CA1266274A - Thiophenone derivatives and process for their production - Google Patents
Thiophenone derivatives and process for their productionInfo
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- CA1266274A CA1266274A CA000508417A CA508417A CA1266274A CA 1266274 A CA1266274 A CA 1266274A CA 000508417 A CA000508417 A CA 000508417A CA 508417 A CA508417 A CA 508417A CA 1266274 A CA1266274 A CA 1266274A
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- 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
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
THIOPHENONE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION
ABSTRACT OF THE DISCLOSURE
Novel thiophenone derivatives are disclosed which are useful as thiotetronic acid precursors and have the formula:
ABSTRACT OF THE DISCLOSURE
Novel thiophenone derivatives are disclosed which are useful as thiotetronic acid precursors and have the formula:
Description
~z~
The invention relates -to new thiophenone deri~atives :that can be simply converted -to -thio-tetronic acid.
Thiotetronic acid itself has important application as an in-termediate product for the production oE (~) thiol-actomycin, a broad-spectrum anti.biotic [Tet~ahedron Letters, Vol 25, No. 46, pp. 5243 to 5~46,.(1984)~.
From E. Benary, Chem. Berichte 46, 2103, (1913), it is known to produce thiote-tronic acid, starting from acetyl-thioglycoyl chloride by reaction with sodium malonate and subsequent ring closure and water treatment. D.B. Macierewicz, Rocz. Chem.-47, 1735, (1973)', duplicated -the reaction of E.
Benary and in doing so obtained thiotetronic acid in a yield of 30.3 p~rcent based on the acetylthioglycoyl chloride used.
The syn-thesis of J.Z. Morterisen et al., Tetrahedron 27, 3839, ., . _ (1971), shows another possibility. Starting with 2,4-dibromo-thiophene, Mortensen et al. obtained.thiotetronic acid in a yield of 46.2 percent over three stages by reaction wi-th bu-tyllithium and t-butylperbenzoate.
Ilowever,'irl these conven-tional syntheses, no-t only are t}le yields too small, but also the starting materials and reagents used hardly allow for an economical industrial process.
A Eurther prob~.em lies in the production of a qualitatively hlgh-grade product, since thi.otetronic acid both during recrystallization and also in aqueous solution easily forms a dimerlc condensation produc-t with -the splitting ofE of wa-ter.
An object oE the invention is to provide alterna-tive thiotetronic acid precursors which are technically easy to produce, can be isolated from the reaction mix-ture, result in high purity and are simple to convert to thiotetronic acid.
: Accordingly,.the invention provides a novel thio-phenone derivative of the general.formuIa: .
RO
~S J~
~ ~, ., , . .
~: . . . ,,, :
: ~ : .. ~. ;,. . . . .
.: ' '': ' '. ' ' .
7'~
wherein R i5 a C1 to C8 alkoxycarbonyl group, a halogen-or lower alkyl-substituted or unsubstituted benzyloxycarbonyl group, or a p-toluenesulfonyl group.
The invention further provides a process for the production of the novel Gompounds of the invention by the reaction of 4-Ghloro-4-chloromethyloxetan-2-one with hydrogen sulfide in the presence of a base, and Gonver~ion of the resultant thiotetronic acid with chloroformate or p-toluenesulfonyl chloride to the desired end product.
The 4-chloro-4-chloromethyloxetan-2-one starting material can be produGed in a simple manner according to the procedure de~cribed in published European Patent Application No. ~0~08 and, after flash distillation, can be used for the conver~ion accordin~ to the invention.
The hydrogen sulfide is advantageously used in gaseous form.
The base i8 advantageously an amine, such as a primary, secondary or tertiary amine, ammonla or even a guanidine. Tertiary amines, e.~ riethylamine, are regarded as partiGularly advantageous.
The chloroformate is advantageously a C1 to G8 alkyl or halogen- or lower alkyl-su~stituted or un~ubst~tutecl benzyl ester of chloroformic acid, with chloroformic acid C1 to C2 alkyl ester~ being preferred.
