DK143109B - OPTICAL ACTIVE LACTON USED AS INTERMEDIATE IN THE SYNTHESIS OF (+) - BIOTIN AND PROCEDURE FOR MANUFACTURING THE OPTIC ACTIVE LACTON - Google Patents

Description

(it) \ R & / (11) PUBLICATION 143109 DENMARK <"> into. · co? d« ime § (21) Application No, 6071 / V (22) Filed on Nov 27, 1970 (24) Running Day 27 · HOV · 1970 (44) The application submitted and _ ·. Ηο ·,

the petition for publication published on JV. m Γ. I yo I

Dl THE RECTORATE FOR

PATENT AND TRADE MARKET (30) Priority requested from it

Nov 29 1969, 17772/69, CH

(71) P. HOFFMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT, Grenzaeherstrasse 124-184, Postfach, CH-4002 Basel, CH.

(72) Inventor: Max Gerecke, 47 Bruderholzstraese, Relnach, CH: Jean Pierre Zlmmermann, 50, Rue du Ballon, St. Louie, FR.

(74) Plenipotentiary in the proceedings:

Plougmann & Vingtoft Patent Office.

(54) Optically active lactone for use as intermediate 1 the synthesis of (+) - biotin and process for producing the optically active lactone.

The present invention relates to a novel optically active lactone for use as an intermediate in the synthesis of (+) - biotin and its derivatives and related compounds, the lactone being characterized in that it has the formula I

0

Av C6H5CH2-F A li-CH2C6H5 "Av.

X0X

In which rings A and B are cis-linked, namely (+) - cis-1,3-di = benzyl-hexahydro-1H-furo [3,4-d] imidazole-2,4-dione, and a particular process for making them.

The lactone may e.g. by reaction with potassium thioacetate at elevated temperature is converted to the corresponding optically active (+) - thio = lactone of formula 0

A

CgH5CH2-1T Å 1T-CH2C6H5 «y / / Ao

\ A

in which the rings A and B are cis-linked. This optically active (+) = -thiolactone, in turn, can e.g. is converted to (+) - biotin analogous to the method described in United States Patent No. 2,489,232 for the racemic thiolac = ton.

The process according to the invention is characterized in that by means of cholesterol or cyclohexanol a racemic trion of formula II is converted

0

A

C6H5CH2-F N-CH2C6H5

-ME

° A0A

to the corresponding semesters of general formulas III and IV

3 143109 0 ί Α Λ C6H5CH2 ^ ιΝ CH2C6H5 C2H2CH2? CH2C6H5 ηΙ ^ η ° β η ^ η

HOOC COOR1 ^ 000 COOH

III I? denoting a cholesteryl or cyclohexyl group, separating the cholesterol halves by fractional crystallization of their triethylamine salts or separating the cyclohexyl halves by fractional crystallization of their ephedrine salts, thus converting the salts of the desired antipode into treatment with lithium boron acid to the (+) - lactone of formula I and optionally hydrolyzes the salts of the unwanted antipode and returns the racemate to the process after its conversion to the trion of formula II.

The (+) antipod of formula I means the optical antipode which is right-turning in benzene.

The racemic trion of formula II used as starting material (cis-1,3-dibenzyl-hexahydro-1H-furo [3,4-d] imidazole-2,4,6-trione) is a known substance and. can be prepared by known methods. For example, it can be obtained by reacting cis-bis-benzylaminoacetic acid with phosgene in the presence of alkali and converting the resulting cis-1,3-dibenzyl-2-oxo-4,5-imidazolidine-dicarboxylic acid to the cyclic trion with formula II by treatment with a dehydrating agent.

The conversion of the trion of formula II to the corresponding half-esters of the general formulas III and IV by means of cholesterol or cyclohexanol is conveniently carried out in an inert organic solvent, preferably in an aromatic hydrocarbon, e.g. benzene, toluene or xylene. The reaction is conveniently carried out at elevated temperature, especially at the reflux temperature of the reaction mixture.

4 143109

The cleavage of the racemic half-esters of the general formulas III and IY is carried out via the diastereomeric salts of these compounds, triethylamine being used when the half-ester is the cholesteryl half-ester and the epliedrin when the lial-ester is the cyclohexyl half-ester. The cleavage is conveniently carried out in an alkanol, e.g. ethanol or isopropanol, or in a lower ketone such as acetone, at a temperature between about 40 ° C and reaction = boiling point of the mixture. By splitting the cholesteryl half-ester with triethylamine, the desired antipode is precipitated first as a right-turn salt. For the cleavage of the cyclohexyl half ester with ephedrine, the (+) - and (-) form of ephedrine can be used. However, (+) - ephedrine is preferably used since the salt of the desired antipode is then precipitated first.

