CA1110385A - Polymeric activated esters of 3,4-di-hydroxy-2,5- diphenyl-thiophene-1,1-di-oxide - Google Patents
Polymeric activated esters of 3,4-di-hydroxy-2,5- diphenyl-thiophene-1,1-di-oxideInfo
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- CA1110385A CA1110385A CA359,156A CA359156A CA1110385A CA 1110385 A CA1110385 A CA 1110385A CA 359156 A CA359156 A CA 359156A CA 1110385 A CA1110385 A CA 1110385A
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Abstract
ABSTRACT OF THE DISCLOSURE:
The present invention relates to novel polymeric activated esters comprising a compound of the formula (I):
(I)
The present invention relates to novel polymeric activated esters comprising a compound of the formula (I):
(I)
Description
This application is a divisional application of the original Canadian patent application No. 279,418 filed on May 30, 1977.
- . The original application relates to cyclic esters of 3,4-dihydroxy-thiophene-l,l-dioxide and of the corresponding -; cyclopentad-ienone compound, of the general formula (l) . ... . ~, . . ~,~ ~
- ' 'O
~ C ~5 ~ 6~5 ;. : ! 10 O O
:` where X is >~C=O, > C=S or -C-C- and Y is > S02 or > C=O.
Accordingly, the compounds according to the invention . - ~ ~ , .. .
of the original application are 3,4-carbonyldioxy-2,5-diphenyl-thiophene-l,l-d~ioxide, 3,4-thiocarbonyldioxy-2,5-diphenyl-. :~; thiophene-l,l-dioxide and 3j4-(dicarbonyldioxy)-2,5-dlphenyl-~ thiophene-l,l-dioxide, 3,4-carbonyldioxy-2,5-diphenyl-cyclo-:~ : pentadienone, 3,4-thiocarbonyl-2,5-diphenyl-cyclopentadienone ::~. - and 3,4-(dicarbonyldioxy)-2,5 diphenyl-cyclopentadienone.., ~ ,~ ~ ., .
The above compounds may be obtained by reacting a - .
compound of the formula (2) "., .. . -C ~ 6H 5 ~ where Y has the above meanings, with a reactive derivative : s ' of carbonic acid, thiocarbonic acid Gr oxalic acid, in a solvent i and in the presence or ahsence of an acid-binding ~~~` ~
: ~ . ::. :. :,. . , - ,,: ' , - , -.". :,, . .: .' i . ' ' .: .. ... .
: . .
U.Z. 32,03 agent.
; 3,4-Dihydroxy-2,5-diphenyl-thiophene-1,1-dioxide is a known compound and can be obtained in accordance wi-th pro-cesses described in the literature, for example by C. G.
Overberger et al, J. Amer. Chem. Soc. ~, (1950), 2856 or M. Chaykovsky et al, J. Org. Chem. 37. (1972), 2018, whilst 3,4-dihydroxy-2,5-diphenyl-cyclopentadienone can be obtained, for example, by the method described by L. Claisen and Th. Evan, Liebigs Ann. Chem. 284, (1895~, 264.
Preferred reactive derivatives of carbonic acid, thio-sarbonic acid or oxalic acid are the acid chlorides, such as phosgene, thiophosgene or oxalyl chloride. However, com-- pounds such as, for example, carbonyldiimidazole can also be ~ used~ -j Advantageous solvents to use are aprotic solvents which are inert under the reaction conditions, dialkyl ethers, eg.
diethyl ether, ~aturated cyclic aliphatic ethers, for example tetrahydro~uran and dioxane,aromatic hydrocarbons, eg. toluene and benæene, chlorinated aliphatic hydrocarbons, eg. methy-20 lene chloride or chloroform,and mlxtures of the said solvents. ;~
The reaction ~ith an acid chloride can be carried out in the conventional manner in the presence of an acid-binding agent.- In particular, aliphatic or cyclic tertiary amines, eg. pyridine or triethylamine, may be used for this purpose.
However, it is particularly advantageous to carry out the reaction without added amine, since it is then unnecessary to remove the amine hydrochloride formed. Under these con-ditions) the oxalyl chloride reacts sufficiently rapidly even ,, , , ~
, -- c - ~
; .
: " .
o.Z. 32,036 at room temperature, whils-t phosgene and thiophosgene may require somewhat longer reaction times or elevated temperatures and/or supera-tmospheric pressure.
In the presence of an acid~binding amine, the reac-tion is generally carried out by dissolving the starting compound of the ~ormula (2) in, for example, anhydrous tetrahydrofuran and adding a tertiary amine, eg. pyridine, in an amount equivalent to the acid chloride used, or in excess, The lacid chloride is then added slowly, advantageously as a solution in a solvent.
If no a~ine is added, the procedure followed is, for example in the case~of the reaction ~ith oxalyl chloride, to - boil the appropriate-starting compound ~rith the oxalyl chloride in anhydrous tetrahydrofuran under reflu~. With phosgene, quanti-tative con~ersion is advantageously achieved at elevated temperatures in an autoclave.
It is advisable to use the acid chloride in excess, wi-th a ra-tio of from 1 : 1.2 to l : 2~5~ -In general, the reactions are carried out with solutions of from 5 to ~0%
strength by weight. - -~ he reactions are carried out at room tempera-ture or elevated temperatures up to the boiling point of the solvent used. Advantageous temperatures are from 30 -to 150C.
In a particularly advantageous embodiment, the reaction is carried out in a closed vessel; in this case, temperatures of from 60 to 100C are preferred~
Where necessary, the ~mi~e hydrochloride which has pre-cipitated is filtered off after completion of the reaction, .
, . .
?Q38S
.
O.Z0 32,036 ~ !
and the reaction solution is concentrated by distilling off the solvent, if necessary under reduced pressure, to cause the product to crystallize. This distillation also removes unconverted acid chloride. If desired, the acid chloride, especially phosgene, can also be removed before the distillation~
by passing a stream of a dry inert gas, eg. nitrogen, into the mixt~re. As a rule, the solution whlch has been con-centrated ls again filtered~and, if necessary, the fil-trate i~ concentrated ~urther until the desired cyclic es-ter begins ~,~
10 to crystallize. The compounds according to the invention -can in general be obtained in a c~ystalllne form, in yields of more than 70%, by then lea~ing the product to stand at from O to 25G.
However, it is also possible to distil off the solvent virtually completely after the reaction has ended, and to ~reat the residue with ~rater to remove the amine hydrochloride, -~
in whlch case the desired cycllc ester ls obtained pure as the residue after a treatment with, for example, acetone/ether. ;~
, ~ -~ m is procedure is particularly suitable ~or the thio-:-~20 carbonyl compounds which are less prone to hydrolyze.
If no acid-binding organic amine has been added, it can `
.
be particularly advantageous to remove the solvent and excess ;
acid chloride by distillation after completion of -the reaction.
The compounds according to the invention are obtained in a high pUlity and can be used, without additional purificatio~
measures (such as recrystallization or extractive boiling with a suitable solvent), as intermediates for further reactions~
The compounds according to the invention are doubly , _ ~ , , . . '~ . , '' .... .... ' : .
.
. O.Z. 32,o36 activated esters and are of importance as highly reactive intermediates which can undergo a diversity of reactions.
Since they undergo substantially the same reaction3 as phosgene, thiophosgene and oxalyl chloride, -they can be used in place of phosgene, thlophosgene and o~alyl chloride as crystalline compounds which are exceptionally suitable ~or measuring out accurately and exceptionally easy to handle.
.
Accordingly, the compounds of the invention can be used as I~solid~ phosgene, thiophosgene or oxalyl chloride and have the further particular advantage that -they are non-toxic.
Reactions of phosgene which the compounds according to the ir~vention also undergo may be found, for example, in the review article in Chem. Reviews, I~ (1973), 75 et seqO
rne reactions of 3,4-carbonyl-dioxy-2,5-diphenyl-thiophene-l,l-dioxide wlth one equivalent of a nucleophilic agent, eg. an amine, alcohol, phenol or carboxylic acid9 pro-duce activated intermediates which ~Ihen reacted, ~ith or wi-thou~
isolation, with a further equivalent of the above-compounds, give ureas, urethanes, esters or amides. At the same time the starting compound, namely 3,4-dihydroxy-2p5-diphenyl-thiophene-l,l-dioxide or -cyclopentadienone~ is formed, ~Ihich can easily be removed from the reaction mixtures by corlverting it to a salt with aqueous sodium bicarbonate solu-tion or some other alkali metal base or alkaline ear-th metal base, and can be recovered by acidification and reconverted to an activated derivative.
The reac-tion with amines, alcohols and phenols can be represented by the following equation:
~ 5 -, .
3~35 O.Z, 32,036 , 0~ X-Z~ x-z'~+~2) ~G~5 C6~5 C6H5 C6~5 .
.'''' ' ' ' ' ~ ~
In the equation, X and Y have the above meanings and Z or ZH ~
is a nucleophilic structure. ~ ~-i For example~ -the reaction of 3,4-carbonyldioxy-2~5 diphenylthiophene~ dioxide with 2 moles of aniline in tetrahydrofuran gives a 9~/0 yield o~ diphenylurea.
This reaction can be modified by carrying it ou-t with ~ one mole o~ anillne and reacting the intermediate first formed -(without having to isolate it), with one mole of another pri-mary or secondary amine, eg. diethylamine, so that unsymmetrically substltuted urea compounds, eg. N,N-diethyl-N9-phenyl-urea, are obtained. - `
- Similar reactions~with alcohols, eg. benzyl alcohol,in - tetrahydrofuran at~room temperature, followed by reaction with an amine or an aminoacid ester, eg. ~-valine tert.-butyl ester, give the corresponding urethane compounds. As is shown in ~ ~-the example, virtually quantitative yields are obtained.
The reaction o~ 3,4-(dicarbonyldioxy)-2,5-diphenyl-thiophene-l,l-dioxide with 2 moles of benzylamine gives a 90~o yield of oxallc acid dibenzylamide. The step~ise reactio~, 20 similar to the manu~acture of unsymmetrically substituted ~ ~ ;
ureas, gives mixed oxalyldiamides, which can virtually not be prepared by other methods.
The reaction of 3,4-carbonyldioxy-2,~diphenyl-thio-phene~ dioxyde with pyrocatechol in tetrahydrofuran gives pyrocatechol carbonate, which is a known compoundl in a -simple manner and in high yields, even at room temperature.
Reactions with carboxylic acids are of particular ` importance; in these, the intermediate obtained can be used as a reactive compound for transEerring acyl radicals.
Accordingly, the compounds of the formula (1) provide a new activating agent for peptide syntheses.
10 An acyl transfer reaction can be represented by the following equation:
C~ ~ /OCOR
~ ~ R- COOH ~ J~ \~ R'NH~ ~ R. CONH-R' + (2) J/ ~ pyridine / C6H5 C6H5 base 6H5 C6H5 (3) 3,4-Carbonyldioxy-2,5-diphenyl-thiophene~ dioxide is reacted with a carboxylic acid to give the mixed anhydride of a vinylogous sulfonic acid of the formula (3), hereinafter also referred to as the activated ester. The activated esters of the formula t3) are readily crystallized, stable compounds -~
which, for example, rapidly react with a primary or secondary amine, advantageously in the presence of tertiary amines, eg.
pyridine or triethylamine, to give the corresponding amide.
It is particularly advantageous that on addition of the amine the activated esters form orange-red anions~ the disappearance of which, accompanied by a change of color to pale yellow, ..
~ .
. ..
-- - ;
~ -7-3~35 . .
O.Z. 32,036 , ~
indicates -the end of the reaction. The sulfone starting material of the formula (23, ~orrned alongside the amide, can easily be removed by extraction by shaking with aqueous bicarbonate. However 7 the acyl transfer reactions can also be carried out as one-vessel reactions, without isolating the activated esters. ;
The reaction o~ a compound according to the invention, -~
of the ~ormula (1), with a carboxylic acid is advantageousiy earried out in an anhydrous aprotic solvent in the presene~
of a tertiary organic amine. The resulting mixed anhydrid~
of the formula (3) reacts extremely well as an acyl transfer agent under mild reaction conditions, giving excellent yields;
for exampla it can be used for react:ion with aminQacid esters, for the manufacture of peptides.
Simple esters of 3,4-dihydro~y-2,5 diphenylthiophene~ dioxide, corresponding -to the formula (3), for éxample 2,5-diphenyl-3-keto-4-propionyloxy-2,3 dihydrothiophene-l,l-dioxide, can also be manufactured by a conventional acylating method.
However, t~e surprising advantage, to be singled out particularly, of the reaction of a compound of the invention, of the formula (1), with a carboxylic acid resides in the ~ac~ ~-that dicyclohexylcarbodiimide (DCC) is not required for the -~
manufacture of the activated ester of the formula (33. The eom-.
pounds of the ~ormula (3~ are obtained in a readily crystal~
lized and therefore very pure form and ~re relatively stable on storage. The high reactivity permits the synthesis o~
steri~ally ~lindered peptides wh`ich can only be obtained with ;` . 3L~.~3~5 .
o.z. ~2,o36 .
great difficulty, if at all, by other methods. For example, the dipeptides described in German Publlshed Application DAS
1,936,159, which are used as sweeteners, and the carboxyl~c acid amides described in German Published Application DAS
- . The original application relates to cyclic esters of 3,4-dihydroxy-thiophene-l,l-dioxide and of the corresponding -; cyclopentad-ienone compound, of the general formula (l) . ... . ~, . . ~,~ ~
- ' 'O
~ C ~5 ~ 6~5 ;. : ! 10 O O
:` where X is >~C=O, > C=S or -C-C- and Y is > S02 or > C=O.
Accordingly, the compounds according to the invention . - ~ ~ , .. .
of the original application are 3,4-carbonyldioxy-2,5-diphenyl-thiophene-l,l-d~ioxide, 3,4-thiocarbonyldioxy-2,5-diphenyl-. :~; thiophene-l,l-dioxide and 3j4-(dicarbonyldioxy)-2,5-dlphenyl-~ thiophene-l,l-dioxide, 3,4-carbonyldioxy-2,5-diphenyl-cyclo-:~ : pentadienone, 3,4-thiocarbonyl-2,5-diphenyl-cyclopentadienone ::~. - and 3,4-(dicarbonyldioxy)-2,5 diphenyl-cyclopentadienone.., ~ ,~ ~ ., .
The above compounds may be obtained by reacting a - .
compound of the formula (2) "., .. . -C ~ 6H 5 ~ where Y has the above meanings, with a reactive derivative : s ' of carbonic acid, thiocarbonic acid Gr oxalic acid, in a solvent i and in the presence or ahsence of an acid-binding ~~~` ~
: ~ . ::. :. :,. . , - ,,: ' , - , -.". :,, . .: .' i . ' ' .: .. ... .
: . .
U.Z. 32,03 agent.
; 3,4-Dihydroxy-2,5-diphenyl-thiophene-1,1-dioxide is a known compound and can be obtained in accordance wi-th pro-cesses described in the literature, for example by C. G.
Overberger et al, J. Amer. Chem. Soc. ~, (1950), 2856 or M. Chaykovsky et al, J. Org. Chem. 37. (1972), 2018, whilst 3,4-dihydroxy-2,5-diphenyl-cyclopentadienone can be obtained, for example, by the method described by L. Claisen and Th. Evan, Liebigs Ann. Chem. 284, (1895~, 264.
Preferred reactive derivatives of carbonic acid, thio-sarbonic acid or oxalic acid are the acid chlorides, such as phosgene, thiophosgene or oxalyl chloride. However, com-- pounds such as, for example, carbonyldiimidazole can also be ~ used~ -j Advantageous solvents to use are aprotic solvents which are inert under the reaction conditions, dialkyl ethers, eg.
diethyl ether, ~aturated cyclic aliphatic ethers, for example tetrahydro~uran and dioxane,aromatic hydrocarbons, eg. toluene and benæene, chlorinated aliphatic hydrocarbons, eg. methy-20 lene chloride or chloroform,and mlxtures of the said solvents. ;~
The reaction ~ith an acid chloride can be carried out in the conventional manner in the presence of an acid-binding agent.- In particular, aliphatic or cyclic tertiary amines, eg. pyridine or triethylamine, may be used for this purpose.
However, it is particularly advantageous to carry out the reaction without added amine, since it is then unnecessary to remove the amine hydrochloride formed. Under these con-ditions) the oxalyl chloride reacts sufficiently rapidly even ,, , , ~
, -- c - ~
; .
: " .
o.Z. 32,036 at room temperature, whils-t phosgene and thiophosgene may require somewhat longer reaction times or elevated temperatures and/or supera-tmospheric pressure.
In the presence of an acid~binding amine, the reac-tion is generally carried out by dissolving the starting compound of the ~ormula (2) in, for example, anhydrous tetrahydrofuran and adding a tertiary amine, eg. pyridine, in an amount equivalent to the acid chloride used, or in excess, The lacid chloride is then added slowly, advantageously as a solution in a solvent.
If no a~ine is added, the procedure followed is, for example in the case~of the reaction ~ith oxalyl chloride, to - boil the appropriate-starting compound ~rith the oxalyl chloride in anhydrous tetrahydrofuran under reflu~. With phosgene, quanti-tative con~ersion is advantageously achieved at elevated temperatures in an autoclave.
It is advisable to use the acid chloride in excess, wi-th a ra-tio of from 1 : 1.2 to l : 2~5~ -In general, the reactions are carried out with solutions of from 5 to ~0%
strength by weight. - -~ he reactions are carried out at room tempera-ture or elevated temperatures up to the boiling point of the solvent used. Advantageous temperatures are from 30 -to 150C.
In a particularly advantageous embodiment, the reaction is carried out in a closed vessel; in this case, temperatures of from 60 to 100C are preferred~
Where necessary, the ~mi~e hydrochloride which has pre-cipitated is filtered off after completion of the reaction, .
, . .
?Q38S
.
O.Z0 32,036 ~ !
and the reaction solution is concentrated by distilling off the solvent, if necessary under reduced pressure, to cause the product to crystallize. This distillation also removes unconverted acid chloride. If desired, the acid chloride, especially phosgene, can also be removed before the distillation~
by passing a stream of a dry inert gas, eg. nitrogen, into the mixt~re. As a rule, the solution whlch has been con-centrated ls again filtered~and, if necessary, the fil-trate i~ concentrated ~urther until the desired cyclic es-ter begins ~,~
10 to crystallize. The compounds according to the invention -can in general be obtained in a c~ystalllne form, in yields of more than 70%, by then lea~ing the product to stand at from O to 25G.
However, it is also possible to distil off the solvent virtually completely after the reaction has ended, and to ~reat the residue with ~rater to remove the amine hydrochloride, -~
in whlch case the desired cycllc ester ls obtained pure as the residue after a treatment with, for example, acetone/ether. ;~
, ~ -~ m is procedure is particularly suitable ~or the thio-:-~20 carbonyl compounds which are less prone to hydrolyze.
If no acid-binding organic amine has been added, it can `
.
be particularly advantageous to remove the solvent and excess ;
acid chloride by distillation after completion of -the reaction.
The compounds according to the invention are obtained in a high pUlity and can be used, without additional purificatio~
measures (such as recrystallization or extractive boiling with a suitable solvent), as intermediates for further reactions~
The compounds according to the invention are doubly , _ ~ , , . . '~ . , '' .... .... ' : .
.
. O.Z. 32,o36 activated esters and are of importance as highly reactive intermediates which can undergo a diversity of reactions.
Since they undergo substantially the same reaction3 as phosgene, thiophosgene and oxalyl chloride, -they can be used in place of phosgene, thlophosgene and o~alyl chloride as crystalline compounds which are exceptionally suitable ~or measuring out accurately and exceptionally easy to handle.
.