Furthermore, it is advantageous for the reaction to ~e performed in a solvent. Solvents that are inert to the reactive educt are suitable, e.g. halogenated hydrocarbons, ethers or carboxylates. For example, methylene chloride, chloroform, and ethereal solvents, ~0 e.y., tetrahydrofuran, can ~e used. Tetrahydrofuran or ethyl acetate is particularly preferred.
The reactants are advantageou~ly used in a molar ratio of 4-chloro-4-Ghloromethyloxetan-2-one to hydrogen sulfide to amine to Ghloroformatetp-toluenesulfonyl 35 chloride of from 1 : 1 : 2.8 : 0. a to 1 : 3 : 4 : 1, preferably from 1 : 2 : 2.~ : 0.~ to 1 : 3 : ~.0 : 1.
~ ' `
It is preferred to operate at a temperature oE -40 to +20C, more preferably from -20 to.-10C.. ~dvantageously, the procedure is such that the ~-chloro-4-chloromet}lyloxetan-
The invention relates -to new thiophenone deri~atives :that can be simply converted -to -thio-tetronic acid.
Thiotetronic acid itself has important application as an in-termediate product for the production oE (~) thiol-actomycin, a broad-spectrum anti.biotic [Tet~ahedron Letters, Vol 25, No. 46, pp. 5243 to 5~46,.(1984)~.
From E. Benary, Chem. Berichte 46, 2103, (1913), it is known to produce thiote-tronic acid, starting from acetyl-thioglycoyl chloride by reaction with sodium malonate and subsequent ring closure and water treatment. D.B. Macierewicz, Rocz. Chem.-47, 1735, (1973)', duplicated -the reaction of E.
Benary and in doing so obtained thiotetronic acid in a yield of 30.3 p~rcent based on the acetylthioglycoyl chloride used.
The syn-thesis of J.Z. Morterisen et al., Tetrahedron 27, 3839, ., . _ (1971), shows another possibility. Starting with 2,4-dibromo-thiophene, Mortensen et al. obtained.thiotetronic acid in a yield of 46.2 percent over three stages by reaction wi-th bu-tyllithium and t-butylperbenzoate.
Ilowever,'irl these conven-tional syntheses, no-t only are t}le yields too small, but also the starting materials and reagents used hardly allow for an economical industrial process.
A Eurther prob~.em lies in the production of a qualitatively hlgh-grade product, since thi.otetronic acid both during recrystallization and also in aqueous solution easily forms a dimerlc condensation produc-t with -the splitting ofE of wa-ter.
An object oE the invention is to provide alterna-tive thiotetronic acid precursors which are technically easy to produce, can be isolated from the reaction mix-ture, result in high purity and are simple to convert to thiotetronic acid.
: Accordingly,.the invention provides a novel thio-phenone derivative of the general.formuIa: .
RO
~S J~
~ ~, ., , . .
~: . . . ,,, :
: ~ : .. ~. ;,. . . . .
.: ' '': ' '. ' ' .
7'~
wherein R i5 a C1 to C8 alkoxycarbonyl group, a halogen-or lower alkyl-substituted or unsubstituted benzyloxycarbonyl group, or a p-toluenesulfonyl group.
The invention further provides a process for the production of the novel Gompounds of the invention by the reaction of 4-Ghloro-4-chloromethyloxetan-2-one with hydrogen sulfide in the presence of a base, and Gonver~ion of the resultant thiotetronic acid with chloroformate or p-toluenesulfonyl chloride to the desired end product.
The 4-chloro-4-chloromethyloxetan-2-one starting material can be produGed in a simple manner according to the procedure de~cribed in published European Patent Application No. ~0~08 and, after flash distillation, can be used for the conver~ion accordin~ to the invention.
The hydrogen sulfide is advantageously used in gaseous form.
The base i8 advantageously an amine, such as a primary, secondary or tertiary amine, ammonla or even a guanidine. Tertiary amines, e.~ riethylamine, are regarded as partiGularly advantageous.
The chloroformate is advantageously a C1 to G8 alkyl or halogen- or lower alkyl-su~stituted or un~ubst~tutecl benzyl ester of chloroformic acid, with chloroformic acid C1 to C2 alkyl ester~ being preferred.