These salts can be directly converted to the lactone of formula I. By means of lithium borohydride, the conversion is conveniently carried out in an atmosphere of an inert gas, e.g. under nitrogen, in an inert organic solvent, e.g. in an ether such as dioxane or tetrahydrofuran or an ether of glycol or diethylene glycol, e.g. diethylene glycol dimethyl ether, at a temperature between approximately room temperature and the reflux of the reaction mixture = temperature. The lithium borohydride used for this purpose may be added as such or formed in situ of sodium or potassium borohydride and lithium chloride or lithium bromide.

The salts mentioned above can also be converted into (+} - cis-1,3-dibenzyl-5-cyclohexyloxy-carbonyl-2-oxo-4) before the reaction with lithium borohydride in a manner known per se by treatment with acid. imidazo = lidin carboxylic acid or to the desired (-) - cis-1,3-dibenzyl-5 = - (3, -cholesteryloxycarbonyl) -2-oxo-4-imidazolidine carboxylic acid, which can be further treated as described for the salts above.

The semi-esters of formulas III and IY formed during the process and their diastereomeric salts with triethylamine or ephedrine are novel compounds.

The salts formed by the racemate cleavage of the unwanted antipodes can be re-hydrolyzed in a manner known per se, whereby the cleavage agents used can be recovered and the obtained cis-1,3-dibenzyl = 143109 5 -2-oxo-4,5 -imidazolidine dicarboxylic acid can be converted to the trio of formula II, which can be returned to the process.

U.S. Patent No. 2,489,232 discloses a process in which racemic biotin is prepared from an acylated racemate corresponding to the optically active lactone of formula I. Since, as is known, only optically active {+) - biotin is biologically active, the racemic biotin produced in this way must then be digested into the optical antipodes. On the one hand, in this reaction all the steps are carried out with racemic material, whereby it is necessary to process a doubled amount of substances. On the other hand, the digestion of racemic biotin in the corresponding antipodes is an extremely complicated process which is also unprofitable, since the undesirable antipode cannot be virtually racemized and returned to the process.

An improvement to this method is disclosed in U.S. Patent No. 2,489,235. Here, the racemate cleavage is already carried out at a faster time, but there is, however, also in this method the disadvantage that most reaction steps are carried out with racemic material and that the undesirable antipode resulting from the cleavage can also practically no longer be racemized and carried. back to the process.

With the optically active lactone according to the invention, there is now provided an optically active intermediate which is used very early in the synthesis of (+) - biotin, and which is produced from a racemic starting product, the undesirable antipode of which can be readily traced after cleavage. to the racemic starting product.

The process of the invention is further illustrated by the following Examples 1-7, and the conversion to (+) - biotin is illustrated in Example 8:

Example 1.

77.5 g of cholesterol are suspended in 500 ml of benzene. To remove moisture, distribute 135 ml of benzene. 45 g of cis-1,3-dibenzyl-hexahydro-1H-furo [3,4-d] imidazole-2,4,6-trione, 6U3109 is then added and the mixture is refluxed for 18 hours. The mixture is cooled and evaporated in vacuo. To remove the benzene, the residue is dissolved twice in 50 ml of acetone, the solvent being distilled off each time. The residue is then dissolved in 450 ml of acetone at 40 ° C and 14.9 g of triethylamine are added. The temperature thereby rises to 50 ° 0. The mixture is allowed to cool slowly to 25 ° C and the crystals (40 g) are filtered off. After recrystallization from 650 ml of ethanol, 30 g of pure (+) - cis-1,3-dibenzyl-5- (3'-chole = steryloxycarbonyl) -2-oxo-4-imidazolidine-carboxylic acid triethylamine = salt are obtained. [.alpha.] D @ 5 = + 8.4 DEG (c = 5.0 in chloroform). Melting point 172 ° C.

The (-) - cis-1,3-dibenzyl-5- (3, -cholesteryloxycarbonyl) = -2-oxo-4-imidazolidine-carboxylic acid liberated from this salt by shaking with ethyl acetate and dilute hydrochloric acid can be crystallized by acetone. = water. Melting point 182 ° C; [α] D = -2.8 ° (c = 5 in CHCl3). From the mother liquor from the first crystallization, upon cooling to 5 ° C, the isomeric (-) - cis-1,3-dibenzyl-5- (3, -cholesteryloxycarbonyl) -2-oxo-4-imidazolidine can be obtained. carboxylic acid triethylamine salt, which after recrystallization from acetone melts at 142 ° C. = -33.2 ° (c = 5 in CHCl3). One of the free acid obtained melts after recrystallization of acetone / water at 150 ° C; [.alpha.] D @ 20 = -24.6 DEG (c = 5 in CHCl3).