Accordingly, the compounds of the invention can be used as I~solid~ phosgene, thiophosgene or oxalyl chloride and have the further particular advantage that -they are non-toxic.
Reactions of phosgene which the compounds according to the ir~vention also undergo may be found, for example, in the review article in Chem. Reviews, I~ (1973), 75 et seqO
rne reactions of 3,4-carbonyl-dioxy-2,5-diphenyl-thiophene-l,l-dioxide wlth one equivalent of a nucleophilic agent, eg. an amine, alcohol, phenol or carboxylic acid9 pro-duce activated intermediates which ~Ihen reacted, ~ith or wi-thou~
isolation, with a further equivalent of the above-compounds, give ureas, urethanes, esters or amides. At the same time the starting compound, namely 3,4-dihydroxy-2p5-diphenyl-thiophene-l,l-dioxide or -cyclopentadienone~ is formed, ~Ihich can easily be removed from the reaction mixtures by corlverting it to a salt with aqueous sodium bicarbonate solu-tion or some other alkali metal base or alkaline ear-th metal base, and can be recovered by acidification and reconverted to an activated derivative.
The reac-tion with amines, alcohols and phenols can be represented by the following equation:
~ 5 -, .
3~35 O.Z, 32,036 , 0~ X-Z~ x-z'~+~2) ~G~5 C6~5 C6H5 C6~5 .
.'''' ' ' ' ' ~ ~
In the equation, X and Y have the above meanings and Z or ZH ~
is a nucleophilic structure. ~ ~-i For example~ -the reaction of 3,4-carbonyldioxy-2~5 diphenylthiophene~ dioxide with 2 moles of aniline in tetrahydrofuran gives a 9~/0 yield o~ diphenylurea.
This reaction can be modified by carrying it ou-t with ~ one mole o~ anillne and reacting the intermediate first formed -(without having to isolate it), with one mole of another pri-mary or secondary amine, eg. diethylamine, so that unsymmetrically substltuted urea compounds, eg. N,N-diethyl-N9-phenyl-urea, are obtained. - `
- Similar reactions~with alcohols, eg. benzyl alcohol,in - tetrahydrofuran at~room temperature, followed by reaction with an amine or an aminoacid ester, eg. ~-valine tert.-butyl ester, give the corresponding urethane compounds. As is shown in ~ ~-the example, virtually quantitative yields are obtained.
The reaction o~ 3,4-(dicarbonyldioxy)-2,5-diphenyl-thiophene-l,l-dioxide with 2 moles of benzylamine gives a 90~o yield of oxallc acid dibenzylamide. The step~ise reactio~, 20 similar to the manu~acture of unsymmetrically substituted ~ ~ ;
ureas, gives mixed oxalyldiamides, which can virtually not be prepared by other methods.
The reaction of 3,4-carbonyldioxy-2,~diphenyl-thio-phene~ dioxyde with pyrocatechol in tetrahydrofuran gives pyrocatechol carbonate, which is a known compoundl in a -simple manner and in high yields, even at room temperature.
Reactions with carboxylic acids are of particular ` importance; in these, the intermediate obtained can be used as a reactive compound for transEerring acyl radicals.
Accordingly, the compounds of the formula (1) provide a new activating agent for peptide syntheses.
10 An acyl transfer reaction can be represented by the following equation:
C~ ~ /OCOR
~ ~ R- COOH ~ J~ \~ R'NH~ ~ R. CONH-R' + (2) J/ ~ pyridine / C6H5 C6H5 base 6H5 C6H5 (3) 3,4-Carbonyldioxy-2,5-diphenyl-thiophene~ dioxide is reacted with a carboxylic acid to give the mixed anhydride of a vinylogous sulfonic acid of the formula (3), hereinafter also referred to as the activated ester. The activated esters of the formula t3) are readily crystallized, stable compounds -~
which, for example, rapidly react with a primary or secondary amine, advantageously in the presence of tertiary amines, eg.
pyridine or triethylamine, to give the corresponding amide.
It is particularly advantageous that on addition of the amine the activated esters form orange-red anions~ the disappearance of which, accompanied by a change of color to pale yellow, ..
~ .
. ..
-- - ;
~ -7-3~35 . .
O.Z. 32,036 , ~
indicates -the end of the reaction. The sulfone starting material of the formula (23, ~orrned alongside the amide, can easily be removed by extraction by shaking with aqueous bicarbonate. However 7 the acyl transfer reactions can also be carried out as one-vessel reactions, without isolating the activated esters. ;
The reaction o~ a compound according to the invention, -~
of the ~ormula (1), with a carboxylic acid is advantageousiy earried out in an anhydrous aprotic solvent in the presene~
of a tertiary organic amine. The resulting mixed anhydrid~
of the formula (3) reacts extremely well as an acyl transfer agent under mild reaction conditions, giving excellent yields;
for exampla it can be used for react:ion with aminQacid esters, for the manufacture of peptides.
Simple esters of 3,4-dihydro~y-2,5 diphenylthiophene~ dioxide, corresponding -to the formula (3), for éxample 2,5-diphenyl-3-keto-4-propionyloxy-2,3 dihydrothiophene-l,l-dioxide, can also be manufactured by a conventional acylating method.
However, t~e surprising advantage, to be singled out particularly, of the reaction of a compound of the invention, of the formula (1), with a carboxylic acid resides in the ~ac~ ~-that dicyclohexylcarbodiimide (DCC) is not required for the -~
manufacture of the activated ester of the formula (33. The eom-.
pounds of the ~ormula (3~ are obtained in a readily crystal~
lized and therefore very pure form and ~re relatively stable on storage. The high reactivity permits the synthesis o~
steri~ally ~lindered peptides wh`ich can only be obtained with ;` . 3L~.~3~5 .
o.z. ~2,o36 .
great difficulty, if at all, by other methods. For example, the dipeptides described in German Publlshed Application DAS
1,936,159, which are used as sweeteners, and the carboxyl~c acid amides described in German Published Application DAS
2,307,263 can readily be manufactured with the aid of the com-pounds according to the invention. Furthermore, the use o~
the compounds according to the invention as intermediates opens up a new method of synthesis of antamanide, a cyclic decapeptide obtained from the L-aminoacids alanine, phenyl-alanine, prollne and valine. Antamanide is a consti-tuent of -the d~ea~h cup Amànita phalloides.
~ y reacting an activated ester of the formula (3) with an o-nitrophenol it is possible to prepare, for example, the o-nitrophenyl esters which are frequentiy difficult to obtain by usin~ DCC; this react1on is sho~nl by the following equation:
the compounds according to the invention as intermediates opens up a new method of synthesis of antamanide, a cyclic decapeptide obtained from the L-aminoacids alanine, phenyl-alanine, prollne and valine. Antamanide is a consti-tuent of -the d~ea~h cup Amànita phalloides.
~ y reacting an activated ester of the formula (3) with an o-nitrophenol it is possible to prepare, for example, the o-nitrophenyl esters which are frequentiy difficult to obtain by usin~ DCC; this react1on is sho~nl by the following equation:
(3) ~ H ~v~ i g NO ~ t (2~
As disclosed in the literature, eg. J. Org. Chemistry ~, (1973), 3565 et seq., or J. Amer. Chem. Soc. 96, (1974), 2234, the o-nitrophenyl esters may be used for further reactions.
~0 The activated es-ters of type (3) react with alcohols, and also with phenols, thiophenols or mercaptans, to form esters. For example, activated propionic acid and benzyl alcohol in tetrahydrofuran, in the presence of triethylamine, _ 9 ~
:, . , ;"
.. ..
. ~............ .
give a very good yield of benzyl propionate.
The formation of cyclic carbonates from 3,4-carbonyl-dioxy-2,5-diphenyl-thiophene-1,1-dioxide and an o-diphenol, for example pyrocatechol, to give the carbonyldioxy compound of pyrocatechol, should also be mentioned:
A further possible use of the compounds is as dehydra-tin~ agents. For example, the oximes of aromatic aldehydes are smoothly converted to the corresponding nitriles.
The Examples further show that the corresponding iso-cyanates can be obtained from the reaction product of a cyclic ~ -carbonate of the formula I with a primary amine. -~;
The novel cyclic esters can also be prepared on poly-meric carriers. Since they undergo the same reactions as phosgene, thiophosgene and oxalyl chloride and since the poly-meric material can easily be reactivated, the advantages over, for example, carbodiimides on the same polymer are self-evident. ;
As far as peptide chemistry is concerned, this ap- ~;
~plication relates to novel polymeric activated esters which 20 ~ are distinguished by a high reactivity and by their ability ~ i to form a salt with the amine component. ~-In thi-s context it is particularly advan~ageous that the manufacture of the polymeric activated esters does not require any dicyclohexylcarbodiimide, so that it is unnecessary to elute the urea which is formed when dicyclohexylcarbodiimide is employed. The ~ proportion of activated ester lies within the ranges which have been disclosed or other polymeric activated esters.
To manufacture the polymeric cyclic esters it is possible to start, for example, from commercial Merrifield , resin,(l) which is reacted with benzylmercaptan in the presence of a base. The further steps are then carried out under similar .
.. :
.
conditions to those which apply in the case of the monomeric compounds.
The following examples illustrate the various aspects of the original and divisional applications but are not intended to limit it.
3,4-Carbonyldioxy-2,5-diphenyl-thiophene~ dioxide a) Without the addition of an amine lO g of 4-hydroxy-3-oxo-2j5-diphenyl-2,3-dihydrothio-phene~ dioxide and 50 ml of a 20% strength by weight solution of phosgene in tetrahydrofuran are heated at 80C in an awtoclave for 24 hours. The solvent and excess phosgene are then distilled off and pure 3,4-carbonyldioxy-2,5-thiophene-l,l-dioxide is - obtained as the residue.
b) With the additlon o an amine lO0 ml of a 20% strength by wei~ht solution of phosgene in toluene ~0~ mole) are added dropwise at 20C to 30 g of
As disclosed in the literature, eg. J. Org. Chemistry ~, (1973), 3565 et seq., or J. Amer. Chem. Soc. 96, (1974), 2234, the o-nitrophenyl esters may be used for further reactions.
~0 The activated es-ters of type (3) react with alcohols, and also with phenols, thiophenols or mercaptans, to form esters. For example, activated propionic acid and benzyl alcohol in tetrahydrofuran, in the presence of triethylamine, _ 9 ~
:, . , ;"
.. ..
. ~............ .
give a very good yield of benzyl propionate.
The formation of cyclic carbonates from 3,4-carbonyl-dioxy-2,5-diphenyl-thiophene-1,1-dioxide and an o-diphenol, for example pyrocatechol, to give the carbonyldioxy compound of pyrocatechol, should also be mentioned:
A further possible use of the compounds is as dehydra-tin~ agents. For example, the oximes of aromatic aldehydes are smoothly converted to the corresponding nitriles.
The Examples further show that the corresponding iso-cyanates can be obtained from the reaction product of a cyclic ~ -carbonate of the formula I with a primary amine. -~;
The novel cyclic esters can also be prepared on poly-meric carriers. Since they undergo the same reactions as phosgene, thiophosgene and oxalyl chloride and since the poly-meric material can easily be reactivated, the advantages over, for example, carbodiimides on the same polymer are self-evident. ;
As far as peptide chemistry is concerned, this ap- ~;
~plication relates to novel polymeric activated esters which 20 ~ are distinguished by a high reactivity and by their ability ~ i to form a salt with the amine component. ~-In thi-s context it is particularly advan~ageous that the manufacture of the polymeric activated esters does not require any dicyclohexylcarbodiimide, so that it is unnecessary to elute the urea which is formed when dicyclohexylcarbodiimide is employed. The ~ proportion of activated ester lies within the ranges which have been disclosed or other polymeric activated esters.
To manufacture the polymeric cyclic esters it is possible to start, for example, from commercial Merrifield , resin,(l) which is reacted with benzylmercaptan in the presence of a base. The further steps are then carried out under similar .
.. :
.
conditions to those which apply in the case of the monomeric compounds.
The following examples illustrate the various aspects of the original and divisional applications but are not intended to limit it.
3,4-Carbonyldioxy-2,5-diphenyl-thiophene~ dioxide a) Without the addition of an amine lO g of 4-hydroxy-3-oxo-2j5-diphenyl-2,3-dihydrothio-phene~ dioxide and 50 ml of a 20% strength by weight solution of phosgene in tetrahydrofuran are heated at 80C in an awtoclave for 24 hours. The solvent and excess phosgene are then distilled off and pure 3,4-carbonyldioxy-2,5-thiophene-l,l-dioxide is - obtained as the residue.
b) With the additlon o an amine lO0 ml of a 20% strength by wei~ht solution of phosgene in toluene ~0~ mole) are added dropwise at 20C to 30 g of
4-hydroxy-3-oxo~2,5-diphenyl-2,3-dihydrothiophene-1,1-dioxide and 17 ml of pyridine in 600 ml of dry tetrahydrofuran, whilst stir-ring vigorously. After one hour thepyridine hydrochloride which - has precipitated is filtered of and the filtrate is freed fromexcess phosgene, using a stream o dry nitrogen, and concentrated under reduced pressure to two-thirds oE the original volume. It . .
is filtered again and the filtrate is concentrated until-3,4-carbo-nyldioxy-2,5-diphenylthiophene-1,1-dioxide crystallizes. After standing overnight at 0C, 24 g, that is to say a73% yield, of yellow-green fluorescent small needles (1) (everyone up to every tenth of the aromatic rings is chloro-methylated, which is approximately equivalent to 0.43 to 2063 moles of Cl/g ~J. Am. Chem. Soc. 85, 2149-2152 (1963)7J. ' ~' . .
:: , . .... .
. .
, o.Z. 32,036 ,, ' which decompose a-t 250C are obtainedc C17HlOOsS (326.3) Calculated: C 62.57 H 3.09 Found: 62,51 3.15 4-Hydroxy 3-oxo-2,5-diphenyl-2,3-dihydrc-thiophene~
- dioxide is recovered by adding sodium hydroxide solution to tne '~
residue"obtained after evaporation of the mother liquor, filtering the mix-ture and acidifying the'filtrate.
;~ EXAMPLE 3 103J4-(Dicarbonyldioxy)-2,5~diphenylthiophene-1,1-dioxide ' :~
; ,~ g of 3 hydroxy-4-oxo-2~5-diphenyl-2,5-dihydrothiophene~
l,l-dioxide, 40 ml of tetrahydrofuran and 5 ml of oxalyl chloride '~' are boiled under re~lux for 2 hours. After filtering the ~ ' reaction mixture and distilling off the tetrahydrofuran, 6.~ g~
that is to say 96% of theory, of the activated oxalate are obtained r~ue. ~his is a yellQw powder the color of egg yolk and decomposes at 245 to 250C.
C18Hl0o6s (3S4-3) Calculated: C 61.01 H 2.85 ; -' 20 Found- 61.00 2.86 -4-Car~onyldioxy-2,5-diphenyl-cyclopentadienone 40 ml of a 20% strength by weight solution of phos~ene in t,oluene are added to 10 g of 4-hydroxy-2,5-diphenyl-4-cyclopentene-1,3-dione 'and 6 g of pyridine in 150 ml of dry tetrahydrofuran.
~fter stirring the mixture for two hours, the pyridine hydro- ;
chloride ~hich has precipit~ted is filtered off. The dark r'ed filtrate is concentrated and 10.5 g (96%) of pure 3,4 .
....
f carbonyldioxy-2,5-diphenyl-cyclope~tadieno~e are obtalned in the form of black-violet cryStals which slowly decompose at above 100C~
C18~l04 (290 3) Calculated:C 74.46H 3.47 Found: 74.47 3 99 3,4-Thiocarbonyldioxy-2,5-diphenylthiophene-l,l-dioxide 6,5 ml of pyridine are added dropwise to 12 g of 3-hydroxy-4-oxo-2,5-diphenyl-2,3-dihydrothiophene l,l-dioxide in 150 ml of dry tetrahydrofuran. 4.55 ml of thiophosgene are then added, whilst cooling with ice and stirring.
- After the mixture has been left to stand for 90 minutes, the tetrahydro~uran and unconverted thiophosgene are distilled off, the residue is digested with 300 ~l of ice water and the precipitate is filtered off and washed several times with water. The filter cake is dried in air. The yield is 11.5 g of crude product and, after boiling thoroughly with acetone~
ether (103, volume/volume) this gi~es 10.1 g, that is to say 75% of theory, of the thiocarbonate in analytical purity.
This is a greenish yellow powder which decomposes at above 240C, becomes solid again and melts again at about 290C.
Cl7Hl0O4S2 (342.4) Calculated: C 59.64 H 2.94 Found: 60.04 2.85 B. EXAMPLES OF REACTIONS WITH THE COMPOUNDS ACCORDING TO THE
INVENTION
Examplcs of t~le prepara~ion of ureas N,N-Diphenylurea __ _ ___ _ _, ~ _ ,,, _ _ . _ ~ -13-.
- O.Z. 32,o36 :
3 26 g of 3,4-carbonyldioxy-2,5-diphenylthiophene~
dioxide in 25 ml of dry tetrahydrofuran are left to stand wi-th 1 86 g of aniline for 30 minutes and during the initial perio~ an exothermic reaction takes place. After the reaction has ended, the mixture is par-titioned between ether and aqueous lN
sodium hydroxide solution and the organic phase is washed with water and dried over magnesium sulfate The yield ~s - , ~.
2 02 g, that is to say 960/o of theory and the melting point is ;
244 _ 247C (melting point quoted in the literature 235 _ 239.5C).
.
N,N-Diethyl-Nt~phenylurea 0 93 g o~ aniline is added to 3.26 g of 2,4~carbonyl-dioxy-2,5-diphenylthiophene~ dioxide in 25 ml of dry tetra~
hydrofuran. The mixture is le~t to stand ~or 30 minutes at 20C, 0.73 g of diethylamine is added and the mixture is ~eft to stand for a further 40 minutes ~fter distilllng off the tetrahydrofuran, t~e residue is taken up in chloroform and the r chloroform solution is washed successively with aqueous lN
hydrochloric acid and twice with aqueous sodium carbonate solu-tion ~-~
and water. After drying over magnesium sulfate and evaporatin~
wlder reduced pressure, 1.4 g of slightly yellowish crystals which~
as the crude product, have a melting point of 81 - 85C (melting point quoted in the li-tera-ture 85C) remain.
Examples of fu~ther unsymmetrically substituted urea com-pounds which are prepared in the indicated manner with the aid of 2~4-carbonyldioxy~2,~-diphenylthiophene-1,1-dioxide are: N-(2-benzthiazolyl)-N'-methylurea, N-phenyl-NJ'-(2-methyl-cyclohexyl) urea, N-(~-tri~luoromethyl-phenyl)-N',N'-dimethyl~urea, N-cyclo-... .
.
.
O.Z. 32,o36 octyl-N',N'-dimethylurea, N-4-fluorophenyl-N~-carboxymethoxy-N~-methyl-urea and N-(4-chlorophenyl)-N7-methyl-N~-tbutyn-l-yl)-urea~
The mel-ting points obtained for these compounds when they ar'e prepared in the above way correspond to the melting points quoted in the literature, Example of the preparat'ion o~ a urethane . .