Furthermore, it is advantageous for the reaction to ~e performed in a solvent. Solvents that are inert to the reactive educt are suitable, e.g. halogenated hydrocarbons, ethers or carboxylates. For example, methylene chloride, chloroform, and ethereal solvents, ~0 e.y., tetrahydrofuran, can ~e used. Tetrahydrofuran or ethyl acetate is particularly preferred.
The reactants are advantageou~ly used in a molar ratio of 4-chloro-4-Ghloromethyloxetan-2-one to hydrogen sulfide to amine to Ghloroformatetp-toluenesulfonyl 35 chloride of from 1 : 1 : 2.8 : 0. a to 1 : 3 : 4 : 1, preferably from 1 : 2 : 2.~ : 0.~ to 1 : 3 : ~.0 : 1.
~ ' `
It is preferred to operate at a temperature oE -40 to +20C, more preferably from -20 to.-10C.. ~dvantageously, the procedure is such that the ~-chloro-4-chloromet}lyloxetan-
2-one, dissolved in the inert solvent, is saturated with hydrogen sulfide, and -then -the amine is added over a period of 30 to 120 mirlutes.
~ Eter the addition of the amine, and without the intermediate thiotetronic acid being separated, treatment with the chloroformate or p-toluenesulfonyl chloride results in direct conversion, in solution to the thiophenone deriva-tive according to the invention.
If the operation is conducted with a double amount, in other words with 1.6 -to 2 mols of chloroformate or p-toluenesul:Eonyl chloride per mol of the oxetanone, disub-stituted thi.ophellone derivat.ives of the formula:
RO
~ J _ OR
wherein R hclS the above-mellt:ioned meanillg, carl be obtained in a simple manner.
Isolation o:E the thiophenone or thiophene deriva-tives can be carried out in a simple way by extrac-tion or by recrystallization. In thls way, yields of more than 70 per-cent, and contents consistently of more than 90 percent, andin some cases of mo.re than 99 percent, can be obtained.
The conversion of thiopherlone and thiophene deriva-tives to thiotetronic acids. is performed under basic condi-tions, advantageously in the presence of an alipha-tic amine or NH3.
AEter a suitable working up, a quali-tatively high-grade thiotetronic acid, with a content of more than 95 percent, can be obtained.
Particularly advantageous compounds, which provide : 35 the lnitially mentioned advantages in the highest degree, are:
., , .
'' ~
`.
~z~
(a) 4-(ethoxycarbonyloxy)thiophen-2(511)-one; and (b) 4-(methoxycarbonyloxy)thiop}1en-2(5~l)-one.
~ s u~sed herein, all par-ts, percentayes, ratios and proportions are on a weight basis unless otherwise stated herein or ot~1erwise obvious herefrom to one skilled in the art.
T11e following Examples illustrate the invention.
EX~MPLE 1 ~ solution of l5.9 g (O.l mol) of 4-chlbro-4-chlorome-thyloxetan-2-one in 300 ml of tetrahydrofuran was cooled to -20C. and saturated with gaseous hydrogen sul~ide.
Then 20.4 g (0.2 mol) of -triethylamine was added dropwise with vigorous stirring over a period of an hour. The reaction solution was allowed to warm to room temperature, stirred again for an hour, and filtered off from -the precipitated salt; and the solution was then evaporated to half its vol-w~e in a rotary evaporator. This solution was mixed with 9.8 g (0.09 mol) of ethyl chloroformate, cooled to 0C. and mixecl dro~wise with 9.l g (0.09 mol) of triethylamir1e. The preclpitated salt was filtered off and the reaction solution was concentrated in a rotary evaporator. The residue was e~xtracted w:Ltll 400 ml of petroleum ether; the resultan-t solu-tion was decanted and coo:Led to -20C. The precipitated crysta:Ls were filtered by suction. 15.0 g of 4-(ethoxycar-bonyloxy)t~liop~1en-2(5~ one was obtained as beige-colored crystals with a m.p. oE 52 to 54ac. and a 99.2 percent con-tent (GC). This corresponded to 14.9 g of lO0 percen-t product or a yield of 79.1 percent based on -the oxetanone used.
