US2417326A - Imidazol thiophan derivatives and process for the manufacture of same - Google Patents

Description

Patented Mar. 11, 1947 IMIDAZOL THIOPHAN DERIVATIVES AND PROCESS FOR THE MANUFACTURE OF SAME Otto Schnider, Jean-Pierre Bourquin, and Andre Griissner, Basel,

Switzerland,

assignors to Hoffmann-La Roche Inc., Nutley, N. J., a corporation of New Jersey No Drawing. Application March .29, 1945, Serial No. 585,570. In Switzerland April 26, 1944 19 Claims. 1

Biotin, which is of vital importance for many an organism, Was recognised to be a derivative of 3,4- (2-oxo-tetrahydroimidazol) -thiophan.

It has now been found that thiop-han-one-(3) carboxylic acid esters can be used as starting materials for the manufacture of derivatives carrying in position 2 an alkyl radical or an omegasubstituted alkyl radical. Compoundscarrying, apart from alkyl radicals, for instance the following radicals, may be employed:omegahydroxya1ky1-, omega-alkoxyalkyl, omega-aryloxyalkylor omega-haloge-nalkyl-radicals.

The thiophan-one-(3)-carboxylic acid esters (I), which carry a suitable substituent in position 2, are initially converted into the corresponding cyanohydrins (II) by means of hydrocyanic acid. The same are saponified Without further purification and the resulting dicarboxylic acids (III) esterified. The 3-hydroxythiophan-3,4-dicarboxylic acid esters (IV), substituted in position 2, are oils capable of being distilled. Upon reacting with halides of phosphorus and sulphur, e, g., thionyl chloride, they are transformed into the 3-chlorine esters (V). By means of reducing agents the halogen can be eliminated, whereby the thiophan-3,4-dicarboxylic acid esters (VI), substituted in position 2, are obtained. From these the way leads to the corresponding acid azides, either by preparing the hydrazides (VII) by means of hydrazin hydrate and treating them with sodium nitrite, or by converting the free acids (VIII) obtained by saponification into the acid chlorides (IX) and treating the latter With sodium azide. By heating With alcohols, the 3,4-di-(carbethoxy-amino) -thiophans (XI), substituted in position 2, are obtained from the azides. On warming with hydrogen halides, e. g., hydrobromic acid, they are converted into the salts of the corresponding 3,4-diamino-thiophans (XII) substituted in position 2. By stirring with phosgene in a Weakly alkaline solution, the d,1- 3,4(2'-OX0 tetrahydroimidazol) -2-X-thiophans (XIII) are obtained therefrom.

CH-C-C 0 OR H IV OHrCH-CO O R In these formulae R stands for lower alkyl, and X is an alkyl radical or an omega-substituted alkyl radical.

This synthesis of compounds with the bicyclic I system XIII is characterised in that the amino ployable substancesshowing the activity of biotin.

Example 1 80 parts by weight of finely powdered potassium cyanide are added to a solution of 188 parts by weight of 2-methyl-3-oxo-thiophan-4.-carboxylic-acid-ethyl-ester in 500 parts by Volume of ether. While stirring and cooling well, 90 parts by volume of concentrated hydrochloric acid are added dropwise in the course of about 2 hours. After evaporation of the 'ether, 300 parts by volume of ethyl alcohol and 300 parts by volume of concentrated hydrochloric acid are added to the remaining 2-methyl-3-hydroXy-3- cyano-thiophan-l-carboirylic acid-ethyl-ester; saponification is effected by first slowly distilling 01f the alcohol and then allowing the product to stand in a boiling water bath for another 2 hours. By concentration in vacuo, 2-methyl-3-hydroxythiophan-3,4-dicarboXy1ic acid is obtained, which can be converted into the Z-methyl-B-hydroxythiophan-3,4-dicarboxylic acid diethyl ester without further purification by means of ethyl alcohol and hydrochloric acid. It boils at a pressure of 0.05 mm. at 101 to 102 C. as an almost colourless, viscous oil.