' N-Benzyloxycarbonyl-L-valine tert.-butyl ester a~ -Activated carbonic acid benzyl ester 3,26 g of 2,4-carbonyldioxy-2,5-diphenylthiophene~
'10 dioxide and 1.08 g of benzyl alcohol are left to stand in 40 ml of dry tetrahydrofur&n for 12 hours at 20C. During this time the intermediate product of ~ormula (3) precipitates. The tetrahydrofuran is dis-tilled o~f and the residue is washed with ,, ether. The yield is ~.95 g, that is to say 95~0 of theory~
, and the melting point 1695, The ~R spectrum shows only t~e expected .signals. ' ' ;~ b) N-Benzyloxycarbonyl-L-valine tert.-butyl ester ,, ,; 2.1 g of the compound obtained as described in a) are 5US - - ;' -pended in 300 ml of tetrahydrofuran and O.90 g of Val-OBut, 1 ml of , ,~ 20 . pyridine and 0,5 ml of triethylamine are added, The red coloration ; ~ changes to yellow a~ter about 30 minutes. The mixture is - , left ~o stand for a further ~0 minutes and worked up by the me-thod described in the exarnple for N,N-diethyl-N'-phenylurea. ~, The yield is 1.51 g, that is to say 99% of theory, of an oil, which ~;
~ on exarnination by N.~ shows only the signals o~ the 'expected ; product.
Example o~ the preparation of an oxalic acid diamide ,~
Oxalic acid dibenzylamide -3.54 g o~ 3,4-(dicarbonyldioxy)-2,5-diphenylthiophene-s :
O.Z. 32,0~6 .' , " ~
l,l~dioxide and 2.4 g of dibenzylamine in 50 ml of dry tetra-hydrofuran are s-tirred at room temperature for 1 hour. After working up in the conventional rnanner, 2;55 g (94%) of oxalic acid dibenzylamide are obtained.
Example o~ the preparation of an es-ter Benzyl propionate:
a) Activated propionic acid ester ~.
i 10 g o~ 4 hydroxy-3-oxo-2,5-diphenyI-2,3-dihydrothiophene-~ l;l dioxide and 2.62 e of pyridine are dissolved in 100 ml o~
tetrahydrofuran. 3.06 g of propionyl chloride in 50 ml of ~tetrahydrofuran are added to this solution. After stirring ~or two hours at room temperature, the solvent is strlpped off~ ;~
the residue is taken up in chloroform and the chloroform solution is shaken with 1 N HCl and saturated sodium bicarbonate solution, ~ ~r, , washed with ~Yater and dried over MgS04. Af-ter stripping off the solvent and recrystaliiæing the residue from petroleum ether e-thyl ac~etate, 11 g ~92%) of activated-propionic acid are obtained.
ClgH1~05S (356.4) Calculated-; C 64.03H ~.53S 9 00 Found: 64,04 4.61 `9 35 - b~ Benzyl propionate 3,56 g of the compound obtained as described in a~ are dissol~ed in 50 ml of chloroform, 1.2 g of benzyl alcohol and 1 ml o~ triethylamine are added. The red coloration which appears initially changes to pale yellow within 2 hours ~fter ~orking up as described under a), 1.5 g (91%) o~ benzyl propion~
ate, which is pure according to ~MRl are obtained `: 93111~85 ., , ". . ............
.
0.Z. 32,036 Example of the elimination of water Conversion of an oxime into its nitrile:
1.55 g of the oxime o~ p-chlorobenzaldehyde and 3.5 g of 3,4-carbonyldioxy 2,5-diphenylthlophene-1,1-dioxide in 25 ml o~
dry toluene are heated at 90 for 45 minutes. The mixture is then washed with aqueous sodium bicarbonate solution and water, After drying over magnesium sui~ate and stripping of~ the solvent, 1125 g (91%) of p-chlorobenzonitrilé which has the melting point ~ -quoted in the li-terature are obtained.
~xamples of activated esters and of acyl transfer reactions ~ -Activated ester of N-tert.-butoxycarbonyl-L-phenylalanine ;~ ~ 1.96 g o~ 3,4-carbonyldioxy-2,5-diphenylthiophene~
~ .
dioxide, 2.33 g of Boc-Phe-OH and 0.49 ml of pyridine are stirred in 50 ml of absolute~methylene chloricle for 2 hours (evolution o~
co2)~ The reaction m~xture is~ washed three times with 20% strength ci-tric acid solution and three times with saturated-sodiwn bioarbonate solutlon,again with citric acid solution and with~water,and dried over ~agnesium sulfate, '~he ~olvent is distilled off under reduced pressurev The yield is 2.63 g, that is to say 96% of theory; the melting point is 169C~and `~
170C after recrystallization from ethyl acetate/petroleumi e-therO
C30II29N07S (547,6) Calculated: C 65.80 H 5.33 N 2,56 S 5.85 Found: 65 D 80 5.41 2.63 5.77 -, . .
N-tert.-Butoxycarbonyl-L-phenylalanyl-L-valine methyl ester -~
0.40ig of valine ~ethyl es-ter hydrochloride is added to a - ...
r ~ ishorange solution of l.ln g 0~ the compound ob-tained above and 0~61 g of triethylamine in 50 ml of dry methylene chloride~
-. : . : " . .. ; ,, i . .. i, , ~:: , ~ ,. .
.
.:
3~5 0.~. 32,036 the color immediately ~hanging to pale yellow The mixtur~
is stirred for a further 15 minutes at 20C and worked up as indicated above. The yield is 0.70 g, that is to say 93% o~
theory.
Activated ester of Boc-Phe from ~,4-dicarboxyldioxy-2,5-diphenyl-thiophene-l,l-dioxide 2.65 g of Boc-Phe and 1 ml of pyridine are added to 4.2 g ~-o~ 3,4-dicarbonyldioxy-275-diphenylthiophene-l,l-dioxide in 40 ml o~ dry tetrahydrofuran Vigorous evolution of gas takes 10 place. After stirring for 12 hoursJ the reaction mixture is ~;
worked up in the con~entional m~nner. The yield of l~.6 g corres- ~
ponds to 84% of -theory. The product is identical to the ~ A
compound prepared from 3,4-carbonyldioxy-2,5 diphenylthiophene-l,l-dioxide.
N-Benzyloxycarbonyl-L-prolyl-L-valine tert butyl ester,using 3,4 carbonyldioxy-2,5-diphenyl-cyclopentadienone -2 050 g of 3,4-carbonyldioxy-2,4-dLphenyl-cyclopentadienone are added to 1 763 g of Z-Pro-OH and 0.560 g of pyridine in 15 ml -;
of absolute tetrahydrofuran. The mixture is left to stand ~or 50 minutes, 1.220 g of L-valine tert -butyl ester are added and after 1 hour working up is carried out in the conventional manner The yield is 2 146 g, that is to say 53% of theory, of N-benzyl-oxycarbonyl-L-prolyl-L-valine tert.-butyl ester ~ith a melting point of 10~-111C. ~
, , ~ , . , ' -- 1~ . . . .
. ' . ' :
.
3~3S o . z . 32, 036 , .
. - ` . . . .
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o ~ ~ ~ O~ ~ O ~ ~
a) ~ o o ~ 0 h ~ ~ V ~ V~ ~ C~ V
~' ' `~ ~
0 :~0 +~O +~ ' O
a) o ~d O ~ æ ~ æ ld -X C~ ~ t ~ X~ ~
O ~ O ~ O ~ ~ ~ O a~ ~ ~d o ~ ~ ~ O ~ -. v ~, ~) V ~ ~ U~ V ~ ~ ~ V ~ ~ ~ V V ~l ~ V ~
?~ I O C~--O rl ~ O
:' ~ , ~ O
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g g , g z; t~ t~ N N ~
19 ' .
.
3~S
0,~ 32?036 [a~ All the compounds gave correct elementary analyses E~]- Crude yields of the products which, according to spectro- ~ -scopy, are the pure compounds [c] A: from the carboxylic acid, pyridine and (2); B: from ..
the carboxylic acid, (1) and dicyclohexylcarbodiimide; C: ~ro~ , the carboxylic acid chloride, (1) and pyridine ~' ~d] ~alues ~or the recrystallized'compo~nds, which are ~
analytically pure. (3c~ ) are in the form of ~ixtures of ;' diastereomers.
,The Table:shows that the yields obtained when (la) is , used as the starting compound (process A) are substantially ~ :
.
,higher than those obtained with the conventional methods ~ and C~
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-- o ~ h h h h ~ h o S~
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~ 21 -, ........ . . ... _ .
: . .. ..
;
, . O . ~ . 32, o~6 As Table 2 shows, even sterically more difIicull dipep-tide derivatives are formed within a few minutes in virtually quantitative yields. The products are characterized without recrystallization and in most cases are analytically pure. Examination o~ the corresponding N- .
trifluoroacetyldipeptlde methyl ester by gas chromatography shows that the activation and the peptide coupling to Z-Pro-Val-OMe ; ~
- proceed withou-t racemization Compe-titive-reaction experiments show that the ac-tivated es-~ers according to formula (3) are more effective acyl transfer agents than the p- and o-nitrophenyl esters frequently used in peptide syntheses (M. Bodanszky et al., J.Org Chem. ~ (1973) 3365)~
Thus, a mixture of equimolar amounts of 4-pivaloyloxy-3-oxo-2,5.
diphenyl~ -dihydrothiophene-l,l dioxide 9 p-nitrophenyl acetate and benz~l~mine gives 97% of N-benzylpivalamide and 3% of N-benzyl--- acetamide (NMR and GC analysis) after 2 hours at room te~perature, ~although pivaloyloxy-3-oxo-2,5-diphenyl-2,3-dlh~dro-thiophene-1,1-dioxide sterically has considerable disadvantages. With valine me~hyl ester, 4-propionyloxy-3-oxo-2,5-diphenyl-2,3_ dihydrothiophene-l,l-dioxide and o-nitrophenyl acetate ~orm a mi~ture of 99% of the N-propionyl derivative and only 1% of the N-acetyl derivative. The high reactivity o~ the esters 3 toward~
amines is probably due to the lact that -the enolate group in the anion accelerates the aminolysis by intramolecular general base catalysis Pa~ticularly advan-tageously, the intermediate products -~
^according to the invention can be used ~or the peptide synthesis in the form of a polymer reagent, bonded -to a resin. Poly--- 22 ~
.
.
3~S
. . ' ' ' . , o.Z. 32,0~6 meric ac-tivated esters can be prepared from commercial Merri-, .
field resin (chloro~ethylated copolymer o~ styrene and 2% of 1~4-divinylbenzene). . .
, The polymer reagent obtainable in this way is in many cases equivalent to phosgene, thiophosgene and oxalyl chloride and this opens up new preparative possibilities. The synthesis of the 1 resin and its use for the synthesis of two sterically hindered -: , d.~peptides is described below: ~-.
:: ~r~ CH2Cl + H~;CH2~ C2H50H (~ ~CH2-S-CH2~ ~",~ "
, 2 2 5 2 ~ OH
C~ C~l > ~ CH2 52 CH2 ~ COCl . ~ RC02H, ~ ~
' ' ' ' ~/ ~ I)CC - : ' ' Q ~ pyridine ~
~ O OCOR
3 p~r~-dlne~ C~
2 , 0 ~
is filtered again and the filtrate is concentrated until-3,4-carbo-nyldioxy-2,5-diphenylthiophene-1,1-dioxide crystallizes. After standing overnight at 0C, 24 g, that is to say a73% yield, of yellow-green fluorescent small needles (1) (everyone up to every tenth of the aromatic rings is chloro-methylated, which is approximately equivalent to 0.43 to 2063 moles of Cl/g ~J. Am. Chem. Soc. 85, 2149-2152 (1963)7J. ' ~' . .
:: , . .... .
. .
, o.Z. 32,036 ,, ' which decompose a-t 250C are obtainedc C17HlOOsS (326.3) Calculated: C 62.57 H 3.09 Found: 62,51 3.15 4-Hydroxy 3-oxo-2,5-diphenyl-2,3-dihydrc-thiophene~
- dioxide is recovered by adding sodium hydroxide solution to tne '~
residue"obtained after evaporation of the mother liquor, filtering the mix-ture and acidifying the'filtrate.
;~ EXAMPLE 3 103J4-(Dicarbonyldioxy)-2,5~diphenylthiophene-1,1-dioxide ' :~
; ,~ g of 3 hydroxy-4-oxo-2~5-diphenyl-2,5-dihydrothiophene~
l,l-dioxide, 40 ml of tetrahydrofuran and 5 ml of oxalyl chloride '~' are boiled under re~lux for 2 hours. After filtering the ~ ' reaction mixture and distilling off the tetrahydrofuran, 6.~ g~
that is to say 96% of theory, of the activated oxalate are obtained r~ue. ~his is a yellQw powder the color of egg yolk and decomposes at 245 to 250C.
C18Hl0o6s (3S4-3) Calculated: C 61.01 H 2.85 ; -' 20 Found- 61.00 2.86 -4-Car~onyldioxy-2,5-diphenyl-cyclopentadienone 40 ml of a 20% strength by weight solution of phos~ene in t,oluene are added to 10 g of 4-hydroxy-2,5-diphenyl-4-cyclopentene-1,3-dione 'and 6 g of pyridine in 150 ml of dry tetrahydrofuran.
~fter stirring the mixture for two hours, the pyridine hydro- ;
chloride ~hich has precipit~ted is filtered off. The dark r'ed filtrate is concentrated and 10.5 g (96%) of pure 3,4 .
....
f carbonyldioxy-2,5-diphenyl-cyclope~tadieno~e are obtalned in the form of black-violet cryStals which slowly decompose at above 100C~
C18~l04 (290 3) Calculated:C 74.46H 3.47 Found: 74.47 3 99 3,4-Thiocarbonyldioxy-2,5-diphenylthiophene-l,l-dioxide 6,5 ml of pyridine are added dropwise to 12 g of 3-hydroxy-4-oxo-2,5-diphenyl-2,3-dihydrothiophene l,l-dioxide in 150 ml of dry tetrahydrofuran. 4.55 ml of thiophosgene are then added, whilst cooling with ice and stirring.
- After the mixture has been left to stand for 90 minutes, the tetrahydro~uran and unconverted thiophosgene are distilled off, the residue is digested with 300 ~l of ice water and the precipitate is filtered off and washed several times with water. The filter cake is dried in air. The yield is 11.5 g of crude product and, after boiling thoroughly with acetone~
ether (103, volume/volume) this gi~es 10.1 g, that is to say 75% of theory, of the thiocarbonate in analytical purity.
This is a greenish yellow powder which decomposes at above 240C, becomes solid again and melts again at about 290C.
Cl7Hl0O4S2 (342.4) Calculated: C 59.64 H 2.94 Found: 60.04 2.85 B. EXAMPLES OF REACTIONS WITH THE COMPOUNDS ACCORDING TO THE
INVENTION
Examplcs of t~le prepara~ion of ureas N,N-Diphenylurea __ _ ___ _ _, ~ _ ,,, _ _ . _ ~ -13-.
- O.Z. 32,o36 :
3 26 g of 3,4-carbonyldioxy-2,5-diphenylthiophene~
dioxide in 25 ml of dry tetrahydrofuran are left to stand wi-th 1 86 g of aniline for 30 minutes and during the initial perio~ an exothermic reaction takes place. After the reaction has ended, the mixture is par-titioned between ether and aqueous lN
sodium hydroxide solution and the organic phase is washed with water and dried over magnesium sulfate The yield ~s - , ~.
2 02 g, that is to say 960/o of theory and the melting point is ;
244 _ 247C (melting point quoted in the literature 235 _ 239.5C).
.
N,N-Diethyl-Nt~phenylurea 0 93 g o~ aniline is added to 3.26 g of 2,4~carbonyl-dioxy-2,5-diphenylthiophene~ dioxide in 25 ml of dry tetra~
hydrofuran. The mixture is le~t to stand ~or 30 minutes at 20C, 0.73 g of diethylamine is added and the mixture is ~eft to stand for a further 40 minutes ~fter distilllng off the tetrahydrofuran, t~e residue is taken up in chloroform and the r chloroform solution is washed successively with aqueous lN
hydrochloric acid and twice with aqueous sodium carbonate solu-tion ~-~
and water. After drying over magnesium sulfate and evaporatin~
wlder reduced pressure, 1.4 g of slightly yellowish crystals which~
as the crude product, have a melting point of 81 - 85C (melting point quoted in the li-tera-ture 85C) remain.
Examples of fu~ther unsymmetrically substituted urea com-pounds which are prepared in the indicated manner with the aid of 2~4-carbonyldioxy~2,~-diphenylthiophene-1,1-dioxide are: N-(2-benzthiazolyl)-N'-methylurea, N-phenyl-NJ'-(2-methyl-cyclohexyl) urea, N-(~-tri~luoromethyl-phenyl)-N',N'-dimethyl~urea, N-cyclo-... .
.
.
O.Z. 32,o36 octyl-N',N'-dimethylurea, N-4-fluorophenyl-N~-carboxymethoxy-N~-methyl-urea and N-(4-chlorophenyl)-N7-methyl-N~-tbutyn-l-yl)-urea~
The mel-ting points obtained for these compounds when they ar'e prepared in the above way correspond to the melting points quoted in the literature, Example of the preparat'ion o~ a urethane . .
' N-Benzyloxycarbonyl-L-valine tert.-butyl ester a~ -Activated carbonic acid benzyl ester 3,26 g of 2,4-carbonyldioxy-2,5-diphenylthiophene~
'10 dioxide and 1.08 g of benzyl alcohol are left to stand in 40 ml of dry tetrahydrofur&n for 12 hours at 20C. During this time the intermediate product of ~ormula (3) precipitates. The tetrahydrofuran is dis-tilled o~f and the residue is washed with ,, ether. The yield is ~.95 g, that is to say 95~0 of theory~
, and the melting point 1695, The ~R spectrum shows only t~e expected .signals. ' ' ;~ b) N-Benzyloxycarbonyl-L-valine tert.-butyl ester ,, ,; 2.1 g of the compound obtained as described in a) are 5US - - ;' -pended in 300 ml of tetrahydrofuran and O.90 g of Val-OBut, 1 ml of , ,~ 20 . pyridine and 0,5 ml of triethylamine are added, The red coloration ; ~ changes to yellow a~ter about 30 minutes. The mixture is - , left ~o stand for a further ~0 minutes and worked up by the me-thod described in the exarnple for N,N-diethyl-N'-phenylurea. ~, The yield is 1.51 g, that is to say 99% of theory, of an oil, which ~;
~ on exarnination by N.~ shows only the signals o~ the 'expected ; product.
Example o~ the preparation of an oxalic acid diamide ,~
Oxalic acid dibenzylamide -3.54 g o~ 3,4-(dicarbonyldioxy)-2,5-diphenylthiophene-s :
O.Z. 32,0~6 .' , " ~
l,l~dioxide and 2.4 g of dibenzylamine in 50 ml of dry tetra-hydrofuran are s-tirred at room temperature for 1 hour. After working up in the conventional rnanner, 2;55 g (94%) of oxalic acid dibenzylamide are obtained.
Example o~ the preparation of an es-ter Benzyl propionate:
a) Activated propionic acid ester ~.
i 10 g o~ 4 hydroxy-3-oxo-2,5-diphenyI-2,3-dihydrothiophene-~ l;l dioxide and 2.62 e of pyridine are dissolved in 100 ml o~
tetrahydrofuran. 3.06 g of propionyl chloride in 50 ml of ~tetrahydrofuran are added to this solution. After stirring ~or two hours at room temperature, the solvent is strlpped off~ ;~
the residue is taken up in chloroform and the chloroform solution is shaken with 1 N HCl and saturated sodium bicarbonate solution, ~ ~r, , washed with ~Yater and dried over MgS04. Af-ter stripping off the solvent and recrystaliiæing the residue from petroleum ether e-thyl ac~etate, 11 g ~92%) of activated-propionic acid are obtained.
ClgH1~05S (356.4) Calculated-; C 64.03H ~.53S 9 00 Found: 64,04 4.61 `9 35 - b~ Benzyl propionate 3,56 g of the compound obtained as described in a~ are dissol~ed in 50 ml of chloroform, 1.2 g of benzyl alcohol and 1 ml o~ triethylamine are added. The red coloration which appears initially changes to pale yellow within 2 hours ~fter ~orking up as described under a), 1.5 g (91%) o~ benzyl propion~
ate, which is pure according to ~MRl are obtained `: 93111~85 ., , ". . ............
