DE3703872A1 - Process for the preparation of D-(+)-biotin - Google Patents

Abstract

D-(+)-biotin can be prepared in a simple and stereospecific manner from optically active hydantoins of the formula I <IMAGE> in which R<1>, R<2>, R<3>, X and Y have the meanings given in Patent Claim 1.

Description

The invention relates to a method for producing D - (+) - biotin from L-cysteine or L-cystine or L-serine via an optically active (7R) -1H, 3H-imidazole [1,5-c] azole as an intermediate.

The invention was based on the object of a new method for the production of optically active D - (+) - biotins To provide, which is the implementation of a racemate resolution and thus discarding or returning the unwanted Avoiding enantiomers.

Process for the stereospecific synthesis of D - (+) - biotin Suitable configurations from sugars are known. So in Tetrahedron Letters No. 32, pp. 2765-2766 (1975), as starting material D-Mannose, in Agric. Biol. Chem. No. 42, p. 465 (1978), D-glucose and in the DE-OS 31 22 562 and DE-OS 33 20 140 D-arabinose as chiral starting material used.

However, all of these methods are by a large number of synthesis steps with consequently low overall yield featured. The because of their sugar nature mostly non-crystallizable intermediates often only obtained and required in unsatisfactory purity, due to their polyfunctionality and  associated chemical lability compliance comparatively narrow reaction parameters. A row sugar is not accessible even from natural sources, which results in a high price.

The use of L-cysteine, as from US-40 09 172, US-41 30 713, US-43 37 345 and Journal of the American Chemical Society No. 99, p. 7020 (1977) the handling of unstable intermediate stages leads on the other hand over a total of 18 stages of recession with separation undesirable isomers only in unsatisfactory yield to optically active D - (+) - biotin.

In a further procedure, Journal of the American Chemical Society No. 105, p. 5946 (1983) and in EP-OS 00 94 776 substituted 3H, 5H-imdiazo [1,5-c] - tetrahydrothiazoles described, from which after resolution of racemate optically active biotin is obtained.

Because the comparatively high number of stages associated with sometimes moderate yields and the need for one These raw materials are also used for optical separation Production of D - (+) - biotin appear to be unsuitable there was still a need for a suitable one Process for simple, economical and stereospecific Production of D - (+) - biotin.

It has now surprisingly been found that D - (+) - biotin from the naturally occurring amino acids L-cysteine or L-cystine or L-serine via an optically active (7R) -1H, 3H-imidazo [1,5-c] azole of the formula I as an intermediate in a stereo-specific manner without additional Racemate separation can be produced. The invention therefore relates to a method for Production of D - (+) - biotin from L-cysteine or L-cystine  or L-serine, characterized in that the synthesis is carried over an intermediate of formula I,

wherein

R¹ and R² are each independently H, unsubstituted or substituted lower Alkyl, cycloalkyl, aryl, aralkyl or Heteroaryl or taken together unsubstituted or substituted alkylene or Heteroalkylene, R³H or one suitable for a nitrogen atom Protection group and X and Y are each independently O or S mean.

In this formula, X is preferably S and Y is preferably O, in particular X = S and Y = O. The radicals R¹ and R² are preferably H, C₁-C₄ alkyl, unsubstituted or by C₁-C₃ alkyl and / or alkoxy mono- or polysubstituted Phenyl or benzyl, in particular, are simultaneous R1 = H, R2 = phenyl. Preferably, the means Rest R³ unsubstituted or by one or several, particularly preferably one or two,  C₁-C₄ alkyl and / or C₁-C₄ alkoxy groups substituted Benzyl, especially unsubstituted benzyl, next to it also C₃-C₅ alk-2-enyl or C₃-C₆ trialkylsilyl. With multiple, preferably double substitution of a phenyl ring, the substituents are preferred same, but they can also be different. They are located preferably in the 4- and / or 2-position, they can also be in the 3-, 5- and / or 6-position.

Accordingly, the subject of the invention is in particular a process for the production of D - (+) - biotin from L-cysteine or L-cystine or L-serine via one Intermediate product of formula I in which at least one of said radicals one of the above has preferred meanings.

The invention further relates to a method for Preparation of the optically active hyantoins of the formula I characterized in that L-cysteine or L-serine with an alkali or alkaline earth metal cyanate or converting thiocyanate into a hydantoin of the formula II,

where X and Y have the meaning given, this with a carbonyl compound of formula III,

R¹-CO-R² (III)

wherein R¹ and R² have the meaning given, with elimination of water to a bicyclic Formula IV implements  

wherein R¹, R², X and Y have the meaning given, and the secondary nitrogen atom of which provides a protective group R³ of the meaning given,
or that L-cysteine or L-serine is reacted with a carbonyl compound of the formula III with the meaning given, with elimination of water, to give an azolidine V,

wherein R¹, R² and X have the meaning given, this with a metal cyanate or thiocyanate a compound of formula IV and further proceed as indicated above, or with a Organoisocyanate or isothiocyanate of the formula VI implements

R³-N = C = Y (VI)

where R³ and Y have the meaning given,
or that L-cystine is reacted with an alkali metal or alkaline earth metal cyanate or thiocyanate to give a bishydantoin of the formula VII,

where YO or S means
this is converted into a hydantoin of the formula II by a reducing agent and reacted further as indicated above, or its nitrogen atom in the 3-position is provided with a protective group R 3 of the meaning given and the bishydantoin of the formula VIII obtained,

wherein R³ and Y have the meaning given, after cleavage by a reducing agent with a carbonyl compound of the formula III,
or that L-cystine is reacted with an organoisocyanate or isothiocyanate of the formula VI given to give a bishydantoin of the formula VIII and the procedure is as described above.

The present invention furthermore relates to the subject a process for producing D - (+) - biotin from Compounds of formula I in which

• a) I is reduced to an alcohol of the formula IX, wherein R¹, R², R³, X and Y have the meaning given, which is converted into an activated ester of formula X, in which R¹, R², R³, X and Y have the meaning given and the radical R⁴ represents an activating ester group which is reacted with an alkali metal or alkaline earth metal cyanide or a cyanosilane to give a nitrile of the formula XI, wherein R¹, R², R³, X and Y have the meaning given, which is reacted with a base or an acid to give an acid derivative of the formula XII, wherein R¹, R², R³, X and Y have the meaning given and R⁵ is H or lower alkyl which is cyclized to a lactone of the formula XIII with elimination of water, wherein R³, X and Y have the meaning given and R⁶ is H or R¹R²CH, which is converted into D - (+) - biotin by known processes, or by
• b) XI is reacted with an organometallic compound to give an oxo compound of the formula XIV, wherein R¹, R², R³, X and Y have the meaning given and Z is OR⁵ or COOR⁵, where R⁵ is H, lower alkyl, cycloalkyl or aryl, which by treatment with an acid and / or a reducing agent to give an imidazolidine of the formula XV is split wherein R³, R⁶, X, Y and Z have the meaning given, which is cyclized under the action of a base to a biotin derivative of the formula XVI, wherein R³, R⁶, X, Y and Z have the meaning given, which is converted into D - (+) - biotin by known processes, or in
• c) XI is reacted with a reducing agent to give an aldehyde of the formula XVII, wherein R¹, R², R³, X and Y have the meaning given, which is condensed with an organophosphorus compound to give an unsaturated carboxylic acid of the formula XVIII, wherein R¹, R², R³, X, Y and Z have the meaning given, which is converted by an acid and / or a reducing agent to a biotin derivative of the formula XIX, wherein R³, R⁶, X, Y and Z have the meaning given, which is converted into D - (+) - biotin by known processes, or in
• d) an oxo compound of the above formula XIV is converted to a biotin derivative of the formula XX under the action of acid, wherein R³, X, Y and Z have the meaning given, which is converted into D - (+) - biotin by known processes.

The compounds of the formula I are prepared according to methods known per se, as described in the literature (e.g. in standard works such as Houben-Weyl, methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart) are described, namely under reaction conditions, as they are known and suitable for the above-mentioned implementations are. You can also use known, make use of variants not mentioned here.

The starting materials of formula II are known or can be made from L-cysteine or by known methods L-serine can be produced, such as in Schöberl, Hamm, Chem. Ber. 81 [1948], 210 and Karabinos, Szabo, J. Amer. Chem. Soc. 66 [1944], 649 stated, by the free amino acids or their acid addition salts with an alkali or alkaline earth metal cyanate or thiocyanate in a suitable solvent such as water, alcohols or mixtures thereof, preferably at an elevated temperature and the intermediate obtained in situ under the action an acid, for example a mineral acid, cyclized.

The reaction of the hydantoins of formula II with carbonyl compounds of the formula III to the bicycles Formula IV can be according to those known for acetalizations and common procedures are carried out as for example in Houben-Weyl, Methods of Organic Chemistry,  Vol. VI / 3, p. 199. Preferably done the implementation of the reactants with the addition of a dehydrating agents such. B. an acid such as Sulfuric acid, phosphoric acid, hydrogen chloride, p-toluenesulfonic acid, an acid derivative such as phosphorus pentoxide, Phosphorus trichloride, phosphorus pentachloride, Phosphorus oxychloride, a metal salt such as anhydrous Calcium chloride, copper sulfate, iron (III) chloride, one acidic ion exchanger or molecular sieves. The distance of the water of reaction formed can also by azeotropic distillation with a suitable solvent such as benzene, toluene, chloroform, dichloromethane respectively. Finally, it is also possible instead a free carbonyl compound of formula III, the Acetal with a suitable alcohol, preferably a lower alcohol to make the compounds Formula IV to use. Conveniently becomes the alcohol released during the reaction continuously removed from the reaction mixture, for example by distillation or adsorption. Can too by an excess of acetal of oxo compound III formed water of reaction are removed.

For the reaction with the hydantoins of formula II an equivalent of carbonyl compound is advantageously used III or their acetal, which simultaneously can serve as a solvent. More appropriate however, it is an additional inert solvent to add. Suitable as inert solvents preferably hydrocarbons such as pentane, hexane, Cyclohexane, benzene, toluene or xylene and chlorinated Hydrocarbons such as dichloromethane, chloroform or Carbon tetrachloride.  

To protect the free nitrogen atom in the bicycles of the formula IV, these are combined with a reactive, the Rest R³ with the meaning given above Compound to the (7R) -1H, 3H-imidazo [1,5-c] azoles of Formula I implemented. Suitable compounds are, for example Benzyl chloride, benzyl bromide, 4-methoxybenzyl chloride, 3,4-dimethoxybenzyl chloride, 4-methylbenzyl chloride, Benzyl tosylate, allyl bromide, metalallyl bromide, Crotyl bromide, chlorodimethyl ether, trimethylchlorosilane or tert. Butyldimethylchlorosilane. The reaction conditions correspond to the introduction of the protective groups known methods such as those from Mac Omie, Protective Groups in Organic Chemistry, Plenum Press, New York, 1973.