lEI-NM~ spec-trum (CDCl3 ~
= 6.42 (t, J3,5 = l.3 Ilz, lH) 4.29 (q, J = 7.1 Elz, 2~1) 4.02 (d, J3,5~ = 1-3 llz, 2H) 1.33 (-t, J = 7.1 Hz, 3H) E~MPLE 2 ~nalogously to Example l, but using 8.50 g (0.9 mol) ' ' ' ;
of methyl cllloroformate instead of ethyl chloroformate, 4-(metlloxycarbollyloxy)-tlliophen-2(511)-one was obtainecl ln a yield of 13.8 g (equals 79.2 percent), based Ol~ the oxetanone used.
rr1le beige-colored procduct has a melting range of 64 -to 66C. and a content of 9201 perccnt as indicated by GC.
H-NMR spectrun- (CDCl , 300 MHz) ~ = 6.49 (t, J3,5 = 1.3 Hz, lH) 4.05 (d, J3,5 = 1.3 Hz, 2H)
~ Eter the addition of the amine, and without the intermediate thiotetronic acid being separated, treatment with the chloroformate or p-toluenesulfonyl chloride results in direct conversion, in solution to the thiophenone deriva-tive according to the invention.
If the operation is conducted with a double amount, in other words with 1.6 -to 2 mols of chloroformate or p-toluenesul:Eonyl chloride per mol of the oxetanone, disub-stituted thi.ophellone derivat.ives of the formula:
RO
~ J _ OR
wherein R hclS the above-mellt:ioned meanillg, carl be obtained in a simple manner.
Isolation o:E the thiophenone or thiophene deriva-tives can be carried out in a simple way by extrac-tion or by recrystallization. In thls way, yields of more than 70 per-cent, and contents consistently of more than 90 percent, andin some cases of mo.re than 99 percent, can be obtained.
The conversion of thiopherlone and thiophene deriva-tives to thiotetronic acids. is performed under basic condi-tions, advantageously in the presence of an alipha-tic amine or NH3.
AEter a suitable working up, a quali-tatively high-grade thiotetronic acid, with a content of more than 95 percent, can be obtained.
Particularly advantageous compounds, which provide : 35 the lnitially mentioned advantages in the highest degree, are:
., , .
'' ~
`.
~z~
(a) 4-(ethoxycarbonyloxy)thiophen-2(511)-one; and (b) 4-(methoxycarbonyloxy)thiop}1en-2(5~l)-one.
~ s u~sed herein, all par-ts, percentayes, ratios and proportions are on a weight basis unless otherwise stated herein or ot~1erwise obvious herefrom to one skilled in the art.
T11e following Examples illustrate the invention.
EX~MPLE 1 ~ solution of l5.9 g (O.l mol) of 4-chlbro-4-chlorome-thyloxetan-2-one in 300 ml of tetrahydrofuran was cooled to -20C. and saturated with gaseous hydrogen sul~ide.
Then 20.4 g (0.2 mol) of -triethylamine was added dropwise with vigorous stirring over a period of an hour. The reaction solution was allowed to warm to room temperature, stirred again for an hour, and filtered off from -the precipitated salt; and the solution was then evaporated to half its vol-w~e in a rotary evaporator. This solution was mixed with 9.8 g (0.09 mol) of ethyl chloroformate, cooled to 0C. and mixecl dro~wise with 9.l g (0.09 mol) of triethylamir1e. The preclpitated salt was filtered off and the reaction solution was concentrated in a rotary evaporator. The residue was e~xtracted w:Ltll 400 ml of petroleum ether; the resultan-t solu-tion was decanted and coo:Led to -20C. The precipitated crysta:Ls were filtered by suction. 15.0 g of 4-(ethoxycar-bonyloxy)t~liop~1en-2(5~ one was obtained as beige-colored crystals with a m.p. oE 52 to 54ac. and a 99.2 percent con-tent (GC). This corresponded to 14.9 g of lO0 percen-t product or a yield of 79.1 percent based on -the oxetanone used.