.
0.Z. 32,036 Example of the elimination of water Conversion of an oxime into its nitrile:
1.55 g of the oxime o~ p-chlorobenzaldehyde and 3.5 g of 3,4-carbonyldioxy 2,5-diphenylthlophene-1,1-dioxide in 25 ml o~
dry toluene are heated at 90 for 45 minutes. The mixture is then washed with aqueous sodium bicarbonate solution and water, After drying over magnesium sui~ate and stripping of~ the solvent, 1125 g (91%) of p-chlorobenzonitrilé which has the melting point ~ -quoted in the li-terature are obtained.
~xamples of activated esters and of acyl transfer reactions ~ -Activated ester of N-tert.-butoxycarbonyl-L-phenylalanine ;~ ~ 1.96 g o~ 3,4-carbonyldioxy-2,5-diphenylthiophene~
~ .
dioxide, 2.33 g of Boc-Phe-OH and 0.49 ml of pyridine are stirred in 50 ml of absolute~methylene chloricle for 2 hours (evolution o~
co2)~ The reaction m~xture is~ washed three times with 20% strength ci-tric acid solution and three times with saturated-sodiwn bioarbonate solutlon,again with citric acid solution and with~water,and dried over ~agnesium sulfate, '~he ~olvent is distilled off under reduced pressurev The yield is 2.63 g, that is to say 96% of theory; the melting point is 169C~and `~
170C after recrystallization from ethyl acetate/petroleumi e-therO
C30II29N07S (547,6) Calculated: C 65.80 H 5.33 N 2,56 S 5.85 Found: 65 D 80 5.41 2.63 5.77 -, . .
N-tert.-Butoxycarbonyl-L-phenylalanyl-L-valine methyl ester -~
0.40ig of valine ~ethyl es-ter hydrochloride is added to a - ...
r ~ ishorange solution of l.ln g 0~ the compound ob-tained above and 0~61 g of triethylamine in 50 ml of dry methylene chloride~
-. : . : " . .. ; ,, i . .. i, , ~:: , ~ ,. .
.
.:
3~5 0.~. 32,036 the color immediately ~hanging to pale yellow The mixtur~
is stirred for a further 15 minutes at 20C and worked up as indicated above. The yield is 0.70 g, that is to say 93% o~
theory.
Activated ester of Boc-Phe from ~,4-dicarboxyldioxy-2,5-diphenyl-thiophene-l,l-dioxide 2.65 g of Boc-Phe and 1 ml of pyridine are added to 4.2 g ~-o~ 3,4-dicarbonyldioxy-275-diphenylthiophene-l,l-dioxide in 40 ml o~ dry tetrahydrofuran Vigorous evolution of gas takes 10 place. After stirring for 12 hoursJ the reaction mixture is ~;
worked up in the con~entional m~nner. The yield of l~.6 g corres- ~
ponds to 84% of -theory. The product is identical to the ~ A
compound prepared from 3,4-carbonyldioxy-2,5 diphenylthiophene-l,l-dioxide.
N-Benzyloxycarbonyl-L-prolyl-L-valine tert butyl ester,using 3,4 carbonyldioxy-2,5-diphenyl-cyclopentadienone -2 050 g of 3,4-carbonyldioxy-2,4-dLphenyl-cyclopentadienone are added to 1 763 g of Z-Pro-OH and 0.560 g of pyridine in 15 ml -;
of absolute tetrahydrofuran. The mixture is left to stand ~or 50 minutes, 1.220 g of L-valine tert -butyl ester are added and after 1 hour working up is carried out in the conventional manner The yield is 2 146 g, that is to say 53% of theory, of N-benzyl-oxycarbonyl-L-prolyl-L-valine tert.-butyl ester ~ith a melting point of 10~-111C. ~
, , ~ , . , ' -- 1~ . . . .
. ' . ' :
.
3~3S o . z . 32, 036 , .
. - ` . . . .
O lr~ ~0 r~ t~ ~D 1~ ~D
~'J Q) O t~ ~ L-- ' 0 0 ~ h ~ ui X ~ ; æ ~; ~ x z ~
O ~ô
o ~ ~ ~ O~ ~ O ~ ~
a) ~ o o ~ 0 h ~ ~ V ~ V~ ~ C~ V
~' ' `~ ~
0 :~0 +~O +~ ' O
a) o ~d O ~ æ ~ æ ld -X C~ ~ t ~ X~ ~
O ~ O ~ O ~ ~ ~ O a~ ~ ~d o ~ ~ ~ O ~ -. v ~, ~) V ~ ~ U~ V ~ ~ ~ V ~ ~ ~ V V ~l ~ V ~
?~ I O C~--O rl ~ O
:' ~ , ~ O
~o ~ ' ' h , .. , ~ ~ qO~
t~ a) , - ~
X a)rl ,: i, I , -O ,~ 0 , , t O ~ ' ' ' ~ . ~ O ~, ~, Vl ~ ~ '' ~
g g , g z; t~ t~ N N ~
19 ' .
.
3~S
0,~ 32?036 [a~ All the compounds gave correct elementary analyses E~]- Crude yields of the products which, according to spectro- ~ -scopy, are the pure compounds [c] A: from the carboxylic acid, pyridine and (2); B: from ..
the carboxylic acid, (1) and dicyclohexylcarbodiimide; C: ~ro~ , the carboxylic acid chloride, (1) and pyridine ~' ~d] ~alues ~or the recrystallized'compo~nds, which are ~
analytically pure. (3c~ ) are in the form of ~ixtures of ;' diastereomers.
,The Table:shows that the yields obtained when (la) is , used as the starting compound (process A) are substantially ~ :
.
,higher than those obtained with the conventional methods ~ and C~
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~ 21 -, ........ . . ... _ .
: . .. ..
;
, . O . ~ . 32, o~6 As Table 2 shows, even sterically more difIicull dipep-tide derivatives are formed within a few minutes in virtually quantitative yields. The products are characterized without recrystallization and in most cases are analytically pure. Examination o~ the corresponding N- .
trifluoroacetyldipeptlde methyl ester by gas chromatography shows that the activation and the peptide coupling to Z-Pro-Val-OMe ; ~
- proceed withou-t racemization Compe-titive-reaction experiments show that the ac-tivated es-~ers according to formula (3) are more effective acyl transfer agents than the p- and o-nitrophenyl esters frequently used in peptide syntheses (M. Bodanszky et al., J.Org Chem. ~ (1973) 3365)~
Thus, a mixture of equimolar amounts of 4-pivaloyloxy-3-oxo-2,5.
diphenyl~ -dihydrothiophene-l,l dioxide 9 p-nitrophenyl acetate and benz~l~mine gives 97% of N-benzylpivalamide and 3% of N-benzyl--- acetamide (NMR and GC analysis) after 2 hours at room te~perature, ~although pivaloyloxy-3-oxo-2,5-diphenyl-2,3-dlh~dro-thiophene-1,1-dioxide sterically has considerable disadvantages. With valine me~hyl ester, 4-propionyloxy-3-oxo-2,5-diphenyl-2,3_ dihydrothiophene-l,l-dioxide and o-nitrophenyl acetate ~orm a mi~ture of 99% of the N-propionyl derivative and only 1% of the N-acetyl derivative. The high reactivity o~ the esters 3 toward~
amines is probably due to the lact that -the enolate group in the anion accelerates the aminolysis by intramolecular general base catalysis Pa~ticularly advan-tageously, the intermediate products -~
^according to the invention can be used ~or the peptide synthesis in the form of a polymer reagent, bonded -to a resin. Poly--- 22 ~
.
.
3~S
. . ' ' ' . , o.Z. 32,0~6 meric ac-tivated esters can be prepared from commercial Merri-, .
field resin (chloro~ethylated copolymer o~ styrene and 2% of 1~4-divinylbenzene). . .
, The polymer reagent obtainable in this way is in many cases equivalent to phosgene, thiophosgene and oxalyl chloride and this opens up new preparative possibilities. The synthesis of the 1 resin and its use for the synthesis of two sterically hindered -: , d.~peptides is described below: ~-.
:: ~r~ CH2Cl + H~;CH2~ C2H50H (~ ~CH2-S-CH2~ ~",~ "
, 2 2 5 2 ~ OH
C~ C~l > ~ CH2 52 CH2 ~ COCl . ~ RC02H, ~ ~
' ' ' ' ~/ ~ I)CC - : ' ' Q ~ pyridine ~
~ O OCOR
3 p~r~-dlne~ C~
2 , 0 ~
5 6a~ R - Z-Val __ .
6b, R = Boc-Val N-R~
.
. . RCONHR' ; . .~ , ~ .
_ ... . , . .. .... , ~ , .
,. . .
,. .,. :
3~
.:
O.Z. 32,o36 ~,~
In order to prepare the polymeric thiobenzyl ether 2, Merrifield resin is heated for a prolonged period with sodium mercap-tide in ethanol.~cording to the sulfur analysis, 1.4 mmoles .~-~of benzylmercaptan/g.of resin are incorporated~ The oxi-dation to the sulfone 3 is carried out with H202/trifluoroace-tic acid anhydride. The oxidation can be discerned from intense ' ~' sulfone bands'at 1,320 and 1,120 cm 1. The condensation, reaction with diethyl oxalate to give the ketosulfone 4 proceeds ~; relatively slowly, The IR bands a-t 1,7~5 and 1,495 cm 1 which : 10 are characteristic of ~ are obtained in their full in-tensity only after.boiling twice with sodium ethylate in ethanol (each time for ~ days). If the resin 4~is.reacted ~7ith phosgene/pyridine in chloroform, -the cyclic carbonate ~, which can be recognized '~
from the typical IR band at 1,888 cm~l, is formed~
When~5 is stirred with Z-Val-OH and pyridine in methylene chloride (24 hours, 20C); the.carbonyl band at 1,888 cm 1 di6-appears and the poIymeric~activated ester 6a forms. A resin . , :' which has an,identical IR spectrum can also be obtained by,r,e-, acting 4 wi-th Z-Val-OH and dicyc}ohexylcarbodiimide (DCC) in D~F. :
The dicyclohexylurea is:remove~ by eluting with methanol, ' In .~ '~
order to determine the content of acti~ated aminoacid este'r, -the : , resin 6a was reacted with benzylamine~ . From the amount of~
Z-L-Val-benzylamide ~ormed, the~proportion of active groups introduced is 0.15 mmole of Z-~al/g of resin~ If the resin is reacted with Val-OMe in methylene chloride for 130 minutes at 20C, the Z-dipeptide ester is again formed in a yield o~ , 0,15 mmolelg of resin. . :
In a second synthesis of the poly~eric ketosulfone, the -- 21~ --.. . . . . . .
- . .
LQ3~3~
O;Z. 32,03~ -.
'' proportion of active groups introduced c~n be improved. With - Boc~Val-OH and DCC in D,~, resln L? glves a polymeric activated ester 6b, which with benzylamine gives 0.48 mmole of Boc-L-val-==
~ ~ne-benzylamide/g of resin l~ the resin (2.3 molar excess) ; is stirred with ~al-OMe in methylene chloride for 200 minutes at 20C, Boc-Val-OMe, which according to the melting point, OR and NMR is identical to the authentic compound, can be isoIa-ted in 41% yield Preparation o~` the polymericactivated carbonate 5 1) Polymeric benzyl sulfide 2 -25 g of Merrifield resin (Merck-Schuchardt) and 12 ml o~
, , benzylmercaptan are added to a solution of 2.3 g o~ sodium in 200 ml of ethanol and the mixtùre is stirred carefully wi-th a ;~
KPG stirrer. After 20-40 hours at 70C, the resin i3 ~iltered o~f and washed successively with meth~nol, water, glacial acetic acid, water and methanol. It is dried at 80 ~100C under reduced pressure produced by an oil pu,~p. -Sulfùr content- 4.~6%; chlorine content; 0 . 29~o~
Z) Polymeric benzylsulfone 3 ~ ~ , 40 ml of 30%str~ngth ~22 are added carefully to 40 ml of ;
trifluoroacetic acid anhydride in 100 ml of me-thylene chloride, whilst cooling with ice. A~ter adding 15 g of resin-2, the mixture is stirred ~or 10-15 hours at 20C and the resin is then ;-~iltered o~, washed successively with me-thylene chloride, water and methanol and dried at 80-100C under reduced pressure produced by an oil pump.
IR (KBr): intense bands at 1,320 and 1,120 cm 1 (_S02_).
Sul~ur content: 3,90~. , ; `
~ .
, ... . .
3~3~
' . ' O.Z. 32,o36 ;, 3) Polymeric ketosulfone 4 ' ~-40 ml of diethyl o~alate and lO g of resin 3 are added to a solution of 2 g of sodium in 400 ml o~ ethanol. The mixture is heated under reflux for 3 days and during this time the solu-tion develops a brown coloration. The resin is then ~iltered off, washed successively with ethanol (5 x lOO ml), ` -water (10 x 100 ml), ~lacial acetic acid,(5 x 100 ml), water (5 x lOO ml) and methanol (5 x lOO ml) and dried for several hours at 80-100C under reduced pressure produced by an oil pump. In order to ac,hieve complete conversion, the resin thus obtained is subjected to a further condensation reaction with diethyl oxalate, ~ ' IR ~KBr): characteristic bands at 1,715 and 1,495 cm l, -the intensi-ty of which increases after the second condensatlon' reaction.
Sulfur con-tent: 3.68%.
4) Polymeric activated carbonate ~
' 2-5 ml'of phosgene are added to 8 g of -the polymeric keto$ulfone 4 in ïoo ml of chloroform and 5 ml of pyridine. The mixture is stirred ~or about 5 hours and the resin is filtered ' off:and~ in order to remove the pyridine hydrochloride, lS ex-tracted in a Soxhlet apparatus with phosgene-containing chloro- ~' ~orm (acetone/solid carbon dioxide condenser), The resin is dried at 60C under reduced pressure produced by an oil pump, I~ (KBr)~ 888 cm~l (-o-co-o-?, Use of the polymers 4 and ~ for amide and peptide syntheses , 5) Polymeriç activated ester of Z-L-valine! 6a . ' a) From resin ~: 5 g of polymer~c activated carbonate ~ are 'stlrred with 1,25 g of Z-Val-OH and 1 ml of pyridine in 50 ml of .
- 26 - .
3~5 .
.
, O.Z. 32,036 - . :
, .
absolute tetr~hydrofuran for 1~ hours a-t 20C, The resin ; is f~ltered off, ~ashed with T~ and dried at 60C under reduced pressure produced by an oil pump. Unconverted Z-Val-OH can be recovered after evaporating the reaction and wash solutlons.
b) From resin 4: 5 g of the polymeric ketosulfone 4 are stirred with 2.5~ g of Z-Val-OX and 2,06 g of dicyclohexylcarbodiimide in 30 ml of DMF for 2 hours at 0C and for 3 hours a-t 20C. The resin is filtered off, washed thoroughly with metY~lan~ dried a~
60C under reduced pressure produced by an oil pump. The 10 resins6a obtained by the two rou-tes had the same IR spectrum.
6b, R = Boc-Val N-R~
.
. . RCONHR' ; . .~ , ~ .
_ ... . , . .. .... , ~ , .
,. . .
,. .,. :
3~
.:
O.Z. 32,o36 ~,~
In order to prepare the polymeric thiobenzyl ether 2, Merrifield resin is heated for a prolonged period with sodium mercap-tide in ethanol.~cording to the sulfur analysis, 1.4 mmoles .~-~of benzylmercaptan/g.of resin are incorporated~ The oxi-dation to the sulfone 3 is carried out with H202/trifluoroace-tic acid anhydride. The oxidation can be discerned from intense ' ~' sulfone bands'at 1,320 and 1,120 cm 1. The condensation, reaction with diethyl oxalate to give the ketosulfone 4 proceeds ~; relatively slowly, The IR bands a-t 1,7~5 and 1,495 cm 1 which : 10 are characteristic of ~ are obtained in their full in-tensity only after.boiling twice with sodium ethylate in ethanol (each time for ~ days). If the resin 4~is.reacted ~7ith phosgene/pyridine in chloroform, -the cyclic carbonate ~, which can be recognized '~
from the typical IR band at 1,888 cm~l, is formed~
When~5 is stirred with Z-Val-OH and pyridine in methylene chloride (24 hours, 20C); the.carbonyl band at 1,888 cm 1 di6-appears and the poIymeric~activated ester 6a forms. A resin . , :' which has an,identical IR spectrum can also be obtained by,r,e-, acting 4 wi-th Z-Val-OH and dicyc}ohexylcarbodiimide (DCC) in D~F. :
The dicyclohexylurea is:remove~ by eluting with methanol, ' In .~ '~
order to determine the content of acti~ated aminoacid este'r, -the : , resin 6a was reacted with benzylamine~ . From the amount of~
Z-L-Val-benzylamide ~ormed, the~proportion of active groups introduced is 0.15 mmole of Z-~al/g of resin~ If the resin is reacted with Val-OMe in methylene chloride for 130 minutes at 20C, the Z-dipeptide ester is again formed in a yield o~ , 0,15 mmolelg of resin. . :
In a second synthesis of the poly~eric ketosulfone, the -- 21~ --.. . . . . . .
- . .
LQ3~3~
O;Z. 32,03~ -.
'' proportion of active groups introduced c~n be improved. With - Boc~Val-OH and DCC in D,~, resln L? glves a polymeric activated ester 6b, which with benzylamine gives 0.48 mmole of Boc-L-val-==
~ ~ne-benzylamide/g of resin l~ the resin (2.3 molar excess) ; is stirred with ~al-OMe in methylene chloride for 200 minutes at 20C, Boc-Val-OMe, which according to the melting point, OR and NMR is identical to the authentic compound, can be isoIa-ted in 41% yield Preparation o~` the polymericactivated carbonate 5 1) Polymeric benzyl sulfide 2 -25 g of Merrifield resin (Merck-Schuchardt) and 12 ml o~
, , benzylmercaptan are added to a solution of 2.3 g o~ sodium in 200 ml of ethanol and the mixtùre is stirred carefully wi-th a ;~
KPG stirrer. After 20-40 hours at 70C, the resin i3 ~iltered o~f and washed successively with meth~nol, water, glacial acetic acid, water and methanol. It is dried at 80 ~100C under reduced pressure produced by an oil pu,~p. -Sulfùr content- 4.~6%; chlorine content; 0 . 29~o~
Z) Polymeric benzylsulfone 3 ~ ~ , 40 ml of 30%str~ngth ~22 are added carefully to 40 ml of ;
trifluoroacetic acid anhydride in 100 ml of me-thylene chloride, whilst cooling with ice. A~ter adding 15 g of resin-2, the mixture is stirred ~or 10-15 hours at 20C and the resin is then ;-~iltered o~, washed successively with me-thylene chloride, water and methanol and dried at 80-100C under reduced pressure produced by an oil pump.
IR (KBr): intense bands at 1,320 and 1,120 cm 1 (_S02_).
Sul~ur content: 3,90~. , ; `
~ .
, ... . .
3~3~
' . ' O.Z. 32,o36 ;, 3) Polymeric ketosulfone 4 ' ~-40 ml of diethyl o~alate and lO g of resin 3 are added to a solution of 2 g of sodium in 400 ml o~ ethanol. The mixture is heated under reflux for 3 days and during this time the solu-tion develops a brown coloration. The resin is then ~iltered off, washed successively with ethanol (5 x lOO ml), ` -water (10 x 100 ml), ~lacial acetic acid,(5 x 100 ml), water (5 x lOO ml) and methanol (5 x lOO ml) and dried for several hours at 80-100C under reduced pressure produced by an oil pump. In order to ac,hieve complete conversion, the resin thus obtained is subjected to a further condensation reaction with diethyl oxalate, ~ ' IR ~KBr): characteristic bands at 1,715 and 1,495 cm l, -the intensi-ty of which increases after the second condensatlon' reaction.