The reaction partners are preferably reacted in a suitable solvent with the addition of a basic reagent. Suitable solvents are in particular ethers such as diethyl ether, di-n-butyl ether, THF, dioxane or anisole, ketones such as acetone, butanone or cyclohexanone, amides such as DMF or phosphoric acid hexamethyltriamide, Hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as carbon tetrachloride or tetrachlorethylene and sulfoxides such as dimethyl sulfoxide or sulfolane.

A preferred reaction is the implementation of a bicyclic compound of the formula IV with a reactive, the rest of R³ bearing connection, preferably in a basic environment, with bases in particular Alkali metal hydroxides such as sodium or potassium hydroxide, Alkali metal carbonates or bicarbonates such as sodium carbonate, Sodium bicarbonate, potassium carbonate or potassium hydrogen carbonate, alkali metal acetates such as sodium or potassium acetate, alkaline earth metal hydroxides such as Calcium hydroxide, alkali metal hydrides such as sodium hydride,  Amides such as sodium amide, lithium diisopropylamide, alcoholates such as sodium methylate, sodium ethylate, lithium ethylate or organic bases such as triethylamine, pyridine, lutidine, Collidine or quinoline are important.

The reaction temperature is usually between -50 ° C and + 250 ° C, preferably between -20 ° C and + 80 ° C. The reactions are usually at these temperatures finished after 15 minutes to 48 hours.

In another process for making the compounds Formula II uses L-cysteine or L-serine with a carbonyl compound of formula III to one Azolidine V. Compounds of formula V and method are known from their manufacture, for example Schubert, J. Biol. Chem. 114 (1936), 341, Uskovi et al., J. Amer. Chem. Soc. 97 (1975), 5936, Lieberman et al. ibid. 70 (1948), 3094 and US-39 57 794 and US-40 09 172. Those for the production of the connections are also suitable of the formula IV specified reaction conditions.

Azolidines of the formula V can be prepared using alkali metal or alkaline earth metal cyanates or thiocyanates under the already for the production of connections of the Formula II specified reaction conditions in compounds of the formula IV and further as indicated in the Imidazo [1,5-c] azoles of the formula I are transferred.

However, it is more expedient to use the azoles of the formula V with an organoisocyanate or isothiocyanate Formula VI directly to the Imidazo [1,5-c] azoles of Implement Formula I. Organoisocyanates and isothiocyanates of formula VI are known or can known methods such as in Houben-Weyl, Methods of Organic Chemistry, Vol. VIII, p. 75 u. IX, p. 773, can be obtained.  

From Lieberman, J. Amer. Chem. Soc. 70 (1948), 3094 and Crabb et al., Tetrahedron 29 (1973), 3389, is the implementation of hydantoins with phenyl and methyl isocyanate known. According to these methods, the reaction can also the azoles of formula V with the organoisocyanates or -isothiocyanates of the formula VI take place. Preferably is the implementation of the reactants in a suitable Solvents carried out such. B. ether like Diethyl ether, di-n-butyl ether, THF, dioxane or anisole, Ketones such as acetone, butanone or cyclohexanone, amides such as DMF or phosphoric acid hexamethyl triamide, hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as carbon tetrachloride or tetrachlorethylene and sulfoxides such as dimethyl sulfoxide or Sulfolan. Basic solvents are also suitable such as pyridine, lutidine, collidine, diethylamine or Triethylamine and mixtures of these bases with the solvents specified above.

It may be appropriate to use the primary formed carbamoyl or thiocarbamoyl compound isolate and in a separate reaction step to cyclize with elimination of water. As a water-releasing Acids are suitable, for example such as sulfuric acid, hydrogen chloride, toluenesulfonic acid or bases such as sodium or potassium hydroxide. You can do this in the presence or absence of a inert solvent at temperatures between about 0 ° C and 150 ° C, preferably between about 20 ° C and 100 ° C, work; come as a solvent, for. B. water and alcohols such as methanol, ethanol, isopropanol or Butanol into consideration.  

In another process for making the compounds of formula II, L-cystine is used with a Alkali metal or alkaline earth metal cyanate or thiocyanate to a bishydantoin of formula VII. To the same methods can be used which have already been used to prepare the hydantoins of the formula II were given, the same or similar reaction conditions apply.

From the bishydantoins of formula VII can be Treat with a reducing agent hydantoine Formula II (X = S) obtained from which according to the preceding given methods the imidazo [1,5-c] thiazoles of the formula I (X = S) can be produced. Suitable reducing agents are, for example, Houben-Weyl, Methods of organic chemistry, vol. 15/1, p. 798. Sodium / liquid ammonia are preferably suitable, Zinc / acid or phosphonium iodide for reductive cleavage the disulfide bond. Conveniently one leads the Reduction of the bishydantoins of formula VII with a Equivalent, especially with an excess of reducing agent through in an appropriate, chemical nature the reagent adapted solvent such. B. water, liquid ammonia, alcohols such as methanol, ethanol, Isopropanol, acids such as hydrochloric acid, sulfuric acid, Formic acid, acetic acid, ethers such as diethyl ether, THF or dioxane or mixtures thereof, useful at temperatures between approximately -50 ° C and + 150 ° C.

A particularly advantageous process for splitting the Disulfide bond in the compounds of formula VII consists in thiolysis with a suitable one Mercaptan such as B. thiophenol, butane-1,4-dithiol or 1,4-dithio-threitol analogous to that of Hase, Walter, Inst. J. Pept. Prot. Res. 5 (1973), 283  Way of working. The reaction partners are implemented expediently in a suitable solvent such as e.g. B. aqueous alkali metal hydroxide solutions, chlorinated hydrocarbons or liquid ammonia at temperatures between about -40 ° C and + 120 ° C.

The bishydantoins of the formula VII can also be used a protective group of the formula R³. For Production of these protected bishydantoins Formula VIII can be used for the production of the Compounds of formula I from the bicycles of formula IV specified methods are used, whereby same or similar reaction conditions for use reach.

Another method of making the protected Bishydantoins of formula VIII consists in the implementation of L-cystine with an organoisocyanate or isothiocyanate the formula VI given in analogy to the preparation of compounds of formula I from azolidines of the formula V, whereby one looks the same or similar Process used as already for the production of the Compounds of formula I specified.

To convert the compounds of formula VIII in the (7aR) - (1H, 3H-imidazo [1,5-c] thiazoles of the formula I (X = S) these are in one of the manufacture of hydantoins corresponding to formula II from the disulfides of formula VII Way using the same or similar Process and reaction conditions with one Reducing agent or a thiolysis Reagent treated and on, according to the manufacture of compounds of formula V, with a carbonyl compound Formula III implemented.  

A method for producing D - (+) - biotin from I is that an oxo compound of formula I to an alcohol of formula IX is reduced. Suitable Methods are, for example, Houben-Weyl, methods organic chemistry, vol. 4 / 1c + 4 / 1d.

The reduction can e.g. B. done by catalytic Hydrogenation at temperatures between about 0 ° C and about 200 ° C and pressures between about 1 and 200 bar in one inert solvents, e.g. B. an alcohol like Methanol, ethanol or isopropanol, an ether such as Tetrahydrofuran (THF) or dioxane, an ester such as Ethyl acetate, a carboxylic acid such as acetic acid or a hydrocarbon such as cyclohexane. As catalysts are suitable precious metals such as Pt or Pd in the form of oxides (e.g. PtO₂, PdO) a carrier (e.g. Pd on carbon, calcium carbonate or strontium carbonate) or in finely divided form can be used.

Reductions with complex hydrides are also possible such as boranes such as diborane, sodium boranate, Lithium cyano trihydro borate, metal hydrides such as sodium hydride, aluminum hydride, silicon hydrides such as triethylsilane, tributyltin hydride and mixed Hydrides such as lithium alanate, sodium alanate, sodium bis (2-methoxy-ethoxy) dihydridoaluminate, potassium boranate or lithium boranate.

The reaction of the oxo compounds of the formula I with the Reducing agents are expediently carried out in a suitable one Solvents at temperatures between about -100 ° C and + 150 ° C, especially between about 0 ° and 100 °; as a solvent come depending on the chemical nature of the Reducing agent z. B. water, alcohols such as methanol, Ethanol, isopropanol, butanol, ethers such as tetrahydrofuran, Dioxane, diethyl ether, ethylene glycol dimethyl ether  and hydrocarbons such as pentane, cyclohexane, Benzene, toluene into consideration.

To activate the hydroxyl group in the alcohols of Formula IX, these are combined with a reactive, the R⁴-bearing compound R⁴-Q implemented, wherein R⁴ for example alkanoyl such as acetyl, aroyl such as benzoyl, 4-nitrobenzoyl, alkylsulfonyl such as methanesulfonyl, ethanesulfonyl, Trifluoromethanesulfonyl, arylsulfonyl such as Phenylsulfonyl, aralkylsulfonyl such as benzylsulfonyl. Furthermore, R⁴ is a radical Azol-M, in which Azol for a nitrogenous, unsubstituted or substituted and / or condensed five-membered ring such as imidazole, 1,2,4-triazole, 1,2,3- Triazole, benzotriazole, benzimidazole, pyrazole, 3,5-dimethylpyrazole, Indazole, and M means CO, CS, SO, SO₂, S. R⁴ is preferably acetyl, imidazol-1-ylcarbonyl, Imidazol-1-ylsulfinyl, imidazol-1-ylsulfonyl. Q represents halogen, alkoxy, alkanoyloxy or another Balance azole.

Thus, for the production of active radicals of the formula X in particular the conversion of acetyl chloride, Acetic anhydride, 1,1'-carbonyldiimidazole, 1,1'-sulfinyldiimidazole and 1,1'-sulfonyldiimidazole with alcohols of formula IX suitable.

A preferred reaction is the implementation of a Alcohol of formula IX with a reactive, the rest R⁴ load-bearing compound, preferably in a basic Milieu, the bases being in particular organic bases such as triethylamine, pyridine, lutidine, collidine or quinoline are suitable. The reaction temperature is usually between -50 ° C and + 150 ° C, preferably between -20 ° C and + 80 ° C. At these temperatures  the implementations are usually after 15 minutes to 48 hours ended.

For conversion into nitriles of the formula XI, the activated esters of the formula X can be reacted with a cyanide, advantageously with a metal cyanide such as sodium cyanide, potassium cyanide or copper cyanide or a cyanosilane such as, for. B. trimethylsilyl cyanide, b -trimethylsilylpropionitrile or diethylaluminium cyanide, e.g. B. in an inert solvent such as dichloromethane, toluene, pyridine, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone or hexamethylphosphoric triamide at temperatures between -50 ° C and 200 ° C.