262 parts by weight of Z-methyl-S-hydroxythiophan-3,4-dicarboxylic-acid-diethyl-ester are dissolved in 500 parts by volume of chloroform and successively treated with 80 parts by volume of pyridine and 119 parts by volume of thionyl chloride while cooling well with ice. The product is first allowed to stand for 2 hours and then heated for about 40 minutes in a boiling water bath until the evolution of gas has ceased. Thereupon, the product is poured on ice, divided in a separating funnel and washed with water and dilute sodium carbonate solution until neutral reaction sets in. The Z-rnethyl-S-chloro-thiophan-3,4-dicarboxylic-acid-diethyl-ester separated from the chloroform boils at a pressure of 0.1 mm. at 100 to 102 C.

186 parts by Weight of sodium-iodide hydrate are added to a solution of 280 parts by weight of 2-methyl-3-chloro-thiophan-3,4-dicarboxylicacid-diethyl-ester in 4000 parts by volume of 80 percent. acetic acid, and 1400 parts by weight of zinc dust introduced in small portions in the.

course of about 4 hour while stirring. Each time slight warming sets in. After further 'stir- 250 parts by volume of absolute alcohol and the solution heated under reflux with parts by weight of hydrazin hydrate for about 10 hours. After some time, the hydrazide begins to precipitate. The precipitate augments in the course of heating. After cooling, the 2-methyl-thiophan- 3,4-dicarboXylic-acid-dihydrazide is separated, dissolved and allowed to crystallise from hot water. sintering.

A solution of 218 parts by weight of Z-methylthiophan 3,4 dicarboxylic-acid-dihydrazide in 670 parts by volume of 3 n-hydrochloric acid is covered with a layer of 2000 parts by volume of ether and a solution of 140 parts by weight of sodium nitrite in 800 part by volume of water added drop by drop. The resulting acid azide is solublein ether. The other solution is separated from the salt solution when the reaction has come to an. end, the ether driven off and the 2-methyl-thiophan-3,4-dicarboxylic-acid-diazide remaining behind as a light-yellowish. oil is treated with 2000 parts by volume of absolute alcohol. The clear solution is heated to about C., at which temperature a vigorous evolution of nitrogen sets in, which lasts for about halfan-hour. The clear, almost colourless solution is treated with water until it starts to get turbid and cooled. On filtering the colourless Z-methyl- 3,4-di- (carbethoxyamino) -thiophan crystallising in fine needles of melting point 182 to 183 C.

is obtained.

The same diurethan can be obtained by saponifying the 2-methyl-thiophan-3,4-dicarboxylicacid-diethyl-ester, converting the resulting acid into the acid chloride (boiling point 12 mm./135- 137 C.) and reacting the same with sodium azide. The resulting oily, ether-soluble diazide turns into the 2-methyl-3,4.-(dicarbethoxyamino) -thiophan of melting point 182 to 183 C. on warming in absolute alcohol.

276 parts by weight of this urethane are heated for about 1 hour to 105 to 110 C. together with 2760 parts by volume of 45 per cent. hydrobromic acid until the evolution of carbonic acid has come to an end. On concentration in vacuo, the 2-methyl-3, 4-diamino-thiophan-dihydrobromide remains behind as a solid mass. It can be dissolved and allowed to crystallise from a solution in dilute acetone or dilute alcohol. The colourless crystals, inclusive of 2 crystal-water, melt at 225 to 227 C. with decomposition. The diamine is characterised by the following derivatives:

The 2-methyl-3,4-diureido-thiophan melts at 262 C. with decomposition. 'The 2-methyl-3A- diamino-thiophan-dipicrate melts at 243 C. with decomposition. The 2 -methyl- 3,4 -di-(benzoylring for about 12 hours, the zinc acetate is sepamino) -thiophan melts at 271-272 C'. The2- methyl-3,4-di-(acetylamino)rthiophan melts at parts by volume of n-sodium-hydroxide, on the one hand, and parts by weight ofphosgene in form of a 20 per cent. solution in toluene, on

ately begin to precipitate.

is complete. 7 tion'and washed with water. The. 3,4-(2'-oxotetrahydroimidazol) '-2 methyl-thiophan can 'be It melts at 241 to 242 C. after previous 5. crystallised from a solution indilute acetic acid or dilute alcohol. It is easily soluble in alcohols and acetic acid, less easily in acetone and diificult' ly in ether. benzene and water. It carbonises nprolonged heating to 350-350 C.