Sulfur con-tent: 3.68%.
4) Polymeric activated carbonate ~
' 2-5 ml'of phosgene are added to 8 g of -the polymeric keto$ulfone 4 in ïoo ml of chloroform and 5 ml of pyridine. The mixture is stirred ~or about 5 hours and the resin is filtered ' off:and~ in order to remove the pyridine hydrochloride, lS ex-tracted in a Soxhlet apparatus with phosgene-containing chloro- ~' ~orm (acetone/solid carbon dioxide condenser), The resin is dried at 60C under reduced pressure produced by an oil pump, I~ (KBr)~ 888 cm~l (-o-co-o-?, Use of the polymers 4 and ~ for amide and peptide syntheses , 5) Polymeriç activated ester of Z-L-valine! 6a . ' a) From resin ~: 5 g of polymer~c activated carbonate ~ are 'stlrred with 1,25 g of Z-Val-OH and 1 ml of pyridine in 50 ml of .
- 26 - .
3~5 .
.
, O.Z. 32,036 - . :
, .
absolute tetr~hydrofuran for 1~ hours a-t 20C, The resin ; is f~ltered off, ~ashed with T~ and dried at 60C under reduced pressure produced by an oil pump. Unconverted Z-Val-OH can be recovered after evaporating the reaction and wash solutlons.
b) From resin 4: 5 g of the polymeric ketosulfone 4 are stirred with 2.5~ g of Z-Val-OX and 2,06 g of dicyclohexylcarbodiimide in 30 ml of DMF for 2 hours at 0C and for 3 hours a-t 20C. The resin is filtered off, washed thoroughly with metY~lan~ dried a~
60C under reduced pressure produced by an oil pump. The 10 resins6a obtained by the two rou-tes had the same IR spectrum.
6) Syn-thesis of Z-L valine benzylamide , .3 g of the actiYated ester 6a obtained asde~ribed ina)are stirred wi-th 0~5 g Qf benzylamine in 40 ml of chloroform for 2 ~ ;
-:, hours at 20C. The resin i~s filtered off and washed thoroughly ~;
with chloroform and after extracting the filtrates by shaking with N HCl, sodium carbona-te solution and water and dryin~ and evapora-ting, 0~150 ~ of Z-Val benzylamide, which i5 identical to , . . .
an authentic comparative prepar~tion, is obtained, From , this, the propor-tion of active groups introduced is calculated as 0.15 mmole of Z-Val-OH/g of resin 6a. The IR spectrum of the ~ ; resin which has been obtainedafter the reaction agrees with 4,-; :7) Z-Val-OMe ,;
5,61 g of -the resin 6a obtained according to Instruction 5b) are stirred in 40 ml of chloroform with 0,50 ml of pyridine ar,d 0,350go~ L-valine methyl ester hydrochloride for 130 minute~s.
The resin is filtered off and washed wi~h 200 ml of chloro~orm and the ~iltrate is worked up as described in ~epreviousExample, The yield is 0,300 g of Z-Val-Val-OMe and the melting point o~
, 27 .. .. .. . . . . ..
: -' - ' ' . . ' 0.Z. 32,o36 , .
t~le crude product is 120C; according to thc IR and ~ ~ spectrum, this product is iden-tical to -the authentic comparative preparation, 8~ Polymeric activated ester of Boc-L-valine 6b 10 g of resin 4 +~, 6.5 g of Boc-Val-OH and 6.2 g o~ DCC
were':stirred in 30 ml of dimethylformamLde for 2 hours-at 0 . and then for a further 3 hours' at 20C. The resin is f~l-'~ tered off,~ washed thoroughly with methanol and dried at 60 ,' ,~ . , under reduced pressu're,produced by an oll pump.' t) different batch of resinfromthat used ~or the.preparation of 6a '~
9) Boc-L-valine benzylamide . . ' ' 2.22 g of the polymeric activated ester 6b in 30 ml of ~ ' chloroform are stirred with 1 g of benzylamine ~or 15 minutesO
The resin is filtered off and washed with chloro~orm ~nd the com ' bined filtrateæ are extracted by shaking successively with 0.5 N
HCl, sodium carbonate solution and water. After drying and ; evaporating, the productt which is identical to an authentic .sample, is-obtained in a yield of 0.323 g. This gives a content of 0,~8 mmole. o~ Boc-Val-0H/g of resin 6b.
10~ Boc-Yal-Val-0Me 20 . ;7.5 g of the polymeric activated ester 6b (3.5 ~noles Boc-Val-0Hj and 0.250 g of L-valine methyl ester hydrochloride (1.5 mmoles) are st'irred in 100 ml of absolute methylene chloride.
After adding 3 ml of triethyla~ine and 1 ml o~ pyridine, the mix-ture is s-tirred f~r a further 200 minutes. The flltrates are ~rashed successive~y with 0.5 N HGl, sodium carbonate and water, .
.. dried and evaporated u~der,reduced pressure. After recrystal-lization from ether/petroleum'eth~r, 0.200 g of Boc-Yal-Val-0~e i5 obtained (yield 41%, ba~se'd on the L-valine methyl ester ,, ~ ' 28 ., - ..
!. . . . ........ . .. , . _ . . . .
3~ 5 O.Z. 32,036 , hydrochloride empIoyed~ Melting poin-t 159~161, melting point quoted in the literature 165-166~o C, Examples of the preparation of active esters of the formula ~3), o~ reactions of 3,4-carbonyldioxy-2,5-diphenylthiophene-171-dioxide and of the further processing of the resulting compounds 1, 3-(Phenylcarbamyloxy)-4-hydroxy-2,5-diphenylthiophene-171-dioxide . ~
;~ 0.93 g o~ aniline is added to 3.59 g of 3,4-carbonyl-dioxy-2,5-diphenylthiophene-1,1-dioxide in 30 ml of hot ethyl acetate and the reaction soIution developsareddish ~ange coloration ~or a short time, After boiling under reflux for 20 minutesj the solution is concentrated to half the original volume and filtered. The filter residue is washed ln portions with 100 ml of concentrated aqueous N~IC0~ solution c~nd then wi-th 100 ml of 20% s-trength aqueous citric acid solution.
. .
Yield: 3,7 g (88%), melting point 227C (deccmposition) a~ter recrystallization from chloroform/petroleum ether . - . .
C23~17N05S~ calc~ila-ted: C 65,87; H 4,o6; found: C 66.01; H 4~0 2. 3-(Benzylcarbamyloxy)-4-hydroxy-2,5-diphenylthiophene-].,1~
i~, dioxide ` . . 1. 07 g of benzylamine are added to 3,5g g o~ 3,4-carbon~Jl--dioxy-2,5-diphenylthiophene~ dioxide in 30 ml of hot ethyl acetate, The solution is boiled undei~ re~lux for 20 minutes and then ~ashed with three -times 30 mI of concentrated aqueous NaHC03 solu-tion and with three times 30 ml o~ 20% strength aqueous citric acid solution, The ~Jash liquors are extraGtcd with ethyl acetate and the ~ombined organic extrac-ts are dried over magnesium sulfate and evaporated.
., . ' ' ` ' ~
. 29 , .:,:,: .
3~35` ~
. .
~ o. z . 32 ,o~6 ;` . . . . .
~ Yield: 3.6 g (83%), melting~poin-t 200C (decomposition) ;~ , .
after recrystallization from chloroform/pe-troleum ether' ' calculated: C 66.51; H 4.39 found: C 66~,42; H 4.35 3. 3-(N,N-Diethylcarbamyloxy)-4-hydroxy-2,5-diphenylthiophene-' ; . l~l~dioxide ; 730 mg of diethylamine are added to 3.59 g o.~ 3,4 car~onyldioxy-2j5-diphenylthiophene-1,1-dioxide in 30 ml of hot ; , I .
ethyl acetate. The solution is boiled under reflux for 20 minutes, concentrated to halP its Yolume and filtered. The precipitate is washed in portions ~rith 100 ml ~ ~of concentrated aqueous N~HC03 solution and then with 100 ml of : ~ 20% strength aqueous citric acid solution.
' Yield: 3.4 g (85%), meltillg polnt 147~C alter recrystal-lization from chloroform/petroleum ether ' C21H21N55 calculated: ~ ~.02 . , ound: S 8.15 4,;~3-(N,N-Di.cyclohexylcarbamyloxy)-4-hydroxy-2`,5-diphenyl~
~hiophene~ dioxide 1.81 g o~ dicyclohexylamine are added to 3059 g of 3,4- ;~
.
carbonyldioxy-2,5-diphenylthiophene-1,1-dioxide in 30 mI of hot ethyl acetate and the solution devel~ps a deep red coloration ~or ; a short time. After boiling under reflux for 20 minutes 9 the solution is concentrated tG half its vo].ume and filtered, ~he precipitate is treated as described in Example C 3, ~Yield: 4,36 g (~60/o)~ melting point l65C a~ter recrystallization from chloroformjpetroleum ether 29 33 5 calculated: S 6,31 found: S 6,47 ', ~ . ~
3~5 ~ O.Z. 32,0~
.
5.. 3-(Piperidylcarbamylo~y3-4-hydroxy-2,5-diphenylthiophene-1~1-. .
dioxide : 850 mg of piperidine are added to 3.59 g of 3,4-carbonyldioxy-2,5-diphenylthiophene-1,1-dioxide in 30 ml of hot ethyl acetat,e. After boiling under rellux for 20 minutes, 'the solution ~s,washed-three -times wi-th 30 ml of concentra-ted aqueous:NaHC03 solut.ion and -three times with 20% strength aqueous ~ , : c~tric acid solution. The wash liquids are extracted with ;.:
.
eth~l acetate and the combined organic phases are dried over.,.
ma~nesium sulPate. A~ter distilllng of~ the solvent, a yellowish colored product is obtained as the rctsidue and thts is 're~rystallized ~rom chioroformlpe-troleum ether. ~
Yield': 3.3 g (8~/o) ~ melting point 135C. '`~.
C22~21N5S calculated: S 7.78 , ~, , : fo~ld , S 7.77 - 6. 3-(4-Morpholinylcarbam~;oxy)-4-hydroxy~2,5-diphenylthioph~ne dioxide ' -;
.. . .
870 mg of morpholine are' added to 3.59 g of 3,4-carbonyl- -.
dioxy-2,5-diphenylthiophene-1,1-dioxide in 30 ml of hot ethyl ~
t .
acetate and ~he solut.ion is boiled under reflux ~or , : 30 minutes; The solu-tion is then worked up as described i.n . Example C 5. ' Yield: 2.89 ~ (70/0), melting point 174C after . --~recrystallization from chloroform!petroleu~ ether C21H19N6S calculated: C 61.02; H 4.60; N 3,39 found: C 61~21; H 4.65; N 3.47
-:, hours at 20C. The resin i~s filtered off and washed thoroughly ~;
with chloroform and after extracting the filtrates by shaking with N HCl, sodium carbona-te solution and water and dryin~ and evapora-ting, 0~150 ~ of Z-Val benzylamide, which i5 identical to , . . .
an authentic comparative prepar~tion, is obtained, From , this, the propor-tion of active groups introduced is calculated as 0.15 mmole of Z-Val-OH/g of resin 6a. The IR spectrum of the ~ ; resin which has been obtainedafter the reaction agrees with 4,-; :7) Z-Val-OMe ,;
5,61 g of -the resin 6a obtained according to Instruction 5b) are stirred in 40 ml of chloroform with 0,50 ml of pyridine ar,d 0,350go~ L-valine methyl ester hydrochloride for 130 minute~s.
The resin is filtered off and washed wi~h 200 ml of chloro~orm and the ~iltrate is worked up as described in ~epreviousExample, The yield is 0,300 g of Z-Val-Val-OMe and the melting point o~
, 27 .. .. .. . . . . ..
: -' - ' ' . . ' 0.Z. 32,o36 , .
t~le crude product is 120C; according to thc IR and ~ ~ spectrum, this product is iden-tical to -the authentic comparative preparation, 8~ Polymeric activated ester of Boc-L-valine 6b 10 g of resin 4 +~, 6.5 g of Boc-Val-OH and 6.2 g o~ DCC
were':stirred in 30 ml of dimethylformamLde for 2 hours-at 0 . and then for a further 3 hours' at 20C. The resin is f~l-'~ tered off,~ washed thoroughly with methanol and dried at 60 ,' ,~ . , under reduced pressu're,produced by an oll pump.' t) different batch of resinfromthat used ~or the.preparation of 6a '~
9) Boc-L-valine benzylamide . . ' ' 2.22 g of the polymeric activated ester 6b in 30 ml of ~ ' chloroform are stirred with 1 g of benzylamine ~or 15 minutesO
The resin is filtered off and washed with chloro~orm ~nd the com ' bined filtrateæ are extracted by shaking successively with 0.5 N
HCl, sodium carbonate solution and water. After drying and ; evaporating, the productt which is identical to an authentic .sample, is-obtained in a yield of 0.323 g. This gives a content of 0,~8 mmole. o~ Boc-Val-0H/g of resin 6b.
10~ Boc-Yal-Val-0Me 20 . ;7.5 g of the polymeric activated ester 6b (3.5 ~noles Boc-Val-0Hj and 0.250 g of L-valine methyl ester hydrochloride (1.5 mmoles) are st'irred in 100 ml of absolute methylene chloride.
After adding 3 ml of triethyla~ine and 1 ml o~ pyridine, the mix-ture is s-tirred f~r a further 200 minutes. The flltrates are ~rashed successive~y with 0.5 N HGl, sodium carbonate and water, .
.. dried and evaporated u~der,reduced pressure. After recrystal-lization from ether/petroleum'eth~r, 0.200 g of Boc-Yal-Val-0~e i5 obtained (yield 41%, ba~se'd on the L-valine methyl ester ,, ~ ' 28 ., - ..
!. . . . ........ . .. , . _ . . . .
3~ 5 O.Z. 32,036 , hydrochloride empIoyed~ Melting poin-t 159~161, melting point quoted in the literature 165-166~o C, Examples of the preparation of active esters of the formula ~3), o~ reactions of 3,4-carbonyldioxy-2,5-diphenylthiophene-171-dioxide and of the further processing of the resulting compounds 1, 3-(Phenylcarbamyloxy)-4-hydroxy-2,5-diphenylthiophene-171-dioxide . ~
;~ 0.93 g o~ aniline is added to 3.59 g of 3,4-carbonyl-dioxy-2,5-diphenylthiophene-1,1-dioxide in 30 ml of hot ethyl acetate and the reaction soIution developsareddish ~ange coloration ~or a short time, After boiling under reflux for 20 minutesj the solution is concentrated to half the original volume and filtered. The filter residue is washed ln portions with 100 ml of concentrated aqueous N~IC0~ solution c~nd then wi-th 100 ml of 20% s-trength aqueous citric acid solution.
. .
Yield: 3,7 g (88%), melting point 227C (deccmposition) a~ter recrystallization from chloroform/petroleum ether . - . .
C23~17N05S~ calc~ila-ted: C 65,87; H 4,o6; found: C 66.01; H 4~0 2. 3-(Benzylcarbamyloxy)-4-hydroxy-2,5-diphenylthiophene-].,1~
i~, dioxide ` . . 1. 07 g of benzylamine are added to 3,5g g o~ 3,4-carbon~Jl--dioxy-2,5-diphenylthiophene~ dioxide in 30 ml of hot ethyl acetate, The solution is boiled undei~ re~lux for 20 minutes and then ~ashed with three -times 30 mI of concentrated aqueous NaHC03 solu-tion and with three times 30 ml o~ 20% strength aqueous citric acid solution, The ~Jash liquors are extraGtcd with ethyl acetate and the ~ombined organic extrac-ts are dried over magnesium sulfate and evaporated.
., . ' ' ` ' ~
. 29 , .:,:,: .
3~35` ~
. .
~ o. z . 32 ,o~6 ;` . . . . .
~ Yield: 3.6 g (83%), melting~poin-t 200C (decomposition) ;~ , .
after recrystallization from chloroform/pe-troleum ether' ' calculated: C 66.51; H 4.39 found: C 66~,42; H 4.35 3. 3-(N,N-Diethylcarbamyloxy)-4-hydroxy-2,5-diphenylthiophene-' ; . l~l~dioxide ; 730 mg of diethylamine are added to 3.59 g o.~ 3,4 car~onyldioxy-2j5-diphenylthiophene-1,1-dioxide in 30 ml of hot ; , I .
ethyl acetate. The solution is boiled under reflux for 20 minutes, concentrated to halP its Yolume and filtered. The precipitate is washed in portions ~rith 100 ml ~ ~of concentrated aqueous N~HC03 solution and then with 100 ml of : ~ 20% strength aqueous citric acid solution.
' Yield: 3.4 g (85%), meltillg polnt 147~C alter recrystal-lization from chloroform/petroleum ether ' C21H21N55 calculated: ~ ~.02 . , ound: S 8.15 4,;~3-(N,N-Di.cyclohexylcarbamyloxy)-4-hydroxy-2`,5-diphenyl~
~hiophene~ dioxide 1.81 g o~ dicyclohexylamine are added to 3059 g of 3,4- ;~
.
carbonyldioxy-2,5-diphenylthiophene-1,1-dioxide in 30 mI of hot ethyl acetate and the solution devel~ps a deep red coloration ~or ; a short time. After boiling under reflux for 20 minutes 9 the solution is concentrated tG half its vo].ume and filtered, ~he precipitate is treated as described in Example C 3, ~Yield: 4,36 g (~60/o)~ melting point l65C a~ter recrystallization from chloroformjpetroleum ether 29 33 5 calculated: S 6,31 found: S 6,47 ', ~ . ~
3~5 ~ O.Z. 32,0~
.
5.. 3-(Piperidylcarbamylo~y3-4-hydroxy-2,5-diphenylthiophene-1~1-. .
dioxide : 850 mg of piperidine are added to 3.59 g of 3,4-carbonyldioxy-2,5-diphenylthiophene-1,1-dioxide in 30 ml of hot ethyl acetat,e. After boiling under rellux for 20 minutes, 'the solution ~s,washed-three -times wi-th 30 ml of concentra-ted aqueous:NaHC03 solut.ion and -three times with 20% strength aqueous ~ , : c~tric acid solution. The wash liquids are extracted with ;.:
.
eth~l acetate and the combined organic phases are dried over.,.
ma~nesium sulPate. A~ter distilllng of~ the solvent, a yellowish colored product is obtained as the rctsidue and thts is 're~rystallized ~rom chioroformlpe-troleum ether. ~
Yield': 3.3 g (8~/o) ~ melting point 135C. '`~.
C22~21N5S calculated: S 7.78 , ~, , : fo~ld , S 7.77 - 6. 3-(4-Morpholinylcarbam~;oxy)-4-hydroxy~2,5-diphenylthioph~ne dioxide ' -;
.. . .
870 mg of morpholine are' added to 3.59 g of 3,4-carbonyl- -.
dioxy-2,5-diphenylthiophene-1,1-dioxide in 30 ml of hot ethyl ~
t .
acetate and ~he solut.ion is boiled under reflux ~or , : 30 minutes; The solu-tion is then worked up as described i.n . Example C 5. ' Yield: 2.89 ~ (70/0), melting point 174C after . --~recrystallization from chloroform!petroleu~ ether C21H19N6S calculated: C 61.02; H 4.60; N 3,39 found: C 61~21; H 4.65; N 3.47
7, 0-Eth~1-0'-(3-hydroxy-2;'5-diphenylthiophene-1,1-dioxide-carbonate ' .
' -. - 31 ~
-, . - , ...... ......