A preferred method for the production of nitriles of formula XI from activated esters of formula X, wherein R⁴ is a radical Azol-M with the above What is important is an additional activation the ester of formula X by their N-alkylation. Therefor suitable alkylating agents are, for example Alkyl, alkenyl and aryl iodides, bromides and chlorides, sulfates and sulfonates. Their implementation with the activated Esters of the formula X are advantageously carried out in a suitable solvent such as ethers such as diethyl ether, tetrahydrofuran, dioxane or ketones such as acetone, diethyl ketone, methyl isobutyl ketone; they can also be done without the addition of solvents.

Another preferred method of making Nitriles of the formula XI consists of esters of the formula X in the implementation of the latter with a cyanosilane Methods such as those of M. T. Reetz et al., Tetrahedron 39 (1983) 961; T. Hiyama et al., Synthesis 1986 689 or Houben-Weyl, Vol. E5, S 1389 ff (1985) are removed.  

The compounds are particularly suitable for this reaction of the formula X, wherein R⁴ alkanoyl or aroyl, in particular Alkanoyl such as acetyl means. Trimethylsilyl cyanide proves to be a particularly suitable one Cyanation reagent. It is expedient to set it Reactants in an inert solvent such as. B. Dichloromethane or toluene at temperatures from -50 ° C to 150 ° CV, optionally with the addition of a catalyst such as B. Tin (IV) chloride, titanium (IV) chloride, tin (IV) - triflate or zinc bromide.

The esters of formula X can be isolated and in the above indicated way with a cyanide to the nitriles Formula XI are implemented, but they can even in situ, without being isolated and reacted with a cyanide.

Nitriles of formula XI can with bases or acids Acids of the formula XII, in which R⁵ is H, implemented are, in particular alkali metal hydroxides as bases such as sodium or potassium hydroxide, alkali metal carbonates or hydrogen carbonates such as sodium carbonate, Sodium bicarbonate, potassium carbonate or potassium bicarbonate or alkaline earth metal hydroxides such as calcium hydroxide are suitable. As acids are, for example Hydrochloric acid, sulfuric acid or hydrobromic acid suitable. The reaction temperature is usually between -20 ° C and + 200 ° C, preferably between 0 ° C and + 100 ° C. The reactions are at these temperatures usually finished between 30 minutes and 48 hours.

With alcohols R⁵-OH nitriles of the formula XI under Acid catalysis to acid derivatives of the formula XII, in which R⁵ denotes lower alkyl, cycloalkyl or aryl, be implemented.  

Suitable acids are in particular hydrogen chloride, Sulfuric acid and boron trifluoride, for example in Form of its diethyl ether adduct. Advantageously the reaction is carried out in an excess of the alcohol R⁵-OH as a solvent at temperatures between 0 ° C and + 150 ° C through.

The known ones can be obtained from the acid derivatives of the formula XII Lactones of formula XIII can be obtained by from the former the hydroxymethyl (X = O) or mercaptomethyl (X = S) group is set free again

wherein X, Y, R³ and R⁵ have the meaning given above own, R⁶ H or CHR¹R² and R⁷ H, alkanoyl or aroyl under water (R⁵ = H) or alcohol (R⁵ ≠ H) elimination are cyclized.

The bicycles of the formula XII are suitable for example acids such as hydrochloric acid or sulfuric acid, which, conveniently in a solvent, e.g. B. Water or alcohols, to the hydantoins of the Formula XIIa, wherein R⁶ = R⁷ = H, lead.

Heavy metal salts can also be used as cleavage reagent such as silver nitrate, mercury (II) chloride or mercury (II) acetate and the subsequent decomposition of the intermediate metal mercaptides with hydrogen sulfide. For this cleavage reaction Suitable solvents can be found, for example, under  alcohols such as methanol, ethanol, amides such as Dimethylformamide or ethers such as tetrahydrofuran.

With reducing agents, acid derivatives of Formula XII, in which XS means intermediate products of the formula XIIa, in which R⁶ is CHR¹R² and X is S, be implemented. Suitable reducing agents are, for example, metals such as zinc. The split the acid derivatives are made by reduction with metals preferably in an acidic environment. Suitable for this Acids are, for example, mineral acids such as Hydrochloric acid or sulfuric acid or organic acids such as formic acid or acetic acid. Be expedient these acids as solvents or in a mixture with other solvents such as B. alcohols used. The reaction temperature is usually between 0 ° C and 200 ° C, preferably between 20 ° C and 150 ° C. The reactions are at these temperatures usually between 15 minutes and 24 hours completed.

Under the conditions given above usually obtained compounds of the formula XIIa, where R⁷ means H. However, the reduction is in anhydrous Environment with the addition of an acylating agent, such as B. an acid halide or anhydride, this leads to compounds of the formula XIIa, in which R⁷ means alkanoyl or aroyl. Such Compounds are preferably suitable for transfer to Lactones of formula XIII.

The intermediates of formula XIIa obtained can be isolated; however, they will be useful in situ to the known lactones of Formula XIII implemented. The latter lactones often arise already to a large extent or completely  the cleavage of the bicycles of the formula XII. For education the lactones of formula XIII from the intermediates of the formula XIIa, these are with a water or Treating alcohol elimination agents treated. Therefor suitable agents are, for example, in alkali metal salts such as potassium or sodium acetate, potassium thioacetate, in acids such as methanesulfonic acid, p-toluenesulfonic acid, Phosphoric acid, sulfuric acid or hydrochloric acid, in anhydrides such as acetic anhydride or trifluoroacetic anhydride or in other dehydration reagents such as Alumina, potassium hydroxide, cyanic acid or dicyclohexylcarbodiimide to disposal. The application of an excess of the aforementioned lactonizing agents often prove to be beneficial. Suitable reaction conditions for lactonization, for example Houben-Weyl, Methods of Organic Chemistry, Vol. E5, remove.

Compounds of formula XIIa, wherein R⁷ alkanoyl or Aroyl means can be advantageously in lactones of formula XIII by using their corresponding Alkali metal salts, especially their sodium or potassium salts (XIIa, R⁵ = Na, K) of a thermal Subjects epimerization / cyclization. Man carries out the implementation of any in situ produced Alkali metal salts of carboxylic acids of the formula XII advantageous in an inert solvent such as Dimethylformamide, dimethylacetamide, dimethyl sulfoxide or N-methylpyrrolidone at temperatures of 30-200 ° C, especially at 50-150 ° C. The response times range from 30 minutes to 12 hours.

The conversion of the lactones of the formula XIII into D - (+) - Biotin is e.g. B. from DE-20 58 234 and DE-23 31 244 known.  

In another process for the production of D - (+) - Biotin from (7aR) -1H, 3H-imidazo [1,5-c] azoles of the formula I become nitriles of formula XI with an organometallic Connection to oxo compounds of the formula XIV implemented. Suitable organometallic compounds are, for example, those of magnesium (process according to Blaise), of zinc (Reformatzky method), of lithium or aluminum. The reaction conditions to implement the organometallic compounds are based on nature and chemical reactivity of the existing functional groups and can can be selected analogously to known methods, for example in Houben-Weyl, Methods of Organic Chemistry, Vol. VII / 2a, p. 603.

To convert the bicyclic oxo compounds of Formula XIV in the hydantoins of formula XV using a Acid or a reducing agent are suitable same methods of presentation given above the hydantoins of the formula XIIa from the acid derivatives XII. When cleaving using acids Obtaining imidazolidines of the formula XV, in which R⁶H denotes in the case of cleavage by a reducing agent R⁶ in formula XV means R¹R²CH. The reaction conditions are based on the previously specified Methods.

Compounds of formula XV can under basic conditions cyclized to the hemiacetals of formula XVI will. Suitable bases are for example Alkali metal hydroxides such as sodium or potassium hydroxide, Alkali metal carbonates such as sodium hydrogen carbonate, potassium carbonate, Potassium hydrogen carbonate, alkali metal acetates such as sodium or potassium acetate, alkaline earth metal hydroxides and oxides such as calcium hydroxide, calcium oxide or aluminum oxide or organic bases such as triethylamine,  Pyridine, lutidine, piperidine, morpholine, piperazine, Collidine or quinoline. Also suitable basic ion exchanger for the cyclization of compounds of the formula XV. The reaction is expediently carried out in an inert solvent. As inert Solvents are preferably hydrocarbons such as cyclohexane, benzene, toluene, ethers such as tetrahydrofuran, Dioxane, amides such as dimethylformamide, hexamethylphosphoric triamide, Sulfoxides such as dimethyl sulfoxide, Alcohols such as methanol, ethanol, esters such as ethyl acetate or lower carboxylic acids such as formic acid or Acetic acid. Also an excess of organic base is suitable as a solvent, which in combination a particularly preferred with a lower carboxylic acid Represents cyclization medium. The reaction temperatures expediently lie between about 0 ° and 200 ° C, preferably between 20 and 150 ° C, the reaction times between about 1 and 48 hours.

Hemiacetals of the formula XVI are known and can according to known methods, such as DE-20 58 234 can be seen, converted to D - (+) - biotin will.

In another process for the production of D - (+) - Biotin from (7aR) -1H, 3H-imidazo [1,5-c] azoles of the formula I become nitriles of formula XI with a reducing agent converted to an aldehyde of the formula XVII. Therefor suitable processes are, for example, Houben-Weyl, Methods of Organic Chemistry, Vol. 7/1, p. 299 and E3, p. 476. Can be used as a reducing agent e.g. B. tin (II) chloride with hydrogen chloride in ether Solution or hydrogen under Raney nickel catalysis use in an acidic environment. Good results are also by reacting the nitriles of formula XI with 2-mercaptoethanol to the corresponding 2-substituted  1,3-benzooxathiazoles and their reduction to achieve with sodium borohydride. Particularly advantageous the nitriles of the formula XI are reduced with complex hydrides such as sodium hydro-triethoxyaluminate, Lithium hydro-triethoxyalanate or, in particular preferred, with diisobutyl aluminum hydride.

The complex hydrides are implemented with the Nitriles of the formula XI advantageously in an inert Solvent through. Suitable as inert solvents preferably hydrocarbons such as pentane, hexane, Cyclohexane, benzene or toluene or ethers such as diethyl ether, Tetrahydrofuran, dioxane or ethylene glycol dimethyl ether and mixtures of these solvents with one another. The reaction temperatures are expedient between about -120 ° C and + 150 ° C, preferably between -80 ° C and + 100 ° C, the reaction times between about 30 minutes and 24 hours.