Example 2 80 parts by weight of finely pulverised potassium cyanide are added to a solution of 260 parts by weight of Z-(omega-methoxybutyl) -3-oxothiophan-d-carboxylic-acid-ethyl-ester in 540 parts by volume of dibutyl ether and then 106 parts by volume of concentrated hydrochloric acid allowed to drop in during 8 hours while stirring and cooling with ice. The reaction mixture is left to stand overnight at 0 C. The crystallised cyanohydrin with the potassium chloride is separated from the dibutyl-ether solution by suction. The separation of the cyanohydrin from the potassium chloride is eifected by dissolving the former in chloroform. Thechloroform solution is dried with sodium sulphate and after filtration brought to dryness in vacuo at a bath temperature of 30 C. The 2-(omega-methoxybutyl) -3-hydroxy-3-cyano-thiophan-4-carboxyl ic-acid-ethyl-ester, obtained in almost theoretical yield, has a melting point of 88 C. The methyl ester'melts at 81.5 to 835 C.

287 parts by weight of 2 (omega-methoxybutyl) 3 hydroxy-3-cyano-thiophan-4-carboxylic-acidethyl-ester are reacted with a mixture of 600 parts by volume of concentrated hydrochloric acid, 300 parts by volume of water and 1100 parts by volume of ethyl alcohol and boiled under reflux for 48 hours. After evaporation in vacuo, the saponified product is converted into the 2- (omega-methoxybutyl) -3-hydroxy-thiophan-3,4- dicarboxylic-acid-diethyl-ester by means of ethyl alcohol and hydrogen-chloride gas. It boils at a pressure of 0.07 mm. at 145147 C. as a lightyellow, viscous oil. The dimethy] ester boils at a pressure of 0.09 mm. at 146-149" C.

334 parts by weight of 2-(0mega-methoxybutyl) -3-hydroxy-thiophan-3,4dicarboxylic acid diethyl-ester are dissolved in 660 parts by volume of chloroform and reacted with 154 parts by weight of absolute pyridine and 231 parts by weight of thionyl chloride while cooling with ice. Reaction and working-up in accordance with Example 1 yield a yellowish-brown, viscous oil, viz.

2- (omega-methoxybutyl) -3-chloro-thiophan-3,4- dicarboxylic-acid-diethy1-ester, melting point 138-143 C. at 0.03 mm. The dimethyl ester boils at 134't0 137 C. under a pressure of 0.03 mm.

353 parts by weight of 2-(omega-methoxybutyl) -3-chloro-thiophan-3,a-dicarboxylic-acid-di ethyl-ester are dissolved in 5100 parts by Volume of 80 per cent. acetic acid, 230 parts by weight of potassium iodide are added, and, while stirring, 1550 parts by weight of zinc dust are introduced in small portions in the course of 4 hours at a temperature not exceeding 25 C. After working-up in accordance with Example 1, the 2 (omega methoxybutyl-thiophan-3,4-dicarbo-xylic-acid-diethyl-ester boils as a light-yellowish oil at 148 to 150 C. under a, pressure of 0.03 mm.

The 2-(omega-methoxybutyl) -thiophan-3,4-di- 6 carboxylic-acid-dihydrazide precipitates in colourless needles and has a melting point of 204 to 205 C. The same hydrazide is also obtained from the 2- (omega-methoxybutyl) -thiophan-3',4- dicarboxylic-acid-dimethyl-ester.