O.Z. 32,036 460 mg of ethanol are added to 3.59 g of 3,4-carbonyl-diox~-2,5-diphenylthiophene~ dioxide in 30 ml of ethyl acetate.
The solution is ' boiled under reflux for 2 hours and then washed three times with 30 ml of concentrated aqueous NaHC03 solution and three times with 20% s-trength citric acid solution. The wash liquors are e~tracted with ethyl ace-tate and the,combined organic phases are dried over magnesium sulfate and then evaporated. The residue is recrystallized from cyclohexane~
, Yield: 3.01 g (81%~, melting point,129C ' '~
CgH16S06 calculated: ~C 61029; ~ 4.30;
~ound: C 61,31; H 4.19
' -. - 31 ~
-, . - , ...... ......
O.Z. 32,036 460 mg of ethanol are added to 3.59 g of 3,4-carbonyl-diox~-2,5-diphenylthiophene~ dioxide in 30 ml of ethyl acetate.
The solution is ' boiled under reflux for 2 hours and then washed three times with 30 ml of concentrated aqueous NaHC03 solution and three times with 20% s-trength citric acid solution. The wash liquors are e~tracted with ethyl ace-tate and the,combined organic phases are dried over magnesium sulfate and then evaporated. The residue is recrystallized from cyclohexane~
, Yield: 3.01 g (81%~, melting point,129C ' '~
CgH16S06 calculated: ~C 61029; ~ 4.30;
~ound: C 61,31; H 4.19
8. 0-Isobutyl-0'-(3-hydroxy-2,5-diphenylthiophene-1,1-dloxide)- ,-carbonate , 740 mg o~ isobutyl alcohol are added to 3,59 g o~ 3,4-carbonyldioxy-2,5-dip~enyl-thiophene-1~1-dioxide in 30 ml of ethyl acetate. The solution is boiled under re~l-~ for 2 hollrs, and then ~rorked up as described in Example C 7.
, , Yield: 2,78 g (69.5%), melting point 13,2C a~ter recrystallization ~rom,cyclohexane .
21H20S6 c~lculated: ' C 63 0; H 5 0' , fo~lnd: C 62,85; H 4,96
, , Yield: 2,78 g (69.5%), melting point 13,2C a~ter recrystallization ~rom,cyclohexane .
21H20S6 c~lculated: ' C 63 0; H 5 0' , fo~lnd: C 62,85; H 4,96
9, 0-Phenyl-0'-(3-hydroXy-2,5-diphenylthlophene-1,1-dioxide)-carbonate , ' 3.59 g of 3',l~-carbonyldioxy-2,5-diphenylthiophene-1 J 1-dioxide are suspended in 10 ml of acetone and 940 mg of phenol in 5 ml of acetone are added. The mix~ure is "
boi~ under reflux ~or 30 minutes and then filtered. The : ' ; :, '., ': . ': ', ' .
3~
O,Z. 32,036-- filter residue is w~shed with 50 ~1 of concentrated aqueous ~, . . .
NaHC03 solution and then with 50 ml of 20% strength aqueous citric acid solution.
~ield- 3,4 g (81%), melting poln-t 178C after recrystallization from chloroform. :`
C23H166S calculated: C 6~.7; H 3.81 found: . C 65.1; H ~.90
boi~ under reflux ~or 30 minutes and then filtered. The : ' ; :, '., ': . ': ', ' .
3~
O,Z. 32,036-- filter residue is w~shed with 50 ~1 of concentrated aqueous ~, . . .
NaHC03 solution and then with 50 ml of 20% strength aqueous citric acid solution.
~ield- 3,4 g (81%), melting poln-t 178C after recrystallization from chloroform. :`
C23H166S calculated: C 6~.7; H 3.81 found: . C 65.1; H ~.90
10. 0-Cholesteryl 0'~ hydroxy-2,5-diphenylthiophene-1,1-dioxid.e)-carbonate 3,~7 g of cholesterol are added to 3.59 g of 3 9 4-carbonyl-dioxy-2,5-diphenylthiophene-1 t l-dioxide in 30 ml of hot ethyl acetate. The solution is boiled under reflux for 2 hours , and then worked up as described i.n Example C 7, ;~ ~ Yield: 4.48 g (63%)~ melting point 119C after ~`
recrys~allization from chloroform/petroleum ether C4~,Tl5606S calculated: C 74.16; H 7,86 found: C 73.92; H 8,1~ ;
recrys~allization from chloroform/petroleum ether C4~,Tl5606S calculated: C 74.16; H 7,86 found: C 73.92; H 8,1~ ;
11. 3-~N-L(l-Carbomethoxy-ethyl)-carbamyloxy]--4-hydroxy-2,~-diphenylthiophene-I,l-dioxide . 1,03 g o~ L-alanine methyl e.ster are added to 3,59 ~ of 3,4 carbbnyidioxy-2,5~diphenylthiophene~ dioxide in 30 ml o~ !
ethyl acetate, The solution is boiled under reflux ~or 30 minutes and then washed three ~imes with 30 ml of concen-trated aqueous Na~C03 soiution and three times with 20%
strength citric acid solution,. The wash liquors are-extracted with ethyl acetate and the combi~ed organic phases are dried o~er ;~
- ;.
~magnesium sulfate an~ evaporatedO
Yield: 3,73 g (87%), melting point 227C (decomposi-tion) : .. . ,. -, , .
:, ;
o.Z. 32,036 -.
.
(cyclohexane3 ; C21HlgN7S ,Calcula~ed ~ 58.7~; H ~,43 found: C 58,61; H 4~59
ethyl acetate, The solution is boiled under reflux ~or 30 minutes and then washed three ~imes with 30 ml of concen-trated aqueous Na~C03 soiution and three times with 20%
strength citric acid solution,. The wash liquors are-extracted with ethyl acetate and the combi~ed organic phases are dried o~er ;~
- ;.
~magnesium sulfate an~ evaporatedO
Yield: 3,73 g (87%), melting point 227C (decomposi-tion) : .. . ,. -, , .
:, ;
o.Z. 32,036 -.
.
(cyclohexane3 ; C21HlgN7S ,Calcula~ed ~ 58.7~; H ~,43 found: C 58,61; H 4~59
12.. 3~[N-L(l-Carbomethoxy-2-methyl-propyl) carbamyloxy]-4-hydroxy-2,5-diphenylthiop~ene-1,1-dioxide , ~,28 g of I.-valine methyl ester are added to 3.59 g of 3,4-carbonyld.ioxy-Z,5-diphenylthlophene-1,1-dioxide in 30 ml of e~hyl acetate. The solu-tion is boiied under reflux for 30 minutes and then worked up as described in Example C 11~ ~.
Yield: 3,88 g (85%), mel-ting point 230C (decomposition~ '~
. (cyclohexane) C23~23N7S calculated: C 60.39; H 5.0~
~ound: C 60.19; H 5,00 ~13. 0-iso-Prop~1-0'-(4-h~Jdrox~-2,5-diphenylthiophene-1,1-dioxide)-carbonate , 600 mg o isopropanol are added to 3.59 g of 3j4-carbonyl~
.,dioxy-2?5-diphenylthiophene-1,1-dioxide in ~0 ml of e-thyl.aceta~e, l'he mixture is boiied under reflux for 2 hours and then worked up as described'in Example C 11. - . ~ . .
. ;Yield: 3.32 g (86~), melting po.int 131C (cyclohexane) - C20H1~6S calculated: C 62.2; H 4.66 : found, C 62~05; H 4.70 14. 3-[N-L-(l-Carbe-'choxy-3-methyl)-butyl-carbamyloxy]-4-hydro~y-~,5-diphenylthiophene~l,l-dioxid~
' . 1,59 g G~ . L-leucine ethyl ester are adde~ to 3.59 g o~
3 4-carbonyldioxy-2,5-diphenylt~liophene~ dioxide ~n ~0 ml o~
e~hyl acetate. The solution ls boiled under,reflux ~or 1 hour and then worked up as described in Example C 11, .. 34 a~ss .z~ 32,03~
Yield: 4,12 g (85%), melting point 253C (decomposi-tion) (chloroform3 C25H~7N07S calculated: C 61.86; H 5.57 ~ound: C 61.65; H 5.60 15. 3-(N,N~Diphenylcarbamyloxy~-4-hydroxy-2,5-diphenylthiophene-9 l-dioxide 1,58 g o~ diphenylamine are added to ~.59 g of 3,4-carbonyldioxy-2,5 diphenylthiophene-l,l-dioxide in 25 ml o~
~ioxane. The solution is boile.d . under reflux for 45 minutes and then evaporated to dryness. The residue is taken up in 30 ml of ethyl acetate and worked up as des-cribed in Example C 11.
Yield: 3.4 g (71.7%), melting point 216C (chlorofor~/-petroleum ether) :; ; C29H21N5S
16. 0-tert.-Butyl-0'-(3-hydroxy-2,5 diphenylthiophene~
dioxide)-carbona-te . .
740 mg of tert.-butyl alcohol are added -to 3.59 ~ o~ ~' 3,4-carbonyldioxy-2,5-diphenylthiophene-~.,1-dioxide in 30 ml of ethyl ace~ate, The solution is boiled under ref].ux for 2 hours and then worked up as described in ~xample C 11.
Yield: 3.16 g (79~'), melting point (acetone/petroleum ether) ~;
C21H2006S calculated: C 63,00; II 5.00 found: C 62.86; H 5..~9 17. 0-(3-Hydroxy-2,5-diphenylthiophene-1,1-dioxide)-S~benzyl-th~ carbonate 1.24 g of benzylmercaptan are added to 3.59 g o~ 3,4 carbonyldioxy-2,5-diphenylthiophene~ dioxide in ~ ~1 of ~ 35 -. .
~ o.Z, 32,03 , ~ethyl acetate. ~he solution is boiled under reflux for 2 hours and then worked up as described in Example C 11, Yield: ~ 90 g (86.6~o), meltlng point 173C (chloroform) C~4HlaOsS2 calculated: C 64.00; H 4.00 ~ound~ C 63.91~ H 4.lI ' 18. N--Benzyl-N'-phenylurea ' , 540 mg of benzylamine are added to 2.1 g of 3-(N-phenyl-ca~bamyloxy)-4-hydroxy-2,5-diphenylthiophene-1,1-dioxide in 20 ml of e~hyl aceta-te. The solution,is boiled under reflux for.l hour and then washed three times~with 25 ml of concentr~ted aqueous NaHC03 solution and three times with 20~
~ strength aqueous citric acid solution. The wash liqu~rs are extracted with ethyl acetate and the combined organic phases ..
are.dried over magnesiu~ sul~ate. ~f-tc-r eYaporating the fil--. trate, the crystalline residue is recrystallized from dilute ethanol, Yield: 1,02 g (90~/0), meltin~ point 167C ~:
C14H14N2 calculated: C 74.3; H 6.2 found: C 73,95; H 6,15 .
20 1~. M-Benzyl-N',~'-diethylurea . . .
365 mg of die-~hylamine are added to 3.16 g o~ 2-~N~
ben~yl-carbamyloxy)-4-hydroxy-2,5-diphenylthiophene-1,1-.
dioxide in 25 ml o~ ethyl ace~ate, The solution i~ .
boiled . under reflux for 1 hour and -then worked up as des-cribed in Example C 18, Yield: 876 mg (850b), melting point 170C (ethanol~
C12H18~2 calculated: `C;,69,0~; H 8.74 found: C 69,85; I~ 8,63 -, . , ' ~ 36 -o.Z. ~2,o36 ; ~ , . . . ...
20. N,N-Diethyl-N r -phenylurea ~ --~ 365 mg of diethylamine are added to 2.1 g of 3-(M-phenyl-carbamyloxy)-4-hydroxy-2,5-diphenylthiophene-1,1-dioxide in 20 ml o~ ethyl acetate. The solution is boiled under reflux for 1 hour and then worked up as described in Example C 18.
Yield: 758 mg (79%), meltlng point 86C (methanol~
CllH16N2 calculated: C 68.75;- H 8.33 ~o~d. C 68.60; H 8,21 21, 1 Benzyl-carbamylpiperidine 540 mg o~ benzylamLne are added to 2.06 g o~ 3 piperidylcarbamyloxy)-4-hydro~y-2,5-diphenylthiophene-19 l-dioxide in 20 ml of ethyl acetate. The solution i~ boiled under reflux for 1 hour and then worked up as described in Example C 18.
Yield: 1.00 g (92~), me~ting point 165C (m~thanol) C13H18N2 calculated, C 71.56; H 8.26 ~ !;~
~ound: C 70.99; H 8.35 22~ l-Benzyl-carbamyImorpholine 540 mg of benzylamine are added to 2.06 g o~ 3-(4-morpholinylcarba~ylo~y)-4-hydroxy-2,5-diphenyl~hiophene~
dioxide in 20 ml of ethyl acetate. The solution is boiled under reflux for 1 hour and then worked up as described in Example C 18.
Yield: 980 mg (89%), melting point 176C (methanol) C12H16N22 calculated: C 65.~5; H 7,27 ~ound: C 6~.95; H 7i35 23. N,M'-Di-(L-l-carbomethoxy-ethyl)-urea 2.06 g of L-alanine methyl ester are added to 3 59 g o~`
3~
O.Z. 32,036 3,4-carbonyldioxy-2,5-diphenyl-thiophen~-1,1-dioxide in 30 ml of ethyl acetate. The solution is boiled under re~lux for 1 hour and then worked up as described in Example C 18.
Yield: 1.81 g (78%j, melting point 187-192C (methanol) C9H16N25 calculated: C 46.55; H 6.89; N 12.07 found: C 46.40; H 7.01; N 11.73 24. N-Benzyl-N' (L-l-carbomethoxy-ethyl)-urea 503 mg of benzylamine are added to 2.15 g o~ 3-~N-L(l-carbomethoxy-ethyl)-carbamyloxy]-4-hydroxy~-2,5-diphenylthiophene-l,l-dioxide in 25 ml of ethyl aceta-te. The solu-tion is boiled under re~lux for 3 hour and then worked up as described in Example C 18.
Yield: 979 mg (83%), melting point 175C (e-thanol) .
C12H16N23 calculated: C 61 02; H 6.78 found: C ~0.89; ~ 6,85 25. 1-Diphenyl-carbamylpiperi~ine ~ ~1;25 mg of piperidine are added to 2.37 g of 3-(N,N-diphenylcarbamyloxy)-4~ ydroxy-2,5-diphenylthiophene-1,1-dioxide in 2c ml of acetone. The deep red solution is boiled under reflux ~or 1 hour and then ~rorked up~s describedin Example C 18.
,~ Yield: 1 04 g (74.3%), melting point 125C
26. ~holesteryl N-benzyl-carbamate 540 mg of benzylamine are added -to 3 5G g of 0-choles-teryl-0l-(4-hydro;xy-2,5-diphenylthiophene-1,1-dioxide)~carbonate in 25 ml o~ ethyl acetate. The solution is boiled under reflux for 2 hours and then washed three times with 30 ml o~ concentrated aqueou~s ~aHC03 solution and three tlmes with 30 ml of 20% strength citric acid solution. The wash ~ 3~ _ 3~ S
O.Z. 32,036 liquors are extracted with ethyl acetate and the combined organlc phases are dried over magnesium sul~ate and evaporated.
Yield: 2.10 g (81%), melting point 153C (ethanol) C35H5~N02 calculated: C 80.92~ H 10.21, N 2~70 ~;
- found: C 80.80, H 10,40, N 2.82 27. Isobutyl N-benzyl-carbamate 370 mg o~ isobutyl alcohoi are added to 2~00 g of ~-iso-butyl-0'-(4-hydroxy-2,5-diphenylthiophene~ dioxide)-carbonate . .
inl 5 ml o~ ethyl ace-t~te. The solution is boiled under reflux for 2 hours and then worked up as described in Example C 26.
Yield: 859 mg (83%), melting point 88C (ethanol) C12H17N2 calculated: C 68.~9, H 7.77 ~ourld: C 68,199 H 7.90 28, Ethyl N-benzyl-carbamate 540 mg of benzylamine are added to 1.86 g of 0-e-~hyl-0~-- (4- hydroxy-2,5-diphenylthiophene-1,1-dioxide)~carbonate in ;
25 ml of ethyl aceta-te. The inixture is boiled under reflux ~or 2 hours and tnen worked up as described in Ex~mple C 26.
Yield: 81~ mg (91~o), melting point 47C (ethanol3 ClOEI13N2 calculated: C 67. 04, H 7,26 found: C 66.98, H 7.31 29. Ethyl N-phenyl-carb~te 465 mg of aniline are ~dded to 1.86 g of 0-ethyl-0'-(4-hydroxy~2j5-diphenylthiophene~ dioxide)-carbonate in 25 ~1 of ethyl acetate. The mi~ture is boiled under .,,~ . . .
reflux for 2 hours and ~hen wiorked up2s~ibedin Example ~ 26.
o.z. 32,03fi Yield: 734 mg (89/~), melting point 52C (ethanol) C9HllN~t calculated: C 65.45, ~I 6.66 found: C 65.39, H 6.65 30. Isopropyl N-phenyl-carbamate 465 mg of aniline are added to 1.93 g of 0-isopropyl-0 ' -(4~hydroxy-2,5-diphenylthiophene~ dioxide)-carbona-te in 25 ml o~ ethyl acetate, The solution is boiled under r~lux for 2 hours and then worked up 2s described in Example C 26, ~ ield: 771 mg (860/), melting point 89C (ethanol) 10 C10~13Nr' calculated: C 66.96~ H 7.25 ~ ~ound: C 66.78, H 7.32 31. S-Benæyl-thiocarbamylpiperidine 425 mg of piperidine in 10 ml of ethyl acetate are added slowly dropwise to a solution of 2.25 g of 0-(3-hydroxy-2,5-diphenylthiophene-l,l-dioxide)-S-benzyl-thiol-carbonate in 20 ml of-ethyl ace-tate. The mixture is boiled under ~;~
reflux ~or a :~urther 2 hours and then worked up as de~c~ibed in ~xample C 26. ~ihen the organic phase i.s evaporated a yello~is'n colored oil is obtained as the residue and this crystallizes very slowly.
; ~ield: 930 mg (79,~
32. Methyl isocyanate 1.01 g of triethylamine and 675 mg of methylammonium chloride are added to 3 . 59 g of 3, 4-carbonyldioxy-2,5-diphenyl-thiophene~l,l-dio~ide in 50 ml o~ o-dichlorobenzene. The .
so~utic~n is heated at 130C and the methyl isocyanate formed is immediatel~t distilled off fr!~m the reaction mixture.
Yield: 540 mg (95~), boiling point 45C
' -- 1~0 -- , . .
lllQ3~S L
o z. 32, 03~ -~:, The me-thyl isocyanate was identif`ied in -the form o~ N~
methyl-M'-phenylurea.
C8HlON20 calculated: C 64.00, H 6.66 found: C 63.89, H 6.58 33. Phenyl isocyanate 2~1 g of 3-~phenylcarbamyloxy)-4-hydroxy-2,-5-diphenyl-thiophene-l 9 l-dioxide in 50 ml o~ o-dichlorobenzene are heated ~.
at 150C ~or 2 hours. The phenyl isocyanate formed is then ~ ;
distilled off under reduced pressure produced by a water pump~
, Yield: 571 mg (96%), boiling point 60C/15 mm Hg , G7H5N0 calculated: C 70.59, H ~i.20 fo~d: C 70.40, H 4.35 34, Benzyl isocy~na-te 2~16 g o-~ 3-(benzylcarbamyloxy)-4-hydroxy-2,5-diphenyl-thiQphene-ljl-dioxide in ~0 ml of o-dichlorobenzene are heated at 150C for 2 hour~3. The benzyl isocyanate formed is -then dLs-tilled o~f under reduced pressure produced by a ~rater p~p. ~;
- Yield: 625 mg (94~), boiling pointl2 88C
C8~ N0 calculated: C 72.18, H 5.26 ~ound: C 71.85, H 5.20 ~ - ~ 35. L-Carbonyl-alanine methyl ester ; 2.15 g of 3-[N-L~ carbornetho~y)-ethyl-carbamyloxy~
hydroxy-2,5-diphenylthiophene-1,1-dioxi~e are heated barefully u~
to the melting point, under greatly reduced pressure, The isocyanate formed is distilled off direct.