The aldehydes of the formula XVII can be used with suitable Phosphorus organyls in the absence of a base produce the unsaturated compounds of formula XVIII. For example, phosphoranes Transfer to the corresponding ylide according to the in Houben-Weyl, Methods of Organic Chemistry, Vol. 5/16, P. 383, phosphonates after formation of the anion in analog the z. B. in Organic Reaction, Vol. 25, John Wiley, New York, 1978, chap. 2, described method or Phosphine oxides, for example in Houben-Weyl, methods of organic chemistry, vol. XII / 1, p. 167 Way of olefining aldehydes of formula XVII are used. As bases for preparation a reactive phosphorylide, phosphonate or phosphine oxide anions are suitable depending on the deprotonation ability of the used Phosphorus organyls e.g. B. alkali metal hydroxides such as sodium  or potassium hydroxide, alkali metal carbonates such as sodium or potassium carbonate, alcoholates such as sodium methylate, Sodium ethylate, lithium ethylate or Potassium tert-butanolate, alkali metal amides such as potassium or sodium amide, alkali metal organyls such as methyl lithium, Butyllithium or phenyllithium or others organic bases such as lithium diisopropylamide or Sodium methylsulfinylmethylide. One expediently leads carry out the reaction in an inert solvent. Suitable inert solvents are preferably Ethers such as diethyl ether, ethylene glycol dimethyl ether, Tetrahydrofuran or dioxane and amides such as dimethylformamide, Hexamethylphosphoric triamide, dimethylacetamide or N-methylpyrrolidone, also sulfoxides such as dimethyl sulfoxide or sulfolane and hydrocarbons such as pentane, hexane, cyclohexane, benzene or toluene. The reaction temperatures are appropriately appropriate the reactivity of the phosphoroganyls used between about -10 ° C and about + 150 ° C, preferably between + 20 ° C and + 100 ° C, the reaction times between 1 and 48 hours.

After for the cleavage of acid derivatives of the formula XII analogous methods described above the unsaturated bicyclic compounds of the Formula XVIII with acids and / or reducing agents implemented. Hydroxy- Experience (X = O) or mercapto- (X = S) -methylhydantoine ring closure to the under the cleavage conditions Biotin derivatives of the formula XIX, where in the case of a Acid cleavage R⁶ H; in case of a split a reducing agent means R⁶ R¹R²CH. The reaction conditions are based on the previously specified Methods.  

Finally, oxo compounds of formula XIV analogous to the cleavage of acid derivatives of the formula XII, Processes described above in biotin derivatives of the formula XX, wherein R³, X, Y and Z die given meaning.

Biotin derivatives of the formula XIX are known and can according to known methods such. B. in DE-20 58 234, EP-O 036 030 and EP-O 084 377 discloses D - (+) - biotin be implemented.

The method according to the invention thus allows production from optically active D - (+) - biotin to simple and stereospecific in high yields easily accessible, cheap raw materials in few, some of which can be carried out in one-pot processes Synthesis steps and thus represents an essential Progress in the field of biotin synthesis.

Example 1

A solution of 97.32 g kept under nitrogen (0.3 mol) (7aR) -3-phenyl-6-benzyl-1H, 3H-imidazo [1,5-c] - thiazole-5,7 (6H, 7aH) dione in 800 ml of tetrahydrofuran at 6.5 ° C in portions with 6.53 g (0.3 mol) Lithium borohydride added and then 3 hours stirred at room temperature.

Then carefully decompose with 400 ml of ice water, the tetrahydrofuran is largely distilled off and extracted the product with a total of 800 ml of ethyl acetate.

The organic phases are combined, twice with each Washed 150 ml of water, dried over sodium sulfate and concentrated under reduced pressure.  

90.8 g of (7RS, 7aR) -3-phenyl-6-benzyl-7,7a- dihydro-7-hydroxy-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one with a melting point of 151-153 ° C.

[ α ] = -875 °, c = 1 (methanol)

Example 2

In a solution of 324.4 g (1 mol) of (7aR) -3-phenyl-6- benzyl-1H, 3H-imidazo [1,5-c] thiazole-5,7 (6H, 7aH) dione in 1200 ml of tetrahydrofuran is left at room temperature a solution of 43.35 g (1.1 mol) of 96% sodium borohydride flow into 300 ml of water and stir the reaction mixture 12 hours at 50 ° C. Then cools the mixture is removed to 20 ° C., the aqueous phase is separated off and concentrated the organic solution under reduced pressure.

The residue is suspended in 1000 ml of 2-propanol, distilled off 100 ml of solvent and left at 0 ° C. crystallize.

303.5 g of (7R, 7aR) -3-phenyl-6-benzyl-7,7a- dihydro-7-hydroxy-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one with a melting point of 174-175 ° C.

[ α ] = -1026 °, c = 1 (methanol)

Example 3

In a solution of 324.4 g (1 mol) of (7aR) -3-phenyl-6- benzyl-1H, 3H-imidazo [1,5-c] thiazole-5,7 (6H, 7aH) dione in 1200 ml of tetrahydrofuran is left at room temperature a solution of 43.35 g (1.1 mol) of 96% sodium borohydride flow into 300 ml of water and stir the reaction mixture 7 hours at 50 ° C. Then cools  from 20 ° C, the aqueous phase is separated off and the organic solution is concentrated under reduced pressure.

The residue is suspended in 1000 ml of 2-propanol, distilled off 100 ml of solvent and left at 0 ° C. crystallize.

298.7 g (7RS, 7aR) -3-phenyl-6-benzyl-7,7a- are obtained. dihydro-7-hydroxy-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one with a melting point of 164-166 ° C.

[ α ] = -964 °, c = 1 (methanol)

Example 4

In a nitrogen suspension of 97.92 g (0.3 mol) (7RS, 7aR) -3-phenyl-6-benzyl-7,7a- dihydro-7-hydroxy-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one in 300 ml of acetonitrile are 50.27 g within 30 minutes (0.31 mol) 1,1-carbonyldiimidazole at + 10 ° C. The resulting clear solution is stirred for 30 minutes at room temperature, concentrates and distributes the residue between 300 ml of water and 500 ml of ethyl acetate. The organic phase is three times with 100 ml of water washed, dried over sodium sulfate and under concentrated under reduced pressure.

104.6 g of (7RS, 7aR) -3-phenyl-6-benzyl-7,7a- dihydro-7- (imidazol-1-ylcarbonyloxy) -1H, 3H-imidazo- [1,5-c] thiazol-5 (6H) -one as an oil.

[ α ] = -750 °, c = 1 (methanol)

Example 5

In a suspension of 0.96 g (32 mmol) 80% sodium hydride in 20 ml of tetrahydrofuran is added dropwise Nitrogen at room temperature a solution of 9.79 g (30 mmol) (7RS, 7aR) -3-phenyl-6-benzyl-7,7a-dihydro-7- hydroxy-1H, 3H-imidazo [1,5-c] thiazol-5- (6H) -one in 100 ml Tetrahydrofuran and stir the resulting solution 45 minutes at room temperature. Then one Solution of 6.34 g (32 mmol) of 1,1-sulfonyldiimidazole in 80 ml of tetrahydrofuran at room temperature within 10 minutes added dropwise and the mixture for a further 20 minutes touched.

It is concentrated, the residue is mixed with 200 ml Ice water and extracted three times with 100 ml of diethyl ether. The combined organic phases are Dried over sodium sulfate and under reduced Pressure reduced.

After chromatography of the residue on silica gel (Ethyl acetate) 8.1 g of (7RS, 7aR) -3-phenyl- 6-benzyl-7,7a-dihydro-7- (imidazol-1-ylsulfonyloxy) - 1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one as an oil.

[ α ] = -710 °, c = 1 (methanol)

Example 6

In a solution of 97.92 g (0.3 mol) (7RS, 7aR) -3- Phenyl-6-benzyl-7,7a-dihydro-7-hydroxy-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one in 900 ml of pyridine is added dropwise 33.69 g (0.33 mol) of acetic anhydride within 10 minutes and stir the solution for 12 hours at room temperature.  

Then concentrated under reduced pressure, dissolves the residue in 600 ml of toluene, washes three times 100 ml of 1 N hydrochloric acid each and the solvent is distilled from.

110.1 g of (7RS, 7aR) -3-phenyl-6-benzyl-7,7a- dihydro-7-acetoxy-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one as an oil.

[ α ] = -786 °, c = 1 (methanol)

Example 7

In a solution of 210.24 g (0.5 mol) (7RS, 7aR) -3- Phenyl-6-benzyl-7,7a-dihydro-7- (imidazol-1-ylcarbonyloxy) - 1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one in 1500 ml Acetone is added dropwise within 10 minutes 354.85 g (2.5 mol) Iodomethane and stir the solution for 3 hours at room temperature.

It is then concentrated, the residue in 750 ml Dimethylformamide dissolved, with 98.02 g (2 mol) of sodium cyanide added and the mixture at 75 ° C for one hour touched.

The solution is then stirred into 5000 ml of ice water and extracted five times with 500 ml of toluene. The United organic phases are mixed with water as well saturated sodium chloride solution, over sodium sulfate dried and concentrated under reduced pressure.

150.7 g of a mixture of (7R, 7aR) - and (7S, 7aR) -3-phenyl-6-benzyl-7-cyano-7,7a-dihydro-1H, 3H- imidazo [1,5-c] thiazol-5 (6H) -one as an oil, which on silica gel chromatographed with petroleum ether / tert-butyl methyl ether (1: 1, v / v) becomes.  

7S-nitrile: yield 35 g;
Mp .: 102-103 ° C
[ α ] = -795 °, c = 1 (methanol)

7R-nitrile: yield 107 g;
Mp .: 109-110 ° C
[ α ] = -840 °, c = 1 (methanol)

Example 8

45.65 g (0.1 mol) (7RS, 7aR) -3-phenyl-6-benzyl-7,7a-dihydro- 7- (imidazole-1-sulfonyloxy) -1H, 3H-imidazo [1,5-c] - thiazol-5 (6H) -one are placed in 350 ml acetone. In this solution is added dropwise to 60.49 g within 5 minutes (0.5 mol) allyl bromide and stir the reaction mixture 30 minutes at room temperature.

It is then concentrated, the residue in 100 ml 1-methyl-2-pyrrolidone dissolved, the solution with 19.6 g (0.4 mol) of sodium cyanide and added for 45 minutes 80 ° C stirred.

Then the reaction mixture in 1000 ml of ice water stirred in and extracted three times with 200 ml of toluene. The combined organic phases are washed with water and saturated saline, dries over sodium sulfate and constricts under reduced pressure.

16.8 g of a mixture of (7R, 7aR) - and (7S, 7aR) -3-phenyl-6-benzyl-7-cyano-7,7a-dihydro-1H, 3H- imidazo [1,5-c] thiazol-5 (6H) -one as an oil, which on silica gel chromatographed with petroleum ether / tert-butyl methyl ether (1: 1, v / v becomes.  

7S nitrile: yield 3.8 g;
Mp .: 103 ° C
[ a ] = -790 °

7R-nitrile: yield 11.8 g;
Mp .: 109-110 ° C
[ α ] = -845 °, c = 1 (methanol)

Example 9

In a 368.45 g solution kept under nitrogen (1 mole) (7RS, 7aR) -3-phenyl-6-benzyl-7,7a-dihydro-7- acetoxy-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one in 3500 ml Dichloromethane is left at 104.17 g (1.05 mol) at -20 ° C. Trimethylsilylcyanid flow in, then drips with vigorous stirring 189.71 g (1 mol) of titanium (IV) chloride within 15 minutes and stirred for 45 minutes at -20 ° C.

