-t (HPLC~ amounted to 89.3 percent.
This corresponds to 8.0 g of 100 percent product = 75.~
percent yield. 7.5 g of the crude thiotetronic acid was recrystallized hot from 350 ml of toluene. 6.6 g of pale rose-colored microcrystalline product having a meltiny point of 120C and a content (HPLC) of 96 percent was obtained. This corresponded to 6.3 g of 100 percent product = 94 percent yield or ~1.2 percent based on the oxetanone used.
Thiotetronic acid was produced as described in Example 1. However, the thiotetronic acid was not isolated but the tetrahydrofuran (THF) solutlon was concentrated to 50 ml and over a period of one hour 0.3 mole of ketene was fed into this solution at 0C.
Subsequently, the temperature of the reaction solution was allowed to rise to ambient temperature and the solvent was distilled off usin~ a rotation evaporator. The residue was subjected to high vacuum distillation. 13.7 g of 2,4-diacetoxythiophene was obtained, content 95.6 percent, b-~-o 25 105C, which corresponded to 13.1 g of 100 percent product (yield 65.2 percent).
Spectroscopic data:
H-NMR (300 MHz, CDCL3) ~ 2.24 (s, 3H), 2.30 (s, 3H), ~5 6~5~ ~dr J=2.5 HZ, lH), 6.61 (d, lH).
MS (~OeV) m/z=200 (+, 3), 158 (M~-CH2=C=0, 10), 116 (M+-2 CH2-C=0, 35) 43 (100) l.B1 g of the 2,4-diacetoxythiophene wa~ reacted with 3.5 ~ of 20 percent hydrochloric acid and the mixture ~0 was stirred at ambient temperature for 3 hours. After 1 hour, a clear solution developed from the initial emulsion. This colored solution was evaporated under high vacuum. 1.0 y of practically colorless crystalline product was obtained having a melting point of 119 to 121C. (HPLC content: 96.1 percent), This corresponded to 0.96 ~ of 100 percent thiotetronic acid = 96 percent yield.
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. 2,4-Diacetoxythiophene of the formula:
2. A process for preparing 2, 4 -diacetoxythiophene, which comprises reacting 4-chloro-4-chloromethyloxetan-2-one with hydrogen sulfide in the presence of an amine and treating the reactlon mixture with ketene.
3. A process as claimed in claim 2, wherein the amine is a primary amine, a secondary amine, a tertiary amine, ammonia or guanidine.
4. A process as claimed in claim 3, wherein the amine is a tertiary amine.
5. A process as claimed in claim 2, 3 or 4, wherein the reaction is carried out in an inert solvent.
6. A process aR claimed in claim 2, 3 or 4, wherein the educt ratio of 4-chloro-4-chloromethyloxetan-2-one to hydrogen sulfide to amine is from 1:2:2 to 1:4:3.
7. A process as claimed in claim 2, 3 or 4, wherein the reaction temperature is from 0° to -40°C.
8. A process as claimed in claim 2, 3 or 4, wherein the ketene is used in a quantity of from 2 to 4 moles per mole of 4-chloro-4-chloromethyloxetan-2-one.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH192/85A CH663206A5 (en) | 1985-01-16 | 1985-01-16 | METHOD FOR PRODUCING THIOTETRONIC ACID. |
| CH192/85 | 1985-01-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1267905A true CA1267905A (en) | 1990-04-17 |
Family
ID=4181346
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000499621A Expired - Fee Related CA1264472A (en) | 1985-01-16 | 1986-01-15 | Process for the production of thiotetronic acid |
| CA000602707A Expired - Fee Related CA1267905A (en) | 1985-01-16 | 1989-06-13 | Thiophene derivative |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000499621A Expired - Fee Related CA1264472A (en) | 1985-01-16 | 1986-01-15 | Process for the production of thiotetronic acid |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0189096B1 (en) |
| JP (1) | JPS6236375A (en) |
| AT (1) | ATE41929T1 (en) |
| CA (2) | CA1264472A (en) |
| CH (1) | CH663206A5 (en) |
| DE (1) | DE3662688D1 (en) |
| DK (2) | DK162766C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7417150B2 (en) | 2001-04-20 | 2008-08-26 | Bayer Cropscience Ag | Azoles having an insecticidal action |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH667655A5 (en) * | 1986-09-24 | 1988-10-31 | Lonza Ag | METHOD FOR PRODUCING 4-ALKOXY-2 (5H) THIOPHENONES. |
-
1985
- 1985-01-16 CH CH192/85A patent/CH663206A5/en not_active IP Right Cessation
-
1986
- 1986-01-09 JP JP61002839A patent/JPS6236375A/en active Pending
- 1986-01-14 AT AT86100424T patent/ATE41929T1/en not_active IP Right Cessation
- 1986-01-14 EP EP86100424A patent/EP0189096B1/en not_active Expired
- 1986-01-14 DE DE8686100424T patent/DE3662688D1/en not_active Expired
- 1986-01-15 CA CA000499621A patent/CA1264472A/en not_active Expired - Fee Related
- 1986-01-15 DK DK017886A patent/DK162766C/en not_active IP Right Cessation
-
1989
- 1989-06-13 CA CA000602707A patent/CA1267905A/en not_active Expired - Fee Related
-
1991
- 1991-03-27 DK DK056391A patent/DK162642C/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7417150B2 (en) | 2001-04-20 | 2008-08-26 | Bayer Cropscience Ag | Azoles having an insecticidal action |
Also Published As
| Publication number | Publication date |
|---|---|
| DE3662688D1 (en) | 1989-05-11 |
| EP0189096B1 (en) | 1989-04-05 |
| ATE41929T1 (en) | 1989-04-15 |
| EP0189096A1 (en) | 1986-07-30 |
| CA1264472A (en) | 1990-01-16 |
| CH663206A5 (en) | 1987-11-30 |
| JPS6236375A (en) | 1987-02-17 |
| DK162642C (en) | 1992-04-13 |
| DK17886D0 (en) | 1986-01-15 |
| DK162642B (en) | 1991-11-25 |
| DK56391A (en) | 1991-03-27 |
| DK17886A (en) | 1986-07-17 |
| DK56391D0 (en) | 1991-03-27 |
| DK162766B (en) | 1991-12-09 |
| DK162766C (en) | 1992-04-27 |
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|---|---|---|---|
| MKLA | Lapsed |