290 parts by weight of Z-(omega-methoxybutyl) -thiophan-3,4-dicarboxylic-acid dihydrazide are dissolved in 835 parts by volume of 3 n-hydrochloric acid, covered with. a layer of 8000 parts by volume of ether and reacted, while stirring and cooling with ice, with a solution of 138 parts by weight of sodium nitrite in 1000 parts by volume of water added drop by drop. The azide is isolated as described in Example 1 and transformed into the urethane by means of 7000 parts by volume of absolute alcohol. The fine, colourless needles of Z-(omega-methoxybutyl) 3 l-diurethano-thiophan show a melting point hydroxide, and while coo-ling with ice and while stirring, reacted with 99 parts by weight of phosgene (in the form of a 20 per cent. solution in toluene) and 2000 parts by volume of 'n-sodium hydroxide, the latter and the toluene-phosgene solution being added simultaneously and the reaction being effected at a pH of 7 to 8; The reaction product, after addition of glacial acetic acid, is brought to dryness in vacuo and rubbed,

with water. The 3,4-(imidazolidon-2)-2-(omega-bromobutyD-thiophan has a melting point of 1'75.5 C. after dissolving and allowing to crystallise from methanol.

Example 3 Apart from the crystallised dihydrazide of melting point 204 to 205 C. obtained as a result of the preparation of Z-(omega-methoxybutyl) -'thialuminum oxide. One of the isomeric urethanes,

having a melting point of to 126 C., is obtained in crystalline form by eluting with benzene.

348 parts by Weight of Z-(omega-methoxybutyl) -3, l-diurethano-thiophan of melting point 125 to 126 C. are heated with 48 per cent. hydrobromic acid as described in Example 2. The resulting hygroscopic 2-(omega-bromobuty1)-3,4- diamino-thiophan-dihydrobromide is converted into the 3,4-(imidazolidon-2) -2-(omega-bromobutyl) -thiophan by means of phosgene. crystallised compound, from methanol, has a melting point of 163 to 164 (3.; the mixture with the isomer of meltingp'oirit The after recrystallisation" aha-e26:

7' 175.5 C. shows considerable depression of the melting point. I

On chromatographically treating the oily urethanes, further isomers are obtained which can be worked up in the same manner. 1

We claim: 7 1. Process for the manufacture of a d,l-substance of the general formula OH2CH-NH \CHCHN{I wherein the radical X is selected from the group consisting of alkyl, omega-methoxy alkyl and omega-halogeno alkyl, comprising converting 3- 'oXo-thiophan-4-carboxylic-acid-esters, which are substituted in position 2 by the radical X, into the cyano-hydrines, preparing therefrom by saponification and esterification the corresponding 3-hydroxy-3,4-dicarboxylic-acid-esters, eliminating from these compounds the hydroxy-grcup by replacing it by halogen and subsequently reducing the latter, reacting the thus obtained thiophan- 3,4-dicarboxylic-acid-esters, carrying the radical X in position 2, with hydrazin hydrate, reacting upon the acid hydrazides with sodium nitrite in order to obtain the acid azides and decomposing the latter by reacting with alcohol to yield the 3,4-diurethans, converting these by boiling with acids into the salts of the 3,4-diamino-thiophans substituted in position 2 by the radica1 X, and obtaining from these diamines the 2-X-3,4-(2'-oxotetrahydroimidazol)-thiophans by means of phosgene.

2. Process for the manufacture of d,l-2-methyl- 3,4- (2'-oXo-tetrahydroimidazo1) -thiophan, comprising converting 2-methyl-3-oxo-thiophan-4- carboxylic-acid-esters into the cyanohydrines, preparing therefrom by saponiiication and esterification the corresponding 3-hydroxy-3,4.-dicarboxylic-acid-esters, eliminating from these compounds the hydroXy-group by replacing it by halogen and subsequently reducing the latter, reacting the thus obtained 2-methy1-thio-phan-3,4-diii carboxylic-aoid-esters with hydrazin hydrate, reacting upon the acid hydrazides with sodium nitrite in order to obtain the acid azides and decomposing the latter by reacting with alcohol to yield the 3,4-diurethans, converting these by boiling with acids into the salts of the 2-methyl-3,4- diamino-thiophans and obtaining from these diamines the 2-methyl-3,4-(2-oXo-tetrahydroimidazol) -thiophans by means of phosgene.