The red reaction mixture is carefully cured at 0 ° C 1000 ml of 1 N hydrochloric acid are added and the mixture is complete Decolorization stirred at room temperature.

The organic phase is then separated, twice washed with 1000 ml of water, over sodium sulfate dried and concentrated.

321.3 g (7RS, 7aR) -3-phenyl-6-benzyl-7-cyano are obtained. 7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one as an oil.

[ α ] = -823 °, c = 1 (methanol)

Example 10

A suspension of 97.92 g (0.3 mol) (7RS, 7aR) -3-phenyl- 6-benzyl-7,7a-dihydro-7-hydroxy-1H, 3H-imidazo [1,5-c] - thiazol-5 (6H) -one in 1200 ml of toluene is mixed with 31.64 g (0.4 mol) pyridine and 33.69 g (0.33 mol) acetic anhydride added and stirred at 50 ° C for 10 hours.

The solution is cooled to room temperature and washed three times with 200 ml of 1 N hydrochloric acid and distilled 200 ml Toluene.

After cooling to -20 ° C, nitrogen is added with 30.76 g (0.31 mol) of trimethylsilyl cyanide and added dropwise 56.91 g (0.3 mol) of titanium (IV) chloride within 5 minutes to.

The solution is carefully dripped into the brown reaction mixture at 0 ° C 350 ml of 1 N hydrochloric acid and stir to complete Decolorization at room temperature.

The organic phase is separated, twice with each Washed 300 ml of water and concentrated.

89.6 g of (7RS, 7aR) -3-phenyl-6-benzyl-7-cyano- 7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one as an oil.

[ α ] = -817 °, c = 1 (methanol)

Example 11

A solution of 97.92 g (0.3 mol) (7RS, 7aR) -3-phenyl- 6-benzyl-7,7a-dihydro-7-hydroxy-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one in 960 ml dichloromethane is with 47.46 g (0.6 mol) of pyridine and 33.69 g (0.33 mol) of acetic anhydride  added and refluxed for 8 hours cooked.

Cool to room temperature, wash three times with each 300 ml of 1N hydrochloric acid and dried over sodium sulfate.

The solution is then cooled to -20 ° C. and left 30.76 g (0.31 mol) of trimethylsilyl cyanide under nitrogen flow in and drips within 5 minutes 78.15 g (0.3 mol) of tin (IV) chloride.

The reaction mixture is then carefully added at 0 ° C with 350 ml of 1 N hydrochloric acid and stirred at room temperature until complete decolorization.

The organic phase is separated, twice with each Washed 300 ml of water, dried over sodium sulfate and constricted.

86.3 g of (7RS, 7aR) -3-phenyl-6-benzyl-7-cyano- 7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one as an oil.

[ α ] = -826 °, c = 1 (methanol)

Example 12

A solution of 13.42 g (40 mmol) of a mixture (7R, 7aR) - and (7S, 7aR) -3-phenyl-6-benzyl-7-cyano-7,7a- dihydro-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one in 75 ml n-Butanol is mixed with a solution of 7.92 g (0.12 mol) 85% potassium hydroxide in 20 ml of water and Stirred at 100 ° C for 90 minutes.

The solvent is then largely distilled off, mixed with 200 ml of water and extracted three times with 100 ml dichloromethane each.  

In the aqueous phase, dropwise at 0 ° C conc. Hydrochloric acid, until pH 1 is reached, the product sucks off and washes in portions with a total of 100 ml of water.

13.5 g of (7R, 7aR) -3-phenyl-5- (6H) -oxo-6-benzyl- 7,7a-dihydro-1H, 3H-imidazo [1,5] thiazole-7-carboxylic acid with a melting point of 184-185 ° C.

[ α ] = -960 °, c = 1 (methanol)

Example 13

134.17 g (0.4 mol) (7R, 7aR) -3-phenyl-6- are suspended benzyl-7-cyano-7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazole- 5 (6H) -on in 1000 ml conc. Hydrochloric acid and stir that Mixture at 80 ° C for 3 hours. The temperature is then raised to 0 ° C cooled, stirred for 3 hours, suction filtered and in portions washed with 500 ml of water.

This gives 129.8 g of (7R, 7aR) -3-phenyl-5 (6H) -oxo-6-benzyl- 7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazole-7-carboxylic acid with a melting point of 183-184 ° C.

[ α ] = -950 °, c = 1 (methanol)

Example 14

According to the procedure given in Example 13 13.42 g (40 mmol) (7S, 7aR) -3-phenyl-6-benzyl-7-cyano- 7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one and 100 ml conc. Hydrochloric acid 3 hours at 80 ° for reaction brought. After the specified work-up, one obtains (7S, 7aR) -3-phenyl-5 (6H) -oxo-6-benzyl-7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazole-7-carboxylic acid; Mp .: 220-225 ° C.  

Example 15

According to the procedure given in Example 13 134.17 g (0.4 mol) of a mixture of (7R, 7aR) - and (7S, 7aR) -3-phenyl-6-benzyl-7-cyano-7,7a-dihydro-1H, 3H- imidazo [1,5-c] thiazol-5 (6H) -one hydrolyzed with hydrochloric acid. 127.2 g of a mixture of (7R, 7aR) are obtained - and (7S, 7aR) -3-phenyl-5 (6H) -oxo-benzyl-7,7a-dihydro- 1H, 3H-imidazo [1,5-c] thiazole-7-carboxylic acid, which has no defined melting point.

Example 16

To a solution of 20.04 g (0.11 mol) of 1,1-sulfinyldiimidazole (W. Walter, M. Radke; Liebigs Ann.Chem. 1979, 1756-67) in 350 ml dichloromethane Nitrogen at room temperature 32.64 g (0.1 mol) (7RS, 7aR) -3-phenyl-6-benzyl-7-cyano-7,7a-dihydro- 7-hydroxy-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one given.

The clear solution is stirred for 30 minutes at room temperature, washes twice with 150 ml of water each, dries over sodium sulfate and filtered.

37.84 g (0.3 mol) of dimethyl sulfate are added dropwise to the filtrate at 10 ° C (10 minutes) and stir the solution for 4 hours at 20 ° C.

Excess dimethyl sulfate is then destroyed by adding triethylamine at 20 ° C and concentrated under reduced pressure.

The oily residue is dissolved in 100 ml of dimethylformamide, carries 14.7 g (0.3 mol) of sodium cyanide and the reaction mixture is stirred at 85 ° C. for 60 minutes.  

Then the reaction mixture in 500 ml of ice water stirred in and extracted three times with 150 ml of ethyl acetate. Washes the combined organic phases one with water and saturated saline and concentrated under reduced pressure. The hydrolysis of the obtained Nitrile is carried out analogously to that in Example 6 described manner using 200 ml of n-butanol, 19.8 g (0.3 mol) of 85% potassium hydroxide and 40 ml water.

22.68 g of (7R, 7aR) -3-phenyl-5 (6H) -oxo-6- are obtained. benzyl-7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazole-7- carboxylic acid.

Mp .: 180-181 ° C
[ α ] = -945 °, c = 1 (methanol)

Example 17

A solution of 9.92 g (28 mmol) (7R, 7aR) -3-phenyl- 5 (6H) -oxo-6-benzyl-7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazole-7-carboxylic acid in 150 ml of anhydrous acetic acid at 80 ° C in portions with 7.32 g (112 mmol) zinc powder added, another 4 hours at Stirred at 80 ° C., filtered and under reduced pressure constricted.

The residue is dissolved in 500 ml of ethyl acetate, washed with 200 ml of water and 100 ml of saturated saline, dries over sodium sulfate and constricts under reduced pressure Pressure. Crystallized when triturated with diethyl ether the product.

9.39 g of (4R, 5R) -1,3-dibenzyl-2-oxo-5-mercaptomethyl- imidazolidine-4-carboxylic acid with a melting point from 167-169 ° C.

[ α ] = + 60 °, c = 1 (methanol)

Example 18

A solution of 9.92 g (28 mmol) (7R, 7aR) -3-phenyl-5- (6H) -oxo-6-benzyl-7,7a-dihydro-1H, 3H-imidazo [1,5-c] -thiazole- 7-carboxylic acid in a mixture of 100 ml of anhydrous Acetic acid and 4.29 g (42 mmol) of acetic anhydride at 90 ° C in portions with 7.32 g (112 mmol) of zinc powder added and then stirred at 110 ° C. for 2 hours.

It is then cooled to 60 ° C., filtered and concentrated under reduced pressure.

The residue is suspended in 120 ml of water and stirred 60 minutes at room temperature, filtered and dried in a vacuum.

9.5 g of (4R, 5R) -1,3-dibenzyl-2-oxo-5-acetylmercaptomethyl- imidazoline-4-carboxylic acid with a melting point from 135-140 ° C.

[ α ] = + 173 °, c = 1 (methanol)

Example 19

35.64 g (0.1 mol) of (4R, 5R) -1,3-dibenzyl-2-oxo- 5-mercaptomethyl-imidazoline-4-carboxylic acid in 300 ml dimethylacetamide, carries 13.61 g (0.1 mol) of sodium acetate Trihydrate and heats the mixture for 40 minutes 150 ° C.

It is then cooled to room temperature, in 900 ml of water are stirred in and four times with 100 ml of toluene extracted. The combined organic phases be three times with 50 ml of water and once with Washed 50 ml of saturated saline and under  concentrated under reduced pressure. The backlog is out Recrystallized ethyl acetate.

28.76 g (3aS, 6aR) -1,3-dibenzyl-tetrahydrothieno are obtained [3,4-d] imidazole-2 (3H), 4-dione with a melting point from 118-119 ° C.

[ α ] = + 90.8 °, c = 1 (CHCl₃)

Example 20

39.85 g (0.1 mol) of (4R, 5R) -1,3-dibenzyl-2-oxo- 5-acetylmercaptomethyl-imidazoline-4-carboxylic acid in 100 ml Dimethylformamide, carries 11.42 g (0.1 mol) of potassium thioacetate and heats the reaction mixture to 130 ° C for 2 hours.

It is then cooled to room temperature in 800 ml Water stirred in and extracted four times with 100 ml of toluene. The combined organic phases are three times each 50 ml of water and washed once with saturated saline and concentrated under reduced pressure.

The residue is recrystallized from 2-propanol and obtained 25.4 g (3aS, 6aR) -1,3-dibenzyl-tetrahydrothieno [3,4-d] - imidazole-2 (3H), 4-dione with a melting point of 118 ° C.

[ α ] = + 90.7 °, C = 1 (CHCl₃)

Example 21

A solution of 39.85 g (0.1 mole) (4R, 5R) -1,3-dibenzyl-2- oxo-5-acetylmercaptomethyl-imidazoline-4-carboxylic acid in 300 ml of 1N sodium hydroxide solution is at room temperature for 60 minutes stirred, then with conc. Acidified hydrochloric acid to pH 4 and extracted three times with 100 ml of dichloromethane.  