5.9 g of potassium borohydride and 6.075 g of lithium chloride are stirred overnight in 73 ml of tetrahydrofuran under a nitrogen atmosphere. The mixture is then heated to 30 - 35 ° C, followed by a solution of 30 g of (+) - cis-1,3-dibenzyl-5- (3'-cholesteryloxycarbonyl) -2-oxo-4-imidazolidine carboxylic acid triethylamine salt in 160 ml of tetrahydrofuran is added dropwise over 2 hours at a temperature of maximum 50 ° C. The mixture is then refluxed for 2 hours, after which 65 ml of tetrahydrofuran is distilled off under normal pressure. To the residue is then slowly added 73 ml of methanol, and the mixture is refluxed for 1/2 hour. Add 18.25 ml of concentrated hydrochloric acid and boil for an additional 1/2 hour under reflux, whereupon, at atmospheric pressure, solvents are distilled to a volume of 75 ml. 250 ml of methanol are added and the mixture is refluxed for 15 minutes and left overnight at 15 ° C. The precipitated cholesterol is filtered off, washed with water and ethanol and dried. 13.75 g are recovered. The filtrate is evaporated in vacuo to 60 ml, mixed with 75 ml of water and extra = 7 143109 cured three times with chloroform. The extracts are washed with water, dried and evaporated in vacuo. The residue is taken up in 15 ml of ether and left overnight at 8 ° C. The crystals are filtered off and washed with ether. 11.2 g of (+) - cis-1,3-dibenzyl-hexahydro-1H-furo [3,4-d] imidazole-2,4-dione are obtained; [α] D = + 57.2 ° (c = 1 in benzene).

Example 2.

3.04 g of sodium borohydride and 6.96 g of finely powdered lithium bromide are stirred together in 100 ml of diethylene glycol dimethyl ether. A solution of 8.24 g of (+) - cis-1,3-dibenzyl-5- (3'-cholesteryloxycarbonyl) -2 = oxo-4-imidazolidine-carboxylic acid triethylamine salt (prepared according to Example 1) in 240 ml of diethylene glycol dimethyl ether is rapidly added, then the mixture is stirred for 23 hours at 100 ° C. The solvent is evaporated in vacuo, then the residue is added 100 ml of dioxane and then 15 ml of 37 $ aqueous hydrochloric acid. The mixture is then heated to 80 ° C and added 35 ° C. After 5 minutes, cool down. The precipitated cholesterol is filtered off and washed with 30 ml of 87 $ alcohol. The filtrate is evaporated in vacuo to dryness, then the residue is taken up in ethyl acetate and washed with sodium carbonate solution and with water. = Heres again with ethyl acetate After evaporation of the ethyl acetate extracts, the residue is added ether to give 2.42 g of (+) - cis-1,3-dibenzyl-hexahydro-1H-furo [3,4-d] imidazole 2,4-dione, m.p. 118 ° C. [Α] D = + 56 ° (c = 1 in benzene). of the mother liquor is obtained an additional 0.2 g of melting point 117 ° C.

[α] D = + 51.3 ° (c = 1 in benzene).

Example 3

To 1 liter of boiling benzene is added portionwise 336 g of cis-1,3-dibenzyl-hexahydro-1H-furo [3,4-d] imidazole-2,4,6-trione and 110 g of cyclohexanol simultaneously over 1 l / 2 hours. The mixture is refluxed for 16 hours and then evaporated in vacuo. The residue contains, in addition to small amounts of excess cyclohexanol and benzene, practically pure cis-1,3-dibenzyl-5-cyclohexyloxycarbonyl-2-oxo = -4-imidazolidine carboxylic acid. (This can be crystallized by dissolving = 8 143109 in 800 ml of ether and adding 400 ml of n-hexane: mp 130 - 131 ° C). The oily residue is dissolved in 1500 ml of isopropanol = 75 - 80 ° C and mixed with a heated solution of 110 g (+) - ephedrine in 1500 ml of isopropanol. The mixture is allowed to cool to 35 ° C over approx. 11/2 hours, after which the crystals are filtered off. 232 g of ephedrine salt of (+) - cis-1,3-dibenzyl-5-cyclo = hexoxyloxyearbonyl-2-oxo-4-imidazolidine carboxylic acid with dec. 172 DEG-175 DEG C. are obtained. [oc] .jp = + 11 °; [α] D = + 33.3 ° (c = 1 in di = methyl thylformamide).