lEI-NM~ spec-trum (CDCl3 ~
= 6.42 (t, J3,5 = l.3 Ilz, lH) 4.29 (q, J = 7.1 Elz, 2~1) 4.02 (d, J3,5~ = 1-3 llz, 2H) 1.33 (-t, J = 7.1 Hz, 3H) E~MPLE 2 ~nalogously to Example l, but using 8.50 g (0.9 mol) ' ' ' ;
of methyl cllloroformate instead of ethyl chloroformate, 4-(metlloxycarbollyloxy)-tlliophen-2(511)-one was obtainecl ln a yield of 13.8 g (equals 79.2 percent), based Ol~ the oxetanone used.
rr1le beige-colored procduct has a melting range of 64 -to 66C. and a content of 9201 perccnt as indicated by GC.
H-NMR spectrun- (CDCl , 300 MHz) ~ = 6.49 (t, J3,5 = 1.3 Hz, lH) 4.05 (d, J3,5 = 1.3 Hz, 2H)
3.96 (s, 311) EX~MPLE 3 A solu-tion of 16.3 g (0.1 mol) of 4-chloro-4-chloromethyloxetan-2-one in 300 ml of tetrahydrofuran was cooled to -20C. and sa-turatediwi-th gaseous hydrogen sulfide.
Then 20.4 g (0.2 mol) of triethylamine was added dropwise with vigorous stirring over a period of an hour. The reac-tion solution was allowed to warm to room temperature, stirred agaitl For an hour, and Eiltered oEf from the precipi--tated salt; and the solut:Lon was evaporated to half its volume in a rotary evaporator. This solution was mixed with 19.1 g (0.1 mol) of p-toluene-sulfonyl chloride, cooled to 0C. and mixed clropwise with 10.2 g (0.1 mol) of triethylamine.
The prec:lp:Ltated salt was filtered off and the reaction solution was concentrated in a rotary evaporator. The res:Ldue was washed with 50 ml o.E me-thanol . 19 . 8 g of 4-(p-toluenesulfonyloxy)-thiophen-2(5H)-one as DC-pure product with a m.p. o.E 139 to 140C. was obtained. This correspond~d to a yield of 73.3 percent, based on the oxe-tanone used.
lEI-NMR spectrum (CDC13, 300 MHz) = 7.86 (d, J = 8.8 Hz, 211) 7.43 (d, J = 8.8 Hz, 2H) 6.13 (t, J - 1.2 Hz, lEI) 3.96 (d, J - 1.2 Hz, lH) 2.50 (s, 31t) . .
, EX~MPLE 4 ~ nalogously to Example 1, but using 12.3 g (0.9 mol) of butyl chloroformate instead of ethyl chloroformate,
Then 20.4 g (0.2 mol) of triethylamine was added dropwise with vigorous stirring over a period of an hour. The reac-tion solution was allowed to warm to room temperature, stirred agaitl For an hour, and Eiltered oEf from the precipi--tated salt; and the solut:Lon was evaporated to half its volume in a rotary evaporator. This solution was mixed with 19.1 g (0.1 mol) of p-toluene-sulfonyl chloride, cooled to 0C. and mixed clropwise with 10.2 g (0.1 mol) of triethylamine.
The prec:lp:Ltated salt was filtered off and the reaction solution was concentrated in a rotary evaporator. The res:Ldue was washed with 50 ml o.E me-thanol . 19 . 8 g of 4-(p-toluenesulfonyloxy)-thiophen-2(5H)-one as DC-pure product with a m.p. o.E 139 to 140C. was obtained. This correspond~d to a yield of 73.3 percent, based on the oxe-tanone used.
lEI-NMR spectrum (CDC13, 300 MHz) = 7.86 (d, J = 8.8 Hz, 211) 7.43 (d, J = 8.8 Hz, 2H) 6.13 (t, J - 1.2 Hz, lEI) 3.96 (d, J - 1.2 Hz, lH) 2.50 (s, 31t) . .
, EX~MPLE 4 ~ nalogously to Example 1, but using 12.3 g (0.9 mol) of butyl chloroformate instead of ethyl chloroformate,
4-(n-butyloxycarbonyloxy)thiophen-2 (511) -one was obtained in a yield of 75.7 percent based on -the oxetanone used, in the form of liyht brownish-colored crystals with a melting point of 28 to 29C.