The combined organic phases are over sodium sulfate dried and concentrated under reduced pressure.

The residue is dissolved in 100 ml of N-methylpyrrolidone, enters 11.42 g (0.1 mol) of potassium thioacetate and heated the reaction mixture at 130 ° C for 90 minutes.

It is then cooled to room temperature in 800 ml Water stirred in and extracted four times with 100 ml of toluene. The combined organic phases are three times with 50 ml of water and once with saturated saline washed and concentrated under reduced pressure.

The residue is recrystallized from 2-propanol and receives 22.6 g (3aS, 6aR) -1,3-dibenzyl-tetrahydrothieno- [3,4-d] imidazole-2 (3H), 4-dione with a melting point of 119-120 ° C.

[ α ] = + 91.4 °, c = 1 (CHCl₃)

Example 22

A solution of 39.85 g (0.1 mole) (4S, 5R) -1,3-dibenzyl- 2-oxo-5-acetylmercaptomethyl-imidazoline-4-carboxylic acid in 200 ml of methanol is mixed with 100 ml of one molar methanol Potassium hydroxide solution added and under reduced pressure constricted.

The oily residue is dissolved in 100 ml of dimethylformamide and heated to 130 ° C for 3 hours.

It is then cooled to room temperature in 800 ml Water stirred in and extracted four times with 100 ml of toluene. The combined organic phases are three times with 50 ml of water and once with saturated saline washed and concentrated under reduced pressure.  

The residue is recrystallized from 2-propanol and obtained 27.7 g (3aS, 6aR) -1,3-dibenzyltetrahydrothieno [3,4-d] imidazole-2 (3H) -4-dione with a melting point of 119 ° C.

[ α ] = + 91.1 °, c = 1 (CHCl₃)

Example 23

39.85 g (0.1 mol) of (4R, 5R) -1,3-dibenzyl-2-oxo- 5-acetylmercaptomethyl-imidazoline-4-carboxylic acid in 100 ml N-methylpyrrolidone, carries 11.22 g (0.2 mol) Potassium tert-butoxide and heats the reaction mixture 2 hours at 130 ° C.

It is then cooled to room temperature, in 800 ml of water stirred in and four times with 100 ml of toluene extracted. The combined organic phases are washed three times with 50 ml of water and under concentrated under reduced pressure.

The residue is recrystallized from 2-propanol and receives 28.3 g (3aS, 6aR) -1,3-dibenzyltetrahydrothieno- [3,4-d] imidazole-2 (3H), 4-dione with a melting point of 118-119 ° C.

[ α ] = + 90.8 °, c = 1 (CHCl₃)

Example 24

According to the procedure given in Example 23 39.85 g (0.1 mol) (4R, 5R) -1,3-dibenzyl-2-oxo-5-acetylmercaptomethyl- imidazoline-4-carboxylic acid with 5.40 g (0.1 mol) sodium methylate in 100 ml of N-methylpyrrolidone implemented.  

28.0 g (3aS, 6aR) -1,3-dibenzyltetrahydrothieno are obtained [3,4-d] imidazole-2 (3H), 4-dione with a melting point from 119-120 ° C.

[ α ] = + 91.3 °, c = 1 (CHCl₃)

Example 25

According to the procedure given in Example 23 39.85 g (0.1 mol) (4R, 5R) -1,3-dibenzyl-2-oxo-5-acetylmercaptomethyl- imidazoline-4-carboxylic acid with 4.0 g (0.1 mol) sodium hydroxide in 100 ml of N-methylpyrrolidone implemented.

22.9 g (3aS, 6aR) -1,3-dibenzyl-tetrahydrothieno are obtained [3,4-d] imidazole-2 (3H), 4-dione with a melting point of 119 ° C.

[ a ] = + 90.8 °, c = 1 (CHCl₃)

Example 26

A solution of 53.47 g (0.15 mol) (4R, 5S) -1,3-dibenzyl- 2-oxo-5-mercaptomethyl-imidazolidine-4-carboxylic acid in 300 ml of pyridine is at room temperature with 1.43 g (7.5 mmol) toluene-4-sulfonic acid monohydrate and 37.14 g (0.18 mol) of N, N′-dicyclohexylcarbodiimide and 6 Stirred at 20 ° C for hours.

Then it is suctioned off and the filtrate is concentrated reduced pressure.

The residue is dissolved in 400 ml of toluene, washed twice with 50 ml of 1 N hydrochloric acid, concentrated and crystallized from 2-propanol.  

40.6 g (3aS, 6aR) -1,3-dibenzyltetrahydrothieno- [3,4-d] imidazole-2 (3H), 4-dione with a melting point of Get 119-120 ° C.

[ α ] = + 91.3 °, c = 1 (CHCl₃)

Example 27

A solution of 5.35 g (15 mmol) (4R, 5R) -1,3-dibenzyl- 2-oxo-5-mercaptomethyl-imidazolidine-4-carboxylic acid in a mixture of 50 ml dichloromethane and 1.42 g (18 mmol) Pyridine is at 5 ° C with 1.70 g (18 mmol) of methyl chloroformate added and boiled under reflux for 36 hours.

The mixture is then cooled to room temperature twice washed with 25 ml of 1N hydrochloric acid each, over sodium sulfate dried and concentrated under reduced pressure.

The residue is on silica gel with toluene / ethyl acetate (9: 1, v / v) chromatographed.

3.1 g (3aS, 6aR) -1,3-dibenzyltetrahydrothieno- [3,4-d] imidazole-2 (3H), 4-dione with a melting point of 119 ° C.

[ a ] = + 90.9 °, c = 1 (CHCl₃)

Example 28

A solution of 9.92 g (28 mmol) (7S, 7aR) -3-phenyl- 5 (6H) -oxo-6-benzyl-7,7a-dihydro-1H, 3H, imidazo [1,5-c] - thiazole-7-carboxylic acid in 150 ml of anhydrous acetic acid at 80 ° C in portions with 7.32 g (112 mmol) zinc powder added, another 4 hours at Stirred at 80 ° C., filtered and under reduced pressure constricted.  

The residue is dissolved in 300 ml of toluene, washed with 150 ml of water and 75 ml of saturated saline and constricts under reduced pressure. The raw thiolactone is recrystallized from ethyl acetate.

8.0 g (3aS, 6aR) -1,3-dibenzyl-tetrahydrothieno are obtained [3,4-d] imidazole-2 (3H), 4-dione with a melting point from 119-120 ° C.

[ α ] = + 91.2 °, c = 1 (CHCl₃)

Example 29

A solution of 99.24 g (0.28 mol) (7R, 7aR) - and (7S, 7aR) -3-phenyl-5 (6H) -oxo-6-benzyl-7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazole-7-carboxylic acid in 1500 ml anhydrous Acetic acid is added in portions at 80 ° C 73.22 g (1.12 mol) of zinc powder added, a further 4 hours stirred at 80 ° C, filtered and under reduced pressure Pressure reduced.

The residue is dissolved in 1000 ml of dimethylformamide, the solution with 38.1 g (0.28 mol) of sodium acetate trihydrate added and stirred at 125 ° C for 60 minutes.

The mixture is then cooled to room temperature and stirred in 1500 ml of water, extracted four times with 200 ml each Toluene, washes the combined extracts three times each 150 ml of water and once with saturated saline and constricts under reduced pressure.

The residue is recrystallized from ethyl acetate and receives 75.8 g (3aS, 6aR) -1,3-dibenzyl-tetrahydro-thieno- [3,4-d] imidazole-2 (3H), 4-dione with a melting point of 118-119 ° C.  

[ α ] = + 90.6 °, c = 1 (CHCl₃)

Example 30

10.06 g (30 mmol) (7S, 7aR) -3-phenyl-6- are suspended benzyl-7-cyano-7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazole- 5 (6H) -one in 150 ml of saturated methanolic hydrochloric acid and the mixture is stirred at 60 ° C. for 5 hours.

It is then cooled and decomposed with 500 ml of ice water and extracted four times with 150 ml of ethyl acetate.

The combined organic phases are with a total Washed 300 ml of water, dried over sodium sulfate and concentrated under reduced pressure. At the Trituration with diethyl ether crystallizes the product.

10.2 g of (7S, 7aR) -3-phenyl-5 (6H) -oxo-6-benzyl- 7,7a-dihydro-1H, 3H-imidazo [1,5-c] -thiazole-7-carboxylic acid methyl ester with a melting point of 155-156 ° C.

[ α ] = -752 °, c = 1 (methanol)

Example 31

From 10.06 g (30 mmol) (7R, 7aR) -3-phenyl-6- benzyl-7-cyano-7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazole- 5 (6H) -on are according to that given in Example 15 Method of operation 10.1 g (7R, 7aR) -3-phenyl-5 (6H) -oxo- 6-benzyl-7,7a-dihydro-1H, 3H-imidazo [1,5-c] -thiazol-7- carboxylic acid methyl ester obtained as a colorless oil;

[ α ] = -862 °, c = 1 (methanol).

Example 32

A solution of 11.05 g (30 mmol) (7S, 7aR) -3-phenyl- 5 (6H) -oxo-6-benzyl-7,7a-dihydro-1H, 3H-imidazo [1,5-c] - thiazole-7-carboxylic acid methyl ester in 150 ml of anhydrous Acetic acid is added in portions at 80 ° C 7.85 g (120 mmol) of zinc powder added, a further 4 hours stirred at 80 ° C, filtered and under reduced pressure Pressure reduced.

The residue is dissolved in 300 ml of toluene, washed with 150 ml of water and 75 ml of saturated saline and constricts under reduced pressure.

The crude thiolactone is recrystallized from ethyl acetate. 8.4 g (3aS, 6aR) -1,3-dibenyzl-tetrahydro- thieno [3,4-d] imidazole-2 (3H), 4-dione with one Melting point of 120 ° C.

[ α ] = + 91.1 °, c = 1 (CHCl₃)

Example 33

A solution of 11.05 g (30 mmol) (7R, 7aR) -3-phenyl- 5 (6H) -oxo-6-benzyl-7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazole-7-carboxylic acid methyl ester in 150 ml of anhydrous Acetic acid is added in portions at 80 ° C 7.85 g (120 mmol) of zinc powder added, a further 4 hours stirred at 80 ° C, filtered and under reduced pressure Pressure reduced.

The residue is dissolved in 110 ml of dimethylformamide, the solution with 4.08 g (30 mmol) of sodium acetate trihydrate added and stirred at 110 ° C for 60 minutes.  

The mixture is then cooled to room temperature and stirred in 200 ml of water, extracted four times with 100 ml each Toluene, washes the combined extracts three times each 50 ml of water and once with 50 ml of saturated saline and constricts under reduced pressure.