Shake 12.05 g of ephedrine salt of (+) - eis-1,3-dibenzyl-5-cyclohexyloxycarbonyl-2-oxo-4-imidazolidine carboxylic acid with 40 ml of benzene and 10 ml of 3ΪΤ sulfuric acid. The benzene phase is washed twice with 10 ml of water and then evaporated in vacuo. 8.72 g of (+) - cis-1,3-dibenzyl-5 = -cyclohexyloxyearbonyl-2-oxo-4-imidazolidine carboxylic acid are obtained. (This substance can be crystallized by ether-hexane. Mp 82 - 84 ° C.

[α] β5 = + 7.6 °; [α] || ^ = + 29.1 ° (c = 1 in benzene)).

Dissolve 8.77 g of this acid in 20 ml of tetrahydrofuran and 2.02 g of triethylamine are added. The solution is dripped under nitrogen to a boiling solution of 1.2 g of lithium borohydride in 40 ml of tetrahydrofuran. The mixture is refluxed for an additional 2 hours and then gently added 30 ml of 6ϊΓ hydrochloric acid. The reaction mixture is evaporated in vacuo and partitioned between water and benzene. The organic phases washed for neutral reaction are evaporated in vacuo to dryness and the residue is rapidly dissolved in 25 ml of ether. (+) - cis = -1,3-Dibenzyl-hexahydro-1H-furo [3,4-d] imidazole-2,4-dione crystallizes rapidly. 5.88 g are obtained, m.p. 120-121 ° C. [cc] jp = + 58.2 °; [ct] 25 = + 212.8 ° (c = 1 in benzene).

365

Example 4

At 75-80 ° C, 87.2 g of cis-1,3-dibenzyl-5-cyclohexyloxy = carbonyl-2-oxo-4-imidazolidine carboxylic acid (prepared according to Example 3) and 14 ml of triethylamine are dissolved in 400 ml of isopropanol. partly 18.3 g (+) - ephedrine in 400 ml of isopropanol, after which the two hot solutions are combined. The mixture is slowly allowed to cool to 30 - 25 ° C and then filtered. 35 - 36.3 g of crystals are obtained which are recrystallized from 250 ml of ethanol. 27 g of ephedrine salt of (+) - cis-1,3-dibenzyl-5-cyclohexyloxycarbonyl-2-oxo-4 = -imidazolidine carboxylic acid with decomp. 177 - 178 ° C are obtained.

[α] D = + 11.3 °; [α] 21 D = + 32.3 ° (c = 1 in dimethylformamide).

Example 5

A solution of 2 g of lithium borohydride in 50 ml of tetrahydrofuran is heated to 65 ° C and a solution of 12 g of ephedrine salt of (+) - cis-1,3-dibenzyl-5-cyclohexyloxycarbonyl = - is dropped over 30 minutes. 2-oxo-4-imidazolidine carboxylic acid (prepared according to Example 3 or 4) in 250 ml of tetrahydrofuran. After 1 hour, distribute 150 ml of tetrahydrofuran and boil the mixture for a further 20 hours under reflux. Then 50 ml of 6N hydrochloric acid is carefully added and the mixture is heated for a further 1 hour. The mixture is evaporated in vacuo and the residue is taken up in water and benzene. The benzene extract is washed to neutral reaction, dried and evaporated. The residue is crystallized from 50 ml of ether to give 5.9 g (+) - cis = -1,3-dibenzyl-hexahydro-1H-furo [3,4-d] imidazole-2,4-dione, m.p. 119-120 ° C. [α] 22 = + 57.9 °; [cc] 355 = + 206 ° (c = 1 in benzene).

Example 6

The acetone and ethanolic mother liquor of Example 1, Section 1, are evaporated to dryness. The combined residues are dissolved in 700 ml of ethanol, added with 140 g of 28 $ aqueous sodium hydroxide solution and then allowed to stand for 15 hours at room temperature. The alcohol is then distilled off in vacuo and the residue is cooled to 20 ° C. The precipitated cholesterol is filtered off, washed with water and ethanol and dried. 62.5 g - 63.5 g cholesterol are obtained. The filtrate is evaporated in vacuo to 150 ml and the solution is poured into 200 ml of concentrated hydrochloric acid. The precipitate is filtered off and washed and 32 to 33 g of cis-1,3-dibenzyl-2-oxo-4,5-imidazolidine-dicarboxylic acid are obtained.

143109 10

Example 7

The mother liquor of Example 3, Section 1, is evaporated in vacuo to dryness and the residue is partitioned between benzene