H-NMR s~ec-trum (CDC13), 300 MHz) = 6.48 (t, J3,5 = 1.2 Hz, 11l) 4.30 (t, J = 6.9 Hz, 2H) 4.09 (d, J3,5 = 1.2 ~Iz, 2H) 1.73 (m~ 2H) 1.44 (m, 2H) 0.98 (-t, J = 7.2 Elz, 3EI) EX~MPLE 5 ~nalogously to Example 1, but using 15.3 g (0.09 mol) of benzyl chloroEormate ins-tead of ethyl chloroformate, 4-(benzyloxycarbonyloxy)thiophen-2(5H)-orle was obtained in a yield oE 74.1 percent, based on the oxetanone used, in the Eorm of beige-colored crystals with a melting point oE 82 to 83C.
El-NMR spectrum (CDC13r 300 Mllæ) = 7.41 (S, 5EI) ' 6.49 (t, J3,5 = 1.2 llz, lEI)
H-NMR s~ec-trum (CDC13), 300 MHz) = 6.48 (t, J3,5 = 1.2 Hz, 11l) 4.30 (t, J = 6.9 Hz, 2H) 4.09 (d, J3,5 = 1.2 ~Iz, 2H) 1.73 (m~ 2H) 1.44 (m, 2H) 0.98 (-t, J = 7.2 Elz, 3EI) EX~MPLE 5 ~nalogously to Example 1, but using 15.3 g (0.09 mol) of benzyl chloroEormate ins-tead of ethyl chloroformate, 4-(benzyloxycarbonyloxy)thiophen-2(5H)-orle was obtained in a yield oE 74.1 percent, based on the oxetanone used, in the Eorm of beige-colored crystals with a melting point oE 82 to 83C.
El-NMR spectrum (CDC13r 300 Mllæ) = 7.41 (S, 5EI) ' 6.49 (t, J3,5 = 1.2 llz, lEI)
5.28 (s, 2H) 4.07 (d, J3,5 = 1.2 ElZ, 2H) E3XI~MPL,E 6 ~nalogously to Example 1, but using 0.18 mol of ethyl chloroformate and 0.18 mol of triethylamine instead of 0.09 mol of each thereof, 2,4-bis(ethoxycarbonyloxy)-thiophene was obtained in a yield oE 20.1 g (equals 72.7 percent), based on -the oxetanone used. The brownish-colored product had a metling point of 5~ to 8C. and a conten-t of 97.6 per-cent.
E~-NMR spectrum (DMSO-d6, 300 MHz) 35 ~ = 6.97 (d,, ~3,5 = 2.5 i~z, lH) - . ,.:>
-: . . . . ...
' :''` ' :' : .
~ .. , : . -. ~
~; ' .: .
. ( , J3,5 2.5 11z, l11) 4.30 (q, J = 7.0 ~1z, 2E1) 4.25 (q, J = 7.0 ~z, 2~1) 1.30 (t, J = 7.0 ~1z, 311) 1.28 (t, J = 7.0 11z, 3~1) EX~MPLE 7 3.8 g (0.02 mol) of 4-(ethoxycarbonyloxy)thiophen-2(5E1)-one was dissolved in 25 ml of tetrahydrofuran and cooled to -10C. A solution of 2.9 g (0.04 mol) of die-thyl-amine i.n 3S ml of tetrahydrofuran was added thereto. Theprecipitated solid (thiotetronic acid die-thylammonium salt) was filtered off by suction and taken up in 20 ml of water.
It was acidiEied to a pH of l to 2 with concentrated hydro-chloric acid with stirring. The precipita-ted thiote-tronic acid was extracted with 100 ml of ethyl ace-ta-te. '~'he organ-ic phase was dried over Na2SO~ and then the solution was evaporated in a Rotovapor. The res.idue was dried under high vacuum. 2.0 g of -thiotetronic ac.id was o~tained as a nearly white, microcrystalline product with a m.p. of 120 to 122C. ~ri(l~ a content oE 96.9 percen-t (NaO11 titrat.ion).