The residue is recrystallized from ethyl acetate and receives 7.5 g (3aS, 6aR) -1,3-dibenzyl-tetrahydrothieno [3,4-d] imidazole-2 (3H), 4-dione with a melting point of 119 ° C.

[ α ] = + 90.6 °, c = 1 (CHCl₃)

Example 34

One from 3.68 g (30 mmol) of 1-chloro-4-methoxybutane and 0.97 g (40 mmol) magnesium in 15 ml tetrahydrofuran prepared Grignard reagent solution is dropped at 40 ° C to a solution of 6.71 g (20 mmol) under nitrogen (7R, 7aR) -3-phenyl-6-benzyl-7-cyano-7,7a-dihydro-1H, 3H- imidazo [1,5-c] thiazol-5 (6H) -one in 10 ml of tetrahydrofuran. The mixture is stirred at 40 ° C. for 30 minutes, decomposed with 50 ml of ice water and adjust pH 4 with 1N hydrochloric acid. Subsequently is extracted three times with 50 ml ether, Dried over sodium sulfate and under reduced Pressure reduced. The crude product is on silica gel Chromatographed diethyl ether.

6.6 g of (7R, 7aR) -3-phenyl-6-benzyl-7- (5-methoxypentanoyl) - 7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazole- 5 (6H) -one as a yellow oil.

[ α ] = -480 °, c = 1 (methanol)

Example 35

According to the procedure given in Example 19 3.86 g (30 mmol) 1-chloro-4-methoxybutane, 0.97 g (40 mmol) magnesium and 6.71 g (20 mmol) (7S, 7aR) -3- Phenyl-6-benzyl-7-cyano-7,7a-dihydro-1H, 3H-imidazo- [1,5-c] thiazol-5 (6H) -one in 25 ml of tetrahydrofuran with each other implemented.

6.3 g (7R, 7aR) -3-phenyl-6-benzyl-7- (5-methoxypentanoyl) are obtained. 7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazole- 5 (6H) -one as a yellow oil.

[ α ] = -475 °, c = 1 (methanol)

Example 36

A solution of 11.46 g (27 mmol) (7R, 7aR) -3-phenyl-6- benzyl-7- (5-methoxypentanoyl) -7.7a-dihydro-1H, 3H-imidazole [1,5-c] thiazol-5 (6H) -one in 200 ml of anhydrous acetic acid is at 80 ° C in portions with 7.06 g (108 mmol) zinc powder added, another 5 hours at Stirred at 80 ° C., filtered and under reduced pressure constricted.

The residue is taken up in 150 ml of toluene and washed three times with 100 ml of water each time and concentrated again reduced pressure. The residue is (4R, 5R) - 1,3-dibenzyl-2-oxo-4- (5-methoxypentanoyl) -5-mercaptomethyl- received imidazolidine;

[ α ] = -52.6 °, c = 1 (methanol)

The pale yellow oil is dissolved in at room temperature 3.66 g (61 mmol) of anhydrous acetic acid, dropwise with ice cooling 5.19 g (61 mmol) of piperidine and heats the melt with stirring for 90 minutes 100 ° C.

Then it is cooled to 20 ° C., mixed with 150 ml of water and extracted three times with 100 ml each tert-butyl methyl ether. The united organic Phases are washed with 1N hydrochloric acid and water, Dried over sodium sulfate and under reduced Pressure reduced.

Then the solution of the oily residue in 50 ml of acetic acid heated to 100 ° C for 2 hours, cooled and concentrated under reduced pressure.

The residue is taken in 100 ml of tert-butyl methyl ether , wash once with 50 ml of 2N sodium hydroxide solution, then twice with 50 ml of water each, dries over sodium sulfate, concentrated and chromatographed the crude product on silica gel (diethyl ether).

8.1 g (3aS, 6aR) -1,3-dibenzyl-4- (4-methoxybutylidene) are obtained - tetrahydro-thieno [3,4-d] imidazol-2 (3H) -one as an oil.

[ α ] = + 236 °, c = 1 (benzene)

Example 37

To a suspension of 19.95 g (45 mmol) (4-carboxybutyl) triphenylphosphonium bromide in 120 ml of tetrahydrofuran is added dropwise 20 ° C 57.5 ml (92 mmol) of a 1.6 molar solution of n-butyl lithium in n-hexane.  

The mixture is stirred for 40 minutes at room temperature, cools to 0 ° C, carries 7.36 g (55 mmol) of lithium iodide and drips a solution of within 20 minutes 13.42 g (40 mmol) of a mixture of (7R, 7aR) - and (7S, 7aR) -3-phenyl-6-benzyl-7-cyano-7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one in 75 ml THF.

The mixture is then stirred in for one hour Room temperature, then 2 hours at 50 ° C, cools down 0 ° C and decomposes with a mixture of 30 ml of ice water and 25 ml conc. Hydrochloric acid.

The mixture is stirred at room temperature for 30 minutes and distilled most of the solvent under reduced Pressure off. The residue is taken up in 150 ml of ethyl acetate.

After phase separation, the organic solution is twice washed with 50 ml of water, dried over sodium sulfate and concentrated under reduced pressure.

The residue is dissolved in 150 ml of anhydrous acetic acid dissolved and at 80 ° C in portions with 7.85 g (120 mmol) Zinc powder added. The mixture is stirred for 4 hours 90 ° C, filtered and concentrated under reduced pressure.

The oily residue is taken up in 100 ml of toluene, washes three times with 50 ml of water each time and concentrated again reduced pressure. As a backlog (4R, 5R) -1,3-dibenzyl-2-oxo-4- (5-carboxypentanoyl) -5- Mercaptomethyl-imidazolidine obtained.

To dissolve the residue in 7.21 g (120 mmol) of acetic acid 11.92 g (140 mmol) of piperidine are added dropwise at 0.degree and heated the mixture at 100 ° C for 2 hours.  

Then cooled to 25 ° C, mixed with 150 ml of water, adjust to pH 3 with 2 N hydrochloric acid and extracted three times with 100 ml of ethyl acetate. The combined organic solutions are with 1 N Washed hydrochloric acid and water, dried over sodium sulfate and concentrated under reduced pressure. As Residue is (3aS, 4RS, 6aR) -1,3-dibenzyl-4-hydroxy- 4- (4-carboxybutyl) tetrahydro-thieno [3,4-d] imidazole- 2 (3H) -one obtained.

Then the solution of the oily residue in 75 ml of acetic acid heated to 100 ° C for 1 hour Cooled to room temperature and under reduced pressure constricted.

The residue is taken up in 150 ml of ethyl acetate, washes twice with 50 ml of water each, dries over Sodium sulfate, concentrated and chromatographed the crude product on silica gel (toluene / ethyl acetate 3: 1, v / v).

10.1 g (3aS, 6aR) -1,3-dibenzyl-4- (4-carboxybutylidene) are obtained - tetrahydrothieno [3,4-d] imidazol-2 (3H) -one with a melting point of 79-82 ° C.

[ α ] = + 215 °, c = 1 (methanol)

Example 38

To a 5.49 g suspension stirred under nitrogen (226 mmol) magnesium shavings in a mixture of 35 ml diethyl ether and 35 ml of toluene are added dropwise at 23 to 27 ° C a solution of 12.40 g (66 mmol) of 1,2- Dibromoethane in 18 ml of diethyl ether, stirred for 45 minutes Room temperature and then drips a solution of 8.38 g (66 mmol) of 1,4-dichlorobutane in a mixture  18 ml of diethyl ether and 38 ml of toluene within 25 minutes without cooling too.

The mixture is stirred for a further 90 minutes, cooled to -30 ° C. and a solution of 7.38 g drips at this temperature (22 mmol) (7RS, 7aR) -3-phenyl-6-benzyl-7-cyano-7,7a- dihydro-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one in 150 ml Toluene within 30 minutes.

Then carbon dioxide is introduced over 60 minutes, allowing the temperature to rise to 0 ° C. It is then concentrated under reduced pressure and the Residue between 150 ml of 1N hydrochloric acid and 200 ml of ethyl acetate distributed. The organic phase is separated off, Dried over sodium sulfate and under reduced Pressure reduced.

6.05 g (7RS, 7aR) -3-phenyl-6-benzyl-7- (5-carboxypentanoyl) are obtained - 7,7a-dihydro-1H, 3H-imidazole [1,5-c] -5- (6H) - on as left-turning oil in methanol.

The residue is dissolved in 100 ml of anhydrous acetic acid and at 80 ° C in portions with 5.88 g (90 mmol) Zinc powder added. The mixture is stirred for 4 hours 90 ° C, filtered and concentrated under reduced pressure.

To dissolve the residue in 5.40 g (90 mmol) of acetic acid 8.52 g (100 mmol) of piperidine are added dropwise at 0 ° C. and the mixture is heated the mixture at 100 ° C for 2 hours.

Then it is cooled to 25 ° C., mixed with 100 ml Water, adjust to pH 3 with 2 N hydrochloric acid and extract three times with 50 ml of ethyl acetate each.  

The combined organic solutions are with 1 N hydrochloric acid and washed water, dried over sodium sulfate and concentrated under reduced pressure.

The residue is (3aS, 4RS, 6aR) -1,3-dibenzyl-4-hydroxy- 4- (4-carboxybutyl) tetrahydrothieno [3,4-d] imidazole-2 (3H) - on as a right-handed oil in methanol.

Then the solution of the residue in 50 ml of acetic acid Heated to 100 ° C for 1 hour and under reduced pressure Pressure reduced. The residue is taken in 100 ml of ethyl acetate on, wash twice with 50 ml of water each, dry over sodium sulfate, concentrated and chromatographed Crude product on silica gel (toluene / ethyl acetate 3: 1, v / v).

4.2 g (3aS, 6aR) -1,3-dibenzyl-4- (4-carboxybutylidene) are obtained - tetrahydrothieno [3,4-d] imidazol-2 (3H) -one with a melting point of 80-82 ° C.

[ α ] = + 214 °, c = 1 (methanol)

Example 39

To a suspension of 7.53 g stirred under nitrogen (310 mmol) magnesium shavings in 50 ml of diethyl ether a solution of 19.43 g (90 mmol) is obtained within 30 minutes 1,4-dibromobutane in 240 ml of diethyl ether, boiled for 60 minutes under reflux and then dripped at 30 ° C. Solution of 10.06 g (30 mmol) (7RS, 7aR) -3-phenyl-6-benzyl- 7-cyano-7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one in 300 ml of diethyl ether within 10 minutes.

Then the reaction mixture is cooled to -30 ° C. and introduces carbon dioxide for 60 minutes, whereby one the temperature rises to 0 ° C.  

After the solvent has been distilled off, the residue partitioned between 200 ml of 1N hydrochloric acid and 200 ml of ethyl acetate. The organic phase is separated off over sodium sulfate dried and concentrated under reduced pressure. 7.2 g (7RS, 7aR) -3-phenyl-6-benzyl-7- (5-carboxypentanoyl) are obtained. 7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazole-5 (6H) - on as left-turning oil in methanol.