Yield: 587 mg (91%), boiling point 35C/0.8 mm Hg C5H7N03 calculated: C 4~ 51, H 5.43 found: C 46.39, H 5.50 .
38~
.
O.Z. 32,036 36. L-Carbonyl-valine methyl ester 2.28 g of 3-[N-L-(l-carbomethoxy-2-methyl)-propyl-carbamyloxy]-4-hydroxy-2,5-diphenylthiophene-1,1-dioxide are heated carefully up to the melting point, under greatly reduced pressure. The isocyanate formed is distilled off direct.
Yield: 699 mg (89%)~ boiling point 41C/0.8 mm Hg C7HllN3 calcula-ted: C 53.50, H 7 00 ~ound: C 53035 `H 7.10 37. L-Carbonyl-leucine ethyl ester 2.42 g of 3-[N-L-(l-carbethoxy-3-methyl)-butyl-carbamyl- -oxy]-4-hydroxy-2,5-diphenylthiophene-1,1-dioxide are heated care-full~ up to the melting point, under greatly reduced pressure.
The isocyanate formed is distilled off direct.
Yield: 805 mg ~87~), boiling point 51C/0 ~ mm Ho [a~20 -22,3 C9H15N3 calculated: C 58.38, H 8.11 found: ` C-58.25, H 8.10 38. p-Phenylene diisocyanate 504 mg of p-phenylenediamlne are added to 3 59 g of 3,4-carbonyldioxy-2,5-diphenylthiophene-1,1-dioxide in ~0 ml of o-dichlorobenzene. The solution is boiled underreflux for 2 hours and the solven-t is then distilled of~. The solid residue is distilled via a heated distillation bridge, under reduced pressure produced by a wa~er pump, Yield: 520 mg (65%), melting point 93C, boiling point 103C/13~nHg literat~: meltin~ point 94C, boiling point 110C/:L2 ~ Ig ' -D Examp~es of the preparation OL peptides, which can be us~d as . ~ .
structural units for the synthesis of antam~ides:
.
o.Z. 32,03~
1, N-tert.-But~ycarbonyl-L-alanine-L-phenylalanine methyl ester , 526 mg of triethylamine are added to a ~ixture of 942 mg of Boc-Ala ~S02 (the abbrevlation ~ S02 used here and bclow in the conte~Yt o~ the activated aminoacids denotes the rad~cal -3-oxy-4-hydroxy-2,5-diphen~Jlthiophene-l,l-dioxide) and 432 mg o~
Phe-OMe . HGl in 20 ml o~ absolute tetrahydrolura~ n then~xture becomes deep reà, It is stirred for i hour at 20C and in th;e course o~ 15 minutes the color changes -to pale yellow. The sdlvent is then distilled off and the residue is dissolved in ~ ~o methylene chloride, The solution is washed three times with ; 20% streng-th citric acid solution, three times with saturated sodlum bicarbonate solution and twice wLth water, dried over magnesium sulfate and evaporated under reduced pressure.
Yield: 686 mg (98/o) ~ me:lting point 81C
calculated: C 61,70, H 7,4~, N ~.00 fo~d: C 61.73, H 7,26~ N 8,10 [a]U = t6,9 ~ 0.3 c - 1, glacial acetic ac~d 2. L-~lanine-phenylalaniné me-thyl es-ter hydrochloride (elimination of the Boc group from D 1) 686 mgo~theBoc-dipeptid~ester D 1 are dissolved in 15.7 m~
o~ 1 N HCl in glacial acetic acid. Therea~-ter, the solu-tion is stirred ~or 2 hours at room temperature and then evaporated under reduced pressure, The residue is diges-ted with ether.
Yield: 5~4 mg (95%), melting point 150~ ;
calculated: C 54,45, E~ 6~64 found: C 54,13, H ~.59 [a~D = ~57~3 ~ 0~5 c a l,~glacial acetlc acid - 43 - ~
3~35 ., . . . , , . . ,:
.
' ~ O.Z. 32gO36 3. N-tert.-Butoxycarbonyl-L-proline-alanine-L-phenylalanine methyl ester 447 mg of triethylamine are added to a mixture o~ 4~8 mg of Ala-Phe-OMe.HCl D 2 and 8~5 mg o~ Boc-Pro~SOz in 20 ml of absolute te-trahydrofuran, whereupon the'color of the mixture becomes deep red. The mixture is stirred for 1 hour a-t 20C, The pale yellow mixture is then worked up as 'described in ~ample D 1 an~ -the' product is digested with petroleum ether.
' Yield: 731 mg (96~6), melting point 120C
calculated: C 61.50, ~I 7.37 found: C 61.27, H 7,33 4, L-PrQline-L-alanine-L-phenylalanine methyl ester hydrochloride' , (e]imina-tion o~ the Boc group from D 3) ~- .
716 mg of the Boc-tripeptide es-ter D 3 are dissolved~in 12.~ ml o~ 1 N ~ICl ln glacial acetic acid. m ereafter, the solution is stirred ~or 2 hours at room temperature and then ' ' evaporated under reduced pressure. , The resulting oil precipi-tatès as a solid from tetrahydrofuran with petroleum ether.
Yield: 571 mg (93%), amorphous powder calculated: C 53.80, H 6.9~, N 10.45 ~ound: , C,54.23, H 6.~5, N 10,41 ~a~20 = -21.0 ~ 0.5 c - i, glacial ace-tic acid ~ ~ , 5, N-tert,-Buto~Jcarbonyl-L-proline~L-proline-L-alanine-L-phenylalanine methyl es-ter -341 mg o~ triethylamine are added to a mixture of 500,mg o~ Pro-Ala-Phe OMe.HCl D 4 and 647 mg o~ Boc-Pro ~S02 in 20 ml of absolute tetrahydrofur~n wher~lpon th~ mixture develops a deep red coloration. It is stirred for 1 hour at 20C, The pale , - 4~ ~
3~35;
. `
O,Z. 32~J36 yellow mi~ture is then worked up as described in Example D 1.
, ~ Yield: 657 mg (93%), oil.
6, L-Proline-L-proline-L alanine-L phenylalanine me-thyl ester hydrochloride - .
(elimination of the Boc group from D 5) 600 mg ~ ~eBo~tetrapeptide ester D 5 are dissolved in 8,8 ml o~ 1 N HCl in glaclal acetic acid. Thereafter, the solution is stirred for 2 hours at room temperature and then evaporat~ed under reduced pressure.
Yield: 454 mg (86%), melting point 75C
calculated: C 57.43, H 6.92, N 11.65 found: C 57.17 9 H 6,93, N 11.41 7. ~-tert,-Butoxycarbonyl-L-valine~L-proline-L-proline-L-alanine--L-phenylalan~ne methyl ester 184 mg of triethylamine are added to a mixture of ~37 mg of Pro2-Ala-P~le--OMe.HC1 ~ 6 and 350 mg o~ Boc-Val~ S02 in 20 ml of absolute tetrahydrofuran~ whereupon the mix-ture develops a deep re~
coloration. It is stirred for 2 hours at room temperature.
The pale yellow mixture is then worked up as described in Example D 1, - - Yi~ld: 400 mg (89%), oil 8. L-~aline-L-proline-L-proline-L-alanine-L-phenylalanine methyl ester hydrochloride (elimination o~ the Boc group from D 7~
322 mg ~the Boc-pen-tapeptide es~rD 7 are dissolved in .
4 ml o~ 1 N HCl in glacial ace~ic acid. The solution is ~ ;
then stirred for 2 hours ab~oom temperatur~ and evapora-ted under reduced pressure, , - ~5 -.
`
3~ S
' . . o.Z. ~,036 .
Yield: 202 mg (70%), melt.ing point 127 - 129C
9',~ N-tert,-Butoxycarbonyl-L-phenylalanine-L phenylalanine ~ethyl . ~ ester ' ' 788 mg of triethylami-ne are added to a mixture of 648 mg of Phe-OMe.HCl and 1.641 g of Boc-Phe~ S02 in 20 ml of abs.olute tetrahydrofuran,whereupon~-the mixture 'oecomes deep red. It i~
stirred for 1 hour at 20bC. The pale yellow mixture is.then ~ worked up as described in Example D l. -~
- I Yield: 1,250 mg (98%), melting point 132C ' 10. L-Phenylalanine-L-phenylalanine methyl ester hydroc~loride (elimination of the Boc group from D 9) .
, 1,200 mg of -the Boc-dipeptide ester D 9 are dissolved in -2~,5 ml o~ 1 N HCl in glacial acetic acid. The mixture is then stirred,for 2 hours at room temperature and evaporated under '-reduced pressure, "' Yield: 988 mg (97%), melting point 193C ' , ' ~' .
' calculated: C 62.85, H 6.39, N 7.72 , . . .
~oundo - C 62.85; ~ 6.70, N 7,70 11. N-tert.-Butoxycarbonyl-L-proline-L-phenylalanine-L-phenyl~
20 alanine methyl ester - , . ~ : , 687 mg of triethylamine are added to a mixture o~ 94~ mg o~ Phe-Phe-OMe.HCl D 10 and 1,293 mg o~ Boc-Pro ~ S02 in 20 ml o.~
absolute tetrahydrofuran~whereupon the mixture develops a deep red ' colorat~on. . .It is stirred for 1 hour at 20C. The pale yellow mixture is then wor~ed up as described in Example D 1. , ' Yield: 1,317 mg (97%), melting point 115C .
calculated: C 6~.50/ H 7.08,- N 8~03 . , ~ound: C 66.55, H 7.23, N 7,95 .
- 46 - , . :
3~5 .
.
0.~. ~2,036 12. ~-Proline-L-phenylalanine-L-phenylalanine methyl ester hydrochloride (élimination of the Boc group ~rom D 11) . 1,255 mg of the Boc-tripeptide ester D 11 are dissolved in 19 ml of 1 N HCl in glacial acetic acid. Thereaf-ter, -the mixture is stirred for 2 hours at room temperature and then evaporated under reduced pressure.
Yield: 1,011 mg (92~), amorphous powder
Yield: 3,88 g (85%), mel-ting point 230C (decomposition~ '~
. (cyclohexane) C23~23N7S calculated: C 60.39; H 5.0~
~ound: C 60.19; H 5,00 ~13. 0-iso-Prop~1-0'-(4-h~Jdrox~-2,5-diphenylthiophene-1,1-dioxide)-carbonate , 600 mg o isopropanol are added to 3.59 g of 3j4-carbonyl~
.,dioxy-2?5-diphenylthiophene-1,1-dioxide in ~0 ml of e-thyl.aceta~e, l'he mixture is boiied under reflux for 2 hours and then worked up as described'in Example C 11. - . ~ . .
. ;Yield: 3.32 g (86~), melting po.int 131C (cyclohexane) - C20H1~6S calculated: C 62.2; H 4.66 : found, C 62~05; H 4.70 14. 3-[N-L-(l-Carbe-'choxy-3-methyl)-butyl-carbamyloxy]-4-hydro~y-~,5-diphenylthiophene~l,l-dioxid~
' . 1,59 g G~ . L-leucine ethyl ester are adde~ to 3.59 g o~
3 4-carbonyldioxy-2,5-diphenylt~liophene~ dioxide ~n ~0 ml o~
e~hyl acetate. The solution ls boiled under,reflux ~or 1 hour and then worked up as described in Example C 11, .. 34 a~ss .z~ 32,03~
Yield: 4,12 g (85%), melting point 253C (decomposi-tion) (chloroform3 C25H~7N07S calculated: C 61.86; H 5.57 ~ound: C 61.65; H 5.60 15. 3-(N,N~Diphenylcarbamyloxy~-4-hydroxy-2,5-diphenylthiophene-9 l-dioxide 1,58 g o~ diphenylamine are added to ~.59 g of 3,4-carbonyldioxy-2,5 diphenylthiophene-l,l-dioxide in 25 ml o~
~ioxane. The solution is boile.d . under reflux for 45 minutes and then evaporated to dryness. The residue is taken up in 30 ml of ethyl acetate and worked up as des-cribed in Example C 11.
Yield: 3.4 g (71.7%), melting point 216C (chlorofor~/-petroleum ether) :; ; C29H21N5S
16. 0-tert.-Butyl-0'-(3-hydroxy-2,5 diphenylthiophene~
dioxide)-carbona-te . .
740 mg of tert.-butyl alcohol are added -to 3.59 ~ o~ ~' 3,4-carbonyldioxy-2,5-diphenylthiophene-~.,1-dioxide in 30 ml of ethyl ace~ate, The solution is boiled under ref].ux for 2 hours and then worked up as described in ~xample C 11.
Yield: 3.16 g (79~'), melting point (acetone/petroleum ether) ~;
C21H2006S calculated: C 63,00; II 5.00 found: C 62.86; H 5..~9 17. 0-(3-Hydroxy-2,5-diphenylthiophene-1,1-dioxide)-S~benzyl-th~ carbonate 1.24 g of benzylmercaptan are added to 3.59 g o~ 3,4 carbonyldioxy-2,5-diphenylthiophene~ dioxide in ~ ~1 of ~ 35 -. .
~ o.Z, 32,03 , ~ethyl acetate. ~he solution is boiled under reflux for 2 hours and then worked up as described in Example C 11, Yield: ~ 90 g (86.6~o), meltlng point 173C (chloroform) C~4HlaOsS2 calculated: C 64.00; H 4.00 ~ound~ C 63.91~ H 4.lI ' 18. N--Benzyl-N'-phenylurea ' , 540 mg of benzylamine are added to 2.1 g of 3-(N-phenyl-ca~bamyloxy)-4-hydroxy-2,5-diphenylthiophene-1,1-dioxide in 20 ml of e~hyl aceta-te. The solution,is boiled under reflux for.l hour and then washed three times~with 25 ml of concentr~ted aqueous NaHC03 solution and three times with 20~
~ strength aqueous citric acid solution. The wash liqu~rs are extracted with ethyl acetate and the combined organic phases ..
are.dried over magnesiu~ sul~ate. ~f-tc-r eYaporating the fil--. trate, the crystalline residue is recrystallized from dilute ethanol, Yield: 1,02 g (90~/0), meltin~ point 167C ~:
C14H14N2 calculated: C 74.3; H 6.2 found: C 73,95; H 6,15 .
20 1~. M-Benzyl-N',~'-diethylurea . . .
365 mg of die-~hylamine are added to 3.16 g o~ 2-~N~
ben~yl-carbamyloxy)-4-hydroxy-2,5-diphenylthiophene-1,1-.
dioxide in 25 ml o~ ethyl ace~ate, The solution i~ .
boiled . under reflux for 1 hour and -then worked up as des-cribed in Example C 18, Yield: 876 mg (850b), melting point 170C (ethanol~
C12H18~2 calculated: `C;,69,0~; H 8.74 found: C 69,85; I~ 8,63 -, . , ' ~ 36 -o.Z. ~2,o36 ; ~ , . . . ...
20. N,N-Diethyl-N r -phenylurea ~ --~ 365 mg of diethylamine are added to 2.1 g of 3-(M-phenyl-carbamyloxy)-4-hydroxy-2,5-diphenylthiophene-1,1-dioxide in 20 ml o~ ethyl acetate. The solution is boiled under reflux for 1 hour and then worked up as described in Example C 18.
Yield: 758 mg (79%), meltlng point 86C (methanol~
CllH16N2 calculated: C 68.75;- H 8.33 ~o~d. C 68.60; H 8,21 21, 1 Benzyl-carbamylpiperidine 540 mg o~ benzylamLne are added to 2.06 g o~ 3 piperidylcarbamyloxy)-4-hydro~y-2,5-diphenylthiophene-19 l-dioxide in 20 ml of ethyl acetate. The solution i~ boiled under reflux for 1 hour and then worked up as described in Example C 18.
Yield: 1.00 g (92~), me~ting point 165C (m~thanol) C13H18N2 calculated, C 71.56; H 8.26 ~ !;~
~ound: C 70.99; H 8.35 22~ l-Benzyl-carbamyImorpholine 540 mg of benzylamine are added to 2.06 g o~ 3-(4-morpholinylcarba~ylo~y)-4-hydroxy-2,5-diphenyl~hiophene~
dioxide in 20 ml of ethyl acetate. The solution is boiled under reflux for 1 hour and then worked up as described in Example C 18.
Yield: 980 mg (89%), melting point 176C (methanol) C12H16N22 calculated: C 65.~5; H 7,27 ~ound: C 6~.95; H 7i35 23. N,M'-Di-(L-l-carbomethoxy-ethyl)-urea 2.06 g of L-alanine methyl ester are added to 3 59 g o~`
3~
O.Z. 32,036 3,4-carbonyldioxy-2,5-diphenyl-thiophen~-1,1-dioxide in 30 ml of ethyl acetate. The solution is boiled under re~lux for 1 hour and then worked up as described in Example C 18.
Yield: 1.81 g (78%j, melting point 187-192C (methanol) C9H16N25 calculated: C 46.55; H 6.89; N 12.07 found: C 46.40; H 7.01; N 11.73 24. N-Benzyl-N' (L-l-carbomethoxy-ethyl)-urea 503 mg of benzylamine are added to 2.15 g o~ 3-~N-L(l-carbomethoxy-ethyl)-carbamyloxy]-4-hydroxy~-2,5-diphenylthiophene-l,l-dioxide in 25 ml of ethyl aceta-te. The solu-tion is boiled under re~lux for 3 hour and then worked up as described in Example C 18.
Yield: 979 mg (83%), melting point 175C (e-thanol) .
C12H16N23 calculated: C 61 02; H 6.78 found: C ~0.89; ~ 6,85 25. 1-Diphenyl-carbamylpiperi~ine ~ ~1;25 mg of piperidine are added to 2.37 g of 3-(N,N-diphenylcarbamyloxy)-4~ ydroxy-2,5-diphenylthiophene-1,1-dioxide in 2c ml of acetone. The deep red solution is boiled under reflux ~or 1 hour and then ~rorked up~s describedin Example C 18.
,~ Yield: 1 04 g (74.3%), melting point 125C
26. ~holesteryl N-benzyl-carbamate 540 mg of benzylamine are added -to 3 5G g of 0-choles-teryl-0l-(4-hydro;xy-2,5-diphenylthiophene-1,1-dioxide)~carbonate in 25 ml o~ ethyl acetate. The solution is boiled under reflux for 2 hours and then washed three times with 30 ml o~ concentrated aqueou~s ~aHC03 solution and three tlmes with 30 ml of 20% strength citric acid solution. The wash ~ 3~ _ 3~ S
O.Z. 32,036 liquors are extracted with ethyl acetate and the combined organlc phases are dried over magnesium sul~ate and evaporated.
Yield: 2.10 g (81%), melting point 153C (ethanol) C35H5~N02 calculated: C 80.92~ H 10.21, N 2~70 ~;
- found: C 80.80, H 10,40, N 2.82 27. Isobutyl N-benzyl-carbamate 370 mg o~ isobutyl alcohoi are added to 2~00 g of ~-iso-butyl-0'-(4-hydroxy-2,5-diphenylthiophene~ dioxide)-carbonate . .
inl 5 ml o~ ethyl ace-t~te. The solution is boiled under reflux for 2 hours and then worked up as described in Example C 26.