This corresponc:1ed to l.9 g of l00 percent product or a yield of ~3.6 percent based on the 4-(ethoxycarbonyloxy)thiophen-2(511)-one used.
:
; 35 ~.... .
. ~
~ . ' ' . `~ '' '-. .
-.
E~-NMR spectrum (DMSO-d6, 300 MHz) 35 ~ = 6.97 (d,, ~3,5 = 2.5 i~z, lH) - . ,.:>
-: . . . . ...
' :''` ' :' : .
~ .. , : . -. ~
~; ' .: .
. ( , J3,5 2.5 11z, l11) 4.30 (q, J = 7.0 ~1z, 2E1) 4.25 (q, J = 7.0 ~z, 2~1) 1.30 (t, J = 7.0 ~1z, 311) 1.28 (t, J = 7.0 11z, 3~1) EX~MPLE 7 3.8 g (0.02 mol) of 4-(ethoxycarbonyloxy)thiophen-2(5E1)-one was dissolved in 25 ml of tetrahydrofuran and cooled to -10C. A solution of 2.9 g (0.04 mol) of die-thyl-amine i.n 3S ml of tetrahydrofuran was added thereto. Theprecipitated solid (thiotetronic acid die-thylammonium salt) was filtered off by suction and taken up in 20 ml of water.
It was acidiEied to a pH of l to 2 with concentrated hydro-chloric acid with stirring. The precipita-ted thiote-tronic acid was extracted with 100 ml of ethyl ace-ta-te. '~'he organ-ic phase was dried over Na2SO~ and then the solution was evaporated in a Rotovapor. The res.idue was dried under high vacuum. 2.0 g of -thiotetronic ac.id was o~tained as a nearly white, microcrystalline product with a m.p. of 120 to 122C. ~ri(l~ a content oE 96.9 percen-t (NaO11 titrat.ion).
This corresponc:1ed to l.9 g of l00 percent product or a yield of ~3.6 percent based on the 4-(ethoxycarbonyloxy)thiophen-2(511)-one used.
:
; 35 ~.... .
. ~
~ . ' ' . `~ '' '-. .
-.
Claims (14)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A thiophenone derivative of the general formula:
wherein R is a C1-C8 alkoxycarbonyl group, a halogen- or lower alkyl-substituted or unsubstituted benzyloxycarbonyl group, or a p-toluenesulfonyl group.
wherein R is a C1-C8 alkoxycarbonyl group, a halogen- or lower alkyl-substituted or unsubstituted benzyloxycarbonyl group, or a p-toluenesulfonyl group.
2. 4-(Ethoxycarbonyloxy)thiophen-2(5H)-one of the formula:
3. 4-(Methoxycarbonyloxy)thiophen-2-(5H)-one of the formula:
4. A process for the preparation of a thiophenone derivative of the general formula:
wherein R is a C1 to C8 alkoxycarbonyl group, a benzyloxycarbonyl group optionally suhstituted by halogen or lower alkyl, or a p-toluenesulfonyl group, which comprises reacting 4-chloro-4-chloromethyloxetan-2-one with hydrogen sulfide in the presence of a base and converting the resulting thiotetronic acid intermediate with a chloroformate or p-toluenesulfonyl chloride to obtain the desired end product.
wherein R is a C1 to C8 alkoxycarbonyl group, a benzyloxycarbonyl group optionally suhstituted by halogen or lower alkyl, or a p-toluenesulfonyl group, which comprises reacting 4-chloro-4-chloromethyloxetan-2-one with hydrogen sulfide in the presence of a base and converting the resulting thiotetronic acid intermediate with a chloroformate or p-toluenesulfonyl chloride to obtain the desired end product.
5. A process according to claim 4, wherein a primary amine, a secondary amine, a tertiary amine, ammonia or a guanidine is used as the base.
6. A process according to claim 4, wherein a tertiary amine is used as the base.
7. A process according to claim 4, 5 or 5, wherein the reaction is performed in an inert solvent.
8. A process according to claim 4, 5 or 6, wherein a C1 to C8 alkyl ester or an unsubstituted or halogen- or lower alkyl-substituted benzyl ester of chloroformic acid is used as the chloroformate.