3. Process for the manufacture of d,l-2- (omegamethoxy-butyl) -3,4- (2' oxo tetrahydroimidazo1) -thiophan, comprising converting 2- (omegamethoxy-butyl) -3-oxo-thiophan l carboxylicacid-esters into the cyano-hydrines, preparing therefrom by saponification and esterification the corresponding 3-hydroxy-BA-dicarboxylic-acidesters, eliminating from these compounds the hydroxy-group by replacing it by halogen and subsequently reducing the latter, reacting the thus obtained 2-(omega-methoxy-butyl)-thiophan-8,4- dicarboXylic-acid-esters with hydrazin hydrate,

reacting upon the acid hydrazides with sodium nitrite in order to obtain the acid azides and decomposing the latter by reacting with alcohol to thiophan, comprising converting 2-(omega-bromo-butyl) -3-oXo-thiophan-4 carboxylic acidesters into the cyano-hydrines, preparing therefrom by saponiiication and esterification the corresponding 3-hydroxy-3, i-dicarboxylic-acid-es ters, eliminating from these compounds the hydroxy-group by replacing it by halogen and sub-' ber selected from the group consisting of alkyl radicals and aliphatic omega-substituted-alkyl radicals.

6. As compositions of matter, d,l2-substituted-' 3,4-(2- 0X0 tetrahydroimidazrol) thiophans, in which the substituent in the 2-position is alkyl.

'1. As compositions of matter, d,l-2-substituted- 3,4-(2'- oxo tetrahydroimidazol) thiophans, in which the substituent in the zepo'sitio'n is aliphatic omcga-substituted-alkyl. V

8. As compositions of matter, d,l-2-substituted- 3,4-(2'- oxo tetrahydroimidazol) thiophans, in which the substituent in the 2-position is methyl.

9. As compositions of matter, d,l2-substituted- 3,4-(2- oxo tetrahydroimidazol) thiophans, in which the substituent in the 2 -position is omegaalkoXy-alkyl.

18. As compositions of matter, d,l-2-substituted-3,4 (2-oXo-tetrahydroirnidazol) -thiophans, in which the substituent in the 2-position is omegaalkoxy-butyl. a

11. As compositions of matter, d,1-2-substituted-3,4-(2'-oXo -tetrahydroimidazol) -thiophans, in

which the substituent in the methoxy-butyl. 7

12. As compositions of matter, d,1-2-substituted-SA- (2'-oX0-tetrahydroimidazol) -thiophans, in

2 -position is omegawhich the substituent in the 2 positionis'omega -ed-3,4-(2- c-Xo tetrahydroimida zol) thiophans,

which comprises converting 2-substituted-3,4-di- (caro-alkoxyamino) -thiophans, in which the substituent in the 2-positi0nis a member selected from the group consisting of alkyl radicals and aliphatic omega-substituted-alkyl radicals, to d,l- Z-substituted '-3, i-(2-- 0x0 tetrahydroimidazol) thiophans, in which the substituent in the 2-position is a member selected from the group consisting of alkyl radicals and alpihatic omega-substituted-aikyl radicals. a

16. A process in accordance with claim 15 which comprises converting the di-carbalkoxyaminothicphan to a di-hydrohalide salt of 2subs tituted-3,4-diamino thiophan by means ofa hydroaliphatic omega-substituted-alkyl radicals, is con- 15 10 verted to a di-hydrobromide-amino salt by means of hydrobromic acid, followed by conversion of said salt to the imidazol-thiophan.

OTTO SCHNIDER. JEAN-PIERRE BOURQUIN. ANDRE GRiissNER.

REFERENCES CITED The following references are of record in the file of this patent:

Jour. Amer. Chem. Soc, vol. 66 (Oct. 1944), page 1756 to 1757. (Copy in U. S. Patent Oflice Scientific Library, Washington, D. C.)