Yield: 859 mg (83%), melting point 88C (ethanol) C12H17N2 calculated: C 68.~9, H 7.77 ~ourld: C 68,199 H 7.90 28, Ethyl N-benzyl-carbamate 540 mg of benzylamine are added to 1.86 g of 0-e-~hyl-0~-- (4- hydroxy-2,5-diphenylthiophene-1,1-dioxide)~carbonate in ;
25 ml of ethyl aceta-te. The inixture is boiled under reflux ~or 2 hours and tnen worked up as described in Ex~mple C 26.
Yield: 81~ mg (91~o), melting point 47C (ethanol3 ClOEI13N2 calculated: C 67. 04, H 7,26 found: C 66.98, H 7.31 29. Ethyl N-phenyl-carb~te 465 mg of aniline are ~dded to 1.86 g of 0-ethyl-0'-(4-hydroxy~2j5-diphenylthiophene~ dioxide)-carbonate in 25 ~1 of ethyl acetate. The mi~ture is boiled under .,,~ . . .
reflux for 2 hours and ~hen wiorked up2s~ibedin Example ~ 26.
o.z. 32,03fi Yield: 734 mg (89/~), melting point 52C (ethanol) C9HllN~t calculated: C 65.45, ~I 6.66 found: C 65.39, H 6.65 30. Isopropyl N-phenyl-carbamate 465 mg of aniline are added to 1.93 g of 0-isopropyl-0 ' -(4~hydroxy-2,5-diphenylthiophene~ dioxide)-carbona-te in 25 ml o~ ethyl acetate, The solution is boiled under r~lux for 2 hours and then worked up 2s described in Example C 26, ~ ield: 771 mg (860/), melting point 89C (ethanol) 10 C10~13Nr' calculated: C 66.96~ H 7.25 ~ ~ound: C 66.78, H 7.32 31. S-Benæyl-thiocarbamylpiperidine 425 mg of piperidine in 10 ml of ethyl acetate are added slowly dropwise to a solution of 2.25 g of 0-(3-hydroxy-2,5-diphenylthiophene-l,l-dioxide)-S-benzyl-thiol-carbonate in 20 ml of-ethyl ace-tate. The mixture is boiled under ~;~
reflux ~or a :~urther 2 hours and then worked up as de~c~ibed in ~xample C 26. ~ihen the organic phase i.s evaporated a yello~is'n colored oil is obtained as the residue and this crystallizes very slowly.
; ~ield: 930 mg (79,~
32. Methyl isocyanate 1.01 g of triethylamine and 675 mg of methylammonium chloride are added to 3 . 59 g of 3, 4-carbonyldioxy-2,5-diphenyl-thiophene~l,l-dio~ide in 50 ml o~ o-dichlorobenzene. The .
so~utic~n is heated at 130C and the methyl isocyanate formed is immediatel~t distilled off fr!~m the reaction mixture.
Yield: 540 mg (95~), boiling point 45C
' -- 1~0 -- , . .
lllQ3~S L
o z. 32, 03~ -~:, The me-thyl isocyanate was identif`ied in -the form o~ N~
methyl-M'-phenylurea.
C8HlON20 calculated: C 64.00, H 6.66 found: C 63.89, H 6.58 33. Phenyl isocyanate 2~1 g of 3-~phenylcarbamyloxy)-4-hydroxy-2,-5-diphenyl-thiophene-l 9 l-dioxide in 50 ml o~ o-dichlorobenzene are heated ~.
at 150C ~or 2 hours. The phenyl isocyanate formed is then ~ ;
distilled off under reduced pressure produced by a water pump~
, Yield: 571 mg (96%), boiling point 60C/15 mm Hg , G7H5N0 calculated: C 70.59, H ~i.20 fo~d: C 70.40, H 4.35 34, Benzyl isocy~na-te 2~16 g o-~ 3-(benzylcarbamyloxy)-4-hydroxy-2,5-diphenyl-thiQphene-ljl-dioxide in ~0 ml of o-dichlorobenzene are heated at 150C for 2 hour~3. The benzyl isocyanate formed is -then dLs-tilled o~f under reduced pressure produced by a ~rater p~p. ~;
- Yield: 625 mg (94~), boiling pointl2 88C
C8~ N0 calculated: C 72.18, H 5.26 ~ound: C 71.85, H 5.20 ~ - ~ 35. L-Carbonyl-alanine methyl ester ; 2.15 g of 3-[N-L~ carbornetho~y)-ethyl-carbamyloxy~
hydroxy-2,5-diphenylthiophene-1,1-dioxi~e are heated barefully u~
to the melting point, under greatly reduced pressure, The isocyanate formed is distilled off direct.
Yield: 587 mg (91%), boiling point 35C/0.8 mm Hg C5H7N03 calculated: C 4~ 51, H 5.43 found: C 46.39, H 5.50 .
38~
.
O.Z. 32,036 36. L-Carbonyl-valine methyl ester 2.28 g of 3-[N-L-(l-carbomethoxy-2-methyl)-propyl-carbamyloxy]-4-hydroxy-2,5-diphenylthiophene-1,1-dioxide are heated carefully up to the melting point, under greatly reduced pressure. The isocyanate formed is distilled off direct.
Yield: 699 mg (89%)~ boiling point 41C/0.8 mm Hg C7HllN3 calcula-ted: C 53.50, H 7 00 ~ound: C 53035 `H 7.10 37. L-Carbonyl-leucine ethyl ester 2.42 g of 3-[N-L-(l-carbethoxy-3-methyl)-butyl-carbamyl- -oxy]-4-hydroxy-2,5-diphenylthiophene-1,1-dioxide are heated care-full~ up to the melting point, under greatly reduced pressure.
The isocyanate formed is distilled off direct.
Yield: 805 mg ~87~), boiling point 51C/0 ~ mm Ho [a~20 -22,3 C9H15N3 calculated: C 58.38, H 8.11 found: ` C-58.25, H 8.10 38. p-Phenylene diisocyanate 504 mg of p-phenylenediamlne are added to 3 59 g of 3,4-carbonyldioxy-2,5-diphenylthiophene-1,1-dioxide in ~0 ml of o-dichlorobenzene. The solution is boiled underreflux for 2 hours and the solven-t is then distilled of~. The solid residue is distilled via a heated distillation bridge, under reduced pressure produced by a wa~er pump, Yield: 520 mg (65%), melting point 93C, boiling point 103C/13~nHg literat~: meltin~ point 94C, boiling point 110C/:L2 ~ Ig ' -D Examp~es of the preparation OL peptides, which can be us~d as . ~ .
structural units for the synthesis of antam~ides:
.
o.Z. 32,03~
1, N-tert.-But~ycarbonyl-L-alanine-L-phenylalanine methyl ester , 526 mg of triethylamine are added to a ~ixture of 942 mg of Boc-Ala ~S02 (the abbrevlation ~ S02 used here and bclow in the conte~Yt o~ the activated aminoacids denotes the rad~cal -3-oxy-4-hydroxy-2,5-diphen~Jlthiophene-l,l-dioxide) and 432 mg o~
Phe-OMe . HGl in 20 ml o~ absolute tetrahydrolura~ n then~xture becomes deep reà, It is stirred for i hour at 20C and in th;e course o~ 15 minutes the color changes -to pale yellow. The sdlvent is then distilled off and the residue is dissolved in ~ ~o methylene chloride, The solution is washed three times with ; 20% streng-th citric acid solution, three times with saturated sodlum bicarbonate solution and twice wLth water, dried over magnesium sulfate and evaporated under reduced pressure.
Yield: 686 mg (98/o) ~ me:lting point 81C
calculated: C 61,70, H 7,4~, N ~.00 fo~d: C 61.73, H 7,26~ N 8,10 [a]U = t6,9 ~ 0.3 c - 1, glacial acetic ac~d 2. L-~lanine-phenylalaniné me-thyl es-ter hydrochloride (elimination of the Boc group from D 1) 686 mgo~theBoc-dipeptid~ester D 1 are dissolved in 15.7 m~
o~ 1 N HCl in glacial acetic acid. Therea~-ter, the solu-tion is stirred ~or 2 hours at room temperature and then evaporated under reduced pressure, The residue is diges-ted with ether.
Yield: 5~4 mg (95%), melting point 150~ ;
calculated: C 54,45, E~ 6~64 found: C 54,13, H ~.59 [a~D = ~57~3 ~ 0~5 c a l,~glacial acetlc acid - 43 - ~
3~35 ., . . . , , . . ,:
.
' ~ O.Z. 32gO36 3. N-tert.-Butoxycarbonyl-L-proline-alanine-L-phenylalanine methyl ester 447 mg of triethylamine are added to a mixture o~ 4~8 mg of Ala-Phe-OMe.HCl D 2 and 8~5 mg o~ Boc-Pro~SOz in 20 ml of absolute te-trahydrofuran, whereupon the'color of the mixture becomes deep red. The mixture is stirred for 1 hour a-t 20C, The pale yellow mixture is then worked up as 'described in ~ample D 1 an~ -the' product is digested with petroleum ether.
' Yield: 731 mg (96~6), melting point 120C
calculated: C 61.50, ~I 7.37 found: C 61.27, H 7,33 4, L-PrQline-L-alanine-L-phenylalanine methyl ester hydrochloride' , (e]imina-tion o~ the Boc group from D 3) ~- .
716 mg of the Boc-tripeptide es-ter D 3 are dissolved~in 12.~ ml o~ 1 N ~ICl ln glacial acetic acid. m ereafter, the solution is stirred ~or 2 hours at room temperature and then ' ' evaporated under reduced pressure. , The resulting oil precipi-tatès as a solid from tetrahydrofuran with petroleum ether.
Yield: 571 mg (93%), amorphous powder calculated: C 53.80, H 6.9~, N 10.45 ~ound: , C,54.23, H 6.~5, N 10,41 ~a~20 = -21.0 ~ 0.5 c - i, glacial ace-tic acid ~ ~ , 5, N-tert,-Buto~Jcarbonyl-L-proline~L-proline-L-alanine-L-phenylalanine methyl es-ter -341 mg o~ triethylamine are added to a mixture of 500,mg o~ Pro-Ala-Phe OMe.HCl D 4 and 647 mg o~ Boc-Pro ~S02 in 20 ml of absolute tetrahydrofur~n wher~lpon th~ mixture develops a deep red coloration. It is stirred for 1 hour at 20C, The pale , - 4~ ~
3~35;
. `
O,Z. 32~J36 yellow mi~ture is then worked up as described in Example D 1.
, ~ Yield: 657 mg (93%), oil.
6, L-Proline-L-proline-L alanine-L phenylalanine me-thyl ester hydrochloride - .
(elimination of the Boc group from D 5) 600 mg ~ ~eBo~tetrapeptide ester D 5 are dissolved in 8,8 ml o~ 1 N HCl in glaclal acetic acid. Thereafter, the solution is stirred for 2 hours at room temperature and then evaporat~ed under reduced pressure.
Yield: 454 mg (86%), melting point 75C
calculated: C 57.43, H 6.92, N 11.65 found: C 57.17 9 H 6,93, N 11.41 7. ~-tert,-Butoxycarbonyl-L-valine~L-proline-L-proline-L-alanine--L-phenylalan~ne methyl ester 184 mg of triethylamine are added to a mixture of ~37 mg of Pro2-Ala-P~le--OMe.HC1 ~ 6 and 350 mg o~ Boc-Val~ S02 in 20 ml of absolute tetrahydrofuran~ whereupon the mix-ture develops a deep re~
coloration. It is stirred for 2 hours at room temperature.
The pale yellow mixture is then worked up as described in Example D 1, - - Yi~ld: 400 mg (89%), oil 8. L-~aline-L-proline-L-proline-L-alanine-L-phenylalanine methyl ester hydrochloride (elimination o~ the Boc group from D 7~
322 mg ~the Boc-pen-tapeptide es~rD 7 are dissolved in .
4 ml o~ 1 N HCl in glacial ace~ic acid. The solution is ~ ;
then stirred for 2 hours ab~oom temperatur~ and evapora-ted under reduced pressure, , - ~5 -.
`
3~ S
' . . o.Z. ~,036 .
Yield: 202 mg (70%), melt.ing point 127 - 129C
9',~ N-tert,-Butoxycarbonyl-L-phenylalanine-L phenylalanine ~ethyl . ~ ester ' ' 788 mg of triethylami-ne are added to a mixture of 648 mg of Phe-OMe.HCl and 1.641 g of Boc-Phe~ S02 in 20 ml of abs.olute tetrahydrofuran,whereupon~-the mixture 'oecomes deep red. It i~
stirred for 1 hour at 20bC. The pale yellow mixture is.then ~ worked up as described in Example D l. -~
- I Yield: 1,250 mg (98%), melting point 132C ' 10. L-Phenylalanine-L-phenylalanine methyl ester hydroc~loride (elimination of the Boc group from D 9) .
, 1,200 mg of -the Boc-dipeptide ester D 9 are dissolved in -2~,5 ml o~ 1 N HCl in glacial acetic acid. The mixture is then stirred,for 2 hours at room temperature and evaporated under '-reduced pressure, "' Yield: 988 mg (97%), melting point 193C ' , ' ~' .
' calculated: C 62.85, H 6.39, N 7.72 , . . .
~oundo - C 62.85; ~ 6.70, N 7,70 11. N-tert.-Butoxycarbonyl-L-proline-L-phenylalanine-L-phenyl~
20 alanine methyl ester - , . ~ : , 687 mg of triethylamine are added to a mixture o~ 94~ mg o~ Phe-Phe-OMe.HCl D 10 and 1,293 mg o~ Boc-Pro ~ S02 in 20 ml o.~
absolute tetrahydrofuran~whereupon the mixture develops a deep red ' colorat~on. . .It is stirred for 1 hour at 20C. The pale yellow mixture is then wor~ed up as described in Example D 1. , ' Yield: 1,317 mg (97%), melting point 115C .
calculated: C 6~.50/ H 7.08,- N 8~03 . , ~ound: C 66.55, H 7.23, N 7,95 .
- 46 - , . :
3~5 .
.
0.~. ~2,036 12. ~-Proline-L-phenylalanine-L-phenylalanine methyl ester hydrochloride (élimination of the Boc group ~rom D 11) . 1,255 mg of the Boc-tripeptide ester D 11 are dissolved in 19 ml of 1 N HCl in glacial acetic acid. Thereaf-ter, -the mixture is stirred for 2 hours at room temperature and then evaporated under reduced pressure.
Yield: 1,011 mg (92~), amorphous powder
13. N-tert.-Butoxycarbonyl-L-proline-L-proline-L-phenylalanine_ L-phenylalanine methyl ester 552 mg of triethylamine are added to a mixture of 965 mg -~
o~ Pro-Phe-Phe-OMe HCl D 12 and 1,044 mg of Boc-Pro ~S02 in 20 ml of absolute tetrahydrofuran, whereupon the mixture de~elops a deq? red ; coloration. It is stirred for 1.5 hours at 20C The pale yellow mixture is then worked up as described in Example D 1.
YieldO 1,183 mg (91%~, oil calculated: C 65.78, H 7.14 .
found: C 65.61 7 H 6.83
o~ Pro-Phe-Phe-OMe HCl D 12 and 1,044 mg of Boc-Pro ~S02 in 20 ml of absolute tetrahydrofuran, whereupon the mixture de~elops a deq? red ; coloration. It is stirred for 1.5 hours at 20C The pale yellow mixture is then worked up as described in Example D 1.
YieldO 1,183 mg (91%~, oil calculated: C 65.78, H 7.14 .
found: C 65.61 7 H 6.83
14. L-Proline-L-proline-L-phenylalanine-L-phenylalanine methyl ester hydrochloride (elimination of the Boc group ~rom D 13) 1,116 mg o~ the Boc-tetrapeptide ester D 13 are dissolved in I4.4 ml of 1 N HCl ln glacial acetic acid. The mixture is then stirred ~or 2 hours at room temperature and evaporated under reduced pressure Yield: 910 mg (91%), amorphous powder N-tert.-Butoxycarbonyl-L-phenylalanine-L-proline-L-proline-. ~
L-phenylalanine-L-phenylalanine methyI ester , .
. . . oOZ. 32,036 420 mg o trie~hyla~ine afe added to a mixture of agl mg of Pro-Pro-Phe-Phe-OMe.HCl D 14 and 875 mg of Boc-Phe ~S02 in 20 ml of absolute tetrahydrofuran J whereupon the mixturedevelops adee , red coloration. It is stirred for 2 hours at 20C. The pa~e yellow mixture is then worked up as described in:Example D 1J
Yield: 1,080 mg (88%), melting point 78 - 80QC . -calculated: C 67.30, H 67908 found C S,90 H 6,96 ,' "~
~, ' ' ' , ', . , ' .
.
.
~ 48 .
L-phenylalanine-L-phenylalanine methyI ester , .
. . . oOZ. 32,036 420 mg o trie~hyla~ine afe added to a mixture of agl mg of Pro-Pro-Phe-Phe-OMe.HCl D 14 and 875 mg of Boc-Phe ~S02 in 20 ml of absolute tetrahydrofuran J whereupon the mixturedevelops adee , red coloration. It is stirred for 2 hours at 20C. The pa~e yellow mixture is then worked up as described in:Example D 1J
Yield: 1,080 mg (88%), melting point 78 - 80QC . -calculated: C 67.30, H 67908 found C S,90 H 6,96 ,' "~
~, ' ' ' , ', . , ' .
.
.
~ 48 .
Claims (3)
1. A polmer-bound ester comprising a compound of the formula (I) ( I ) where X is C=O, C=S, or and Y is SO2 or C=O, said compound being bound via a phenyl radical to a polymer carrier.
2. Thiophene-1,1-dioxide of formula (I) as claimed in claim 1, wherein one of the phenyl rings is a component of a copolymer of styrene and 2 percent of 1,4-divinylbenzene.
3. Thiophene-1,1-dioxide of formula (I) as claimed in claim 1, wherein X is C=O.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA359,156A CA1110385A (en) | 1976-06-05 | 1980-08-27 | Polymeric activated esters of 3,4-di-hydroxy-2,5- diphenyl-thiophene-1,1-di-oxide |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE2625539A DE2625539C2 (en) | 1976-06-05 | 1976-06-05 | Cyclic esters of 3,4-dihydroxy-2,5-diphenyl-thiophene-1,1-dioxide and 3,4-dihydroxy-2,5-diphenyl-cyclopentadienone and their use |
DEP2625539.0 | 1976-06-05 | ||
CA279,418A CA1106388A (en) | 1976-06-05 | 1977-05-30 | Cyclic esters of 3,4-dihydroxy-thiophene-1,1-dioxide compounds and 3,4-dihydroxy-cyclopentadienone compounds |
CA359,156A CA1110385A (en) | 1976-06-05 | 1980-08-27 | Polymeric activated esters of 3,4-di-hydroxy-2,5- diphenyl-thiophene-1,1-di-oxide |
Publications (1)
Publication Number | Publication Date |
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CA1110385A true CA1110385A (en) | 1981-10-06 |
Family
ID=27165098
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Application Number | Title | Priority Date | Filing Date |
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CA359,156A Expired CA1110385A (en) | 1976-06-05 | 1980-08-27 | Polymeric activated esters of 3,4-di-hydroxy-2,5- diphenyl-thiophene-1,1-di-oxide |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6822384B2 (en) | 2000-08-17 | 2004-11-23 | Lumera Corporation | Design and synthesis of advanced NLO materials for electro-optic applicators |
-
1980
- 1980-08-27 CA CA359,156A patent/CA1110385A/en not_active Expired
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6822384B2 (en) | 2000-08-17 | 2004-11-23 | Lumera Corporation | Design and synthesis of advanced NLO materials for electro-optic applicators |
US6864375B2 (en) | 2000-08-17 | 2005-03-08 | Lumera Corporation | Highly stable and efficient nonlinear optical chromophores for electro-optic polymers |
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