9. A process according to claim 5, wherein the ratio of chloroformate/p-toluenesulfonyl chloride to amine to 4-chloro-4-chloromethyloxetan-2-one employed in the reaction is from 0.8 : 2.8 : 1.0 to 1.0 : 4.0 : 1Ø
10. A process according to claim 9, wherein the ratio of 4-chloro-4-chloromethyloxetan-2-one to hydrogen sulfide is from 1 : 1 to 1 : 3.
11. A process according to claim 4, 5 or 6, wherein the operation is conducted at a temperature within the range of -40° to +20°C.
12. A process according to claim 4, wherein 4-(ethoxycarbonyloxy)-thiophen-2(5H)-one of the formula:
is prepared using ethyl chloroformate as the chloroformate .
is prepared using ethyl chloroformate as the chloroformate .
13. A process according to claim 4, wherein 4-(methoxycarbonyloxy)-thiophen-2(5H)-one of the formula:
is prepared using methyl chloroformate as the chloroformate.
is prepared using methyl chloroformate as the chloroformate.
14. A process according to claim 4, which further comprises converting the thiophenone derivative of the general formula:
wherein R is a C1 to C8 alkoxycarbonyl group, a halogen-or lower alkyl-substituted or unsubstituted benzyloxycarbonyl group, or a p-toluenesulfonyl , into thiotetronic acid.
wherein R is a C1 to C8 alkoxycarbonyl group, a halogen-or lower alkyl-substituted or unsubstituted benzyloxycarbonyl group, or a p-toluenesulfonyl , into thiotetronic acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH2158/85A CH668071A5 (en) | 1985-05-21 | 1985-05-21 | THIOPHENONE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF. |
| CH2158/85 | 1985-05-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1266274A true CA1266274A (en) | 1990-02-27 |
Family
ID=4227236
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000508417A Expired - Fee Related CA1266274A (en) | 1985-05-21 | 1986-05-05 | Thiophenone derivatives and process for their production |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0203495B1 (en) |
| JP (1) | JPH0645616B2 (en) |
| AT (1) | ATE40998T1 (en) |
| CA (1) | CA1266274A (en) |
| CH (1) | CH668071A5 (en) |
| DE (1) | DE3662195D1 (en) |
| DK (1) | DK162641C (en) |
| IE (1) | IE58781B1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69115224T2 (en) * | 1990-05-25 | 1996-05-09 | Mitsubishi Chem Corp | METHOD FOR PARA-METHYLOLATING A PHENOLIC COMPOUND. |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0130025B1 (en) * | 1983-06-21 | 1987-07-08 | Pfizer Inc. | 2-alkylthiopenem derivatives |
-
1985
- 1985-05-21 CH CH2158/85A patent/CH668071A5/en not_active IP Right Cessation
-
1986
- 1986-04-28 IE IE111586A patent/IE58781B1/en not_active IP Right Cessation
- 1986-05-05 CA CA000508417A patent/CA1266274A/en not_active Expired - Fee Related
- 1986-05-16 JP JP61112434A patent/JPH0645616B2/en not_active Expired - Lifetime
- 1986-05-20 DK DK233186A patent/DK162641C/en not_active IP Right Cessation
- 1986-05-20 AT AT86106821T patent/ATE40998T1/en not_active IP Right Cessation
- 1986-05-20 DE DE8686106821T patent/DE3662195D1/en not_active Expired
- 1986-05-20 EP EP86106821A patent/EP0203495B1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ATE40998T1 (en) | 1989-03-15 |
| DK233186A (en) | 1986-11-22 |
| JPH0645616B2 (en) | 1994-06-15 |
| DK162641B (en) | 1991-11-25 |
| CH668071A5 (en) | 1988-11-30 |
| EP0203495A1 (en) | 1986-12-03 |
| DE3662195D1 (en) | 1989-04-06 |
| IE861115L (en) | 1986-11-21 |
| DK233186D0 (en) | 1986-05-20 |
| DK162641C (en) | 1992-05-04 |
| JPS61271285A (en) | 1986-12-01 |
| EP0203495B1 (en) | 1989-03-01 |
| IE58781B1 (en) | 1993-11-17 |
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