The residue is dissolved in 150 ml of anhydrous acetic acid dissolved and at 80 ° C in portions with 6.54 g (100 mmol) Zinc powder added. The mixture is stirred for 4 hours 90 ° C, filtered and distilled 140 ml of acetic acid.

After adding 17.03 g (200 mmol) of piperidine at 0 ° C the reaction mixture is heated to 100 ° C. for 2 hours, then mixed with 150 ml of acetic acid, another 60 minutes stirred at 100 ° C and concentrated under reduced pressure.

The residue is taken up in 150 ml of ethyl acetate, washed with 1 N hydrochloric acid and water, dries over sodium sulfate and constricts under reduced pressure.

The residue is (3aS, 6aR) -1,3-dibenzyl-4- (4-carboxybutylidene) - tetrahydrothieno [3,4-d] imidazol-2 (3H) -one receive.

The crude product is dissolved in 40 ml of methanol, mixed with 30 ml of saturated methanolic hydrochloric acid and stir Solution 2 hours at room temperature. After that, under concentrated under reduced pressure and the oily residue taken up in 100 ml of toluene.

The solution is washed twice with 50 ml of water, the solvent is distilled off and chromatographed the crude product on silica gel (toluene / ethyl acetate 9: 1, v / v).  

6.4 g (3aS, 6aR) -1,3-dibenzyl-4- (4-methoxycarbonylbutylidene) are obtained - tetrahydrothieno [3,4-d] imidazole- 2 (3H) -one as an oil.

[ α ] = + 227 °, c = 1 (benzene)

Example 40

According to the procedure given in Example 39 19.49 g (90 mmol) 1,4-dibromobutane, 7.53 g (310 mmol) Magnesium and 10.06 g (30 mmol) (7R, 7aR) -3-phenyl-6- benzyl-7-cyano-7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazole- 5 (6H) -one reacted in 290 ml of diethyl ether.

6.8 g (3aS, 6aR) -1,3-dibenzyl-4- (4-methoxycarbonylbutylidene) are obtained - tetrahydrothieno [3,4-d] imidazole 2 (3H) -one as an oil.

[ α ] = + 225 °, c = 1 (benzene)

Example 41

According to the procedure given in Example 39 19.43 (90 mmol) 1,4-dibromobutane, 7.53 g (310 mmol) Magnesium and 10.06 g (30 mmol) (7S, 7aR) -3-phenyl-6- benzyl-7-cyano-7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazole- 5 (6H) -one reacted in 290 ml of diethyl ether.

5.2 g (3aS, 6aR) -1,3-dibenzyl-4- (4-methoxycarbonylbutylidene) are obtained - tetrahydrothieno [3,4-d] imidazole 2 (3H) -one as an oil.

[ α ] = + 223 °, c = 1 (benzene)

Example 42

To a solution of 33.54 g (0.1 mol) of a mixture from (7R, 7aR) - and (7S, 7aR) -3-phenyl-6-benzyl-7-cyano- 7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one in 250 ml of toluene are added dropwise under nitrogen at -70 ° C 200 ml of a 1 M solution of diisobutyl aluminum hydride in Toluene, warms to 0 ° C within 3 hours and holds more 2 hours at this temperature. Subsequently is decomposed with 5 ml of methanol and saturated in 250 ml Ammonium chloride solution stirred in. You separate the phases and then shake the organic phase 20 minutes with 100 ml of 10% sulfuric acid.

The phases are separated and washed twice with 100 ml each Water, dries over sodium sulfate and concentrated under reduced pressure Pressure.

29.4 g of a mixture of (7R, 7aR) - and (7S, 7aR) -3-phenyl-5 (6H) -oxo-6-benzyl-7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazole-7-carbaldehyde.

Example 43

In a suspension of 19.95 g (45 mmol) (4-carboxybutyl) triphenylphosphonium bromide in 150 ml of tetrahydrofuran is added dropwise at 20 ° C. 57.5 ml (92 mmol) of a 1.6 M solution of n-butyllithium in n-hexane.

The reaction mixture is stirred at 20 ° C. for 60 minutes, cools to 0 ° C and drips a solution within 15 minutes of 13.54 g (40 mmol) of a mixture of (7R, 7aR) -  and (7S, 7aR) -2-oxo-3-phenyl-6-benzyl-7,7a-dihydro-1H, 3H, 6H-imidazo [1,5-c] thiazole-7-carbaldehyde in 50 ml of tetrahydrofuran to. After another 60 minutes it will Reaction mixture stirred in 200 ml of ice water and with conc. Hydrochloric acid brought to pH 2. You separate the phases and extracted the aqueous phase twice with 50 ml each Ethyl acetate. The combined organic phases are washed with water and saturated saline, Dried over sodium sulfate and under reduced Pressure reduced. The raw product is then with Chromatographed ethyl acetate on silica gel.

13.9 g of a mixture of (7R, 7aR) - and (7S, 7aR) -3-phenyl-6-benzyl- (5-carboxy-pent-1-enyl) - 7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one as an oil.

Example 44

A solution of 12.68 g (30 mmol) of a mixture (7R, 7aR) - and (7S, 7aR) -3-phenyl-6-benzyl- (5-carboxy- pent-1-enyl) -7.7a-dihydro-1H, 3H-imidazo [1,5-c] thiazole- 5 (6H) -one in 150 ml of anhydrous acetic acid is added 85 ° C in portions with 7.85 g (120 mmol) of zinc powder added, stirred for a further 4 hours at 85 ° C., filtered and concentrated under reduced pressure. The The residue is chromatographed on silica gel (dichloromethane / Methanol 9: 1, v / v).

4.8 g (3aS, 4S, 6aR) -1,3-dibenzyl-4- (4-carboxybutyl) - are obtained. tetrahydro-thieno [3,4-d] imidazol-2 (3H) -one with a melting point of 88-89 ° C.

[ α ] = -24.3 °, c = 1 (methanol)

Example 45

8.77 g (20 mmol) one according to that in Examples 38-41 the mixture of (7S, 7aR) - and (7R, 7aR) -3-phenyl-6-benzyl-7- (5-carboxypentanoyl) - 7-7a-dihydro-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one are dissolved in 60 ml of methanol and saturated with 40 ml added methanolic hydrochloric acid.

The mixture is stirred for 2 hours at room temperature and concentrated reduced pressure. The residue is dissolved in 100 ml Toluene, washed twice with 50 ml of water, distilled the solvent and chromatographed the crude product on silica gel (ethyl acetate).

3.3 g (3aS, 6aR) -3-benzyl-4- (4-methoxycarbonyl- butlyidene) tetrahydrothieno [3,4-d] imidazol-2- (3H) -one as Oil.

[ α ] = + 215 °, c = 1 (methanol)

Claims (3)

1. A process for the preparation of D - (+) - biotin from L-cysteine or L-cystine or L-serine, characterized in that the synthesis is carried out via an intermediate of formula I, wherein R¹ and R² each independently represent H, unsubstituted or substituted lower alkyl, cycloalkyl, aryl, aralkyl or heteroaryl or, taken together, unsubstituted or substituted alkylene or heteroalkylene, R³H or a protective group suitable for a nitrogen atom and X and Y each independently represent O or S. 2. The method according to claim 1, characterized in that for the preparation of I L-cysteine or L-serine with an alkali or alkaline earth metal cyanate or thiocyanate in a hydantoin of the formula II, in which X and Y have the meaning given, this with a carbonyl compound of the formula III, R¹-CO-R² (III) in which R¹ and R² have the meaning given, with elimination of water to give a biscycle of the formula IV, wherein R¹, R², X and Y have the meaning given, and the secondary nitrogen atom provides a protective group R³ of the meaning given, or that one L-cysteine or L-serine with a carbonyl compound of formula III with the meaning given with elimination of water to one Implement azolidine V, wherein R¹, R² and X have the meaning given, reacting this with a metal cyanate or thiocyanate to give a compound of the formula IV and proceeding as indicated above, or reacting with an organoisocyanate or isothiocyanate of the formula VI, R³-N = C = Y (VI) in which R³ and Y have the meaning given, or in that L-cystine is reacted with an alkali metal or alkaline earth metal cyanate or thiocyanate to give a bishydantoin of the formula VII, where YO or S means
this is converted into a hydantoin of the formula II with a reducing agent or by thiolysis and reacted further as indicated above, or its nitrogen atom in the 3-position is provided with a protective group R 3 of the meaning given and the bishydantoin of the formula VIII obtained, wherein R³ and Y have the meaning given, after cleavage by a reducing agent or by thiolysis with a carbonyl compound of the formula III, or that L-cystine is reacted with an organoisocyanate or isothiocyanate of the formula VI given to give a bishydantoin of the formula VIII and how further stated above. 3. The method according to claim 1, characterized in that D - (+) - biotin is produced from I by

• a) I is reduced to an alcohol of the formula IX, wherein R¹, R², R₃, X and Y have the meaning given, which is converted into an activated ester of formula X, in which R¹, R², R³, X and Y have the meaning given and the radical R⁴ represents an activating ester group which is reacted with an alkali metal or alkaline earth metal cyanide or a cyanosilane to give a nitrile of the formula XI, wherein R¹, R², R³, X and Y have the meaning given, which is reacted with a base or an acid to give an acid derivative of the formula XII, wherein R¹, R², R³, X and Y have the meaning given and R⁵ is H or lower alkyl which is cyclized to a lactone of the formula XIII with elimination of water, wherein R³, X and Y have the meaning given and R⁶ is H or R¹R²CH, which is converted into D - (+) - biotin by known processes, or by
• b) XI is reacted with an organometallic compound to give an oxo compound of the formula XIV, wherein R¹, R², R³, X and Y have the meaning given and Z is OR⁵ or COOR⁵, where R⁵ is H, lower alkyl, cycloalkyl or aryl, which by treatment with an acid and / or a reducing agent to give an imidazolidine of the formula XV is split wherein R³, R⁶, X, Y and Z have the meaning given, which is cyclized to a biotin derivative of the formula XVI under the action of a base, wherein R³, R⁶, X, Y and Z have the meaning given, which is converted into D - (+) - biotin by known processes, or in
• c) XI is reacted with a reducing agent to give an aldehyde of the formula XVII, wherein R¹, R², R³, X and Y have the meaning given, which is condensed with an organophosphorus compound to give an unsaturated carboxylic acid of the formula XVIII, wherein R¹, R², R³, X, Y and Z have the meaning given, which is converted by an acid and / or a reducing agent to a biotin derivative of the formula XIX, wherein R³, R⁶, X, Y and Z have the meaning given, which is converted into D - (+) - biotin by known processes, or in
• d) an oxo compound of the above formula XIV is converted to a biotin derivative of the formula XX under the action of acid, wherein R³, X, Y and Z have the meaning given, which is converted into D - (+) - biotin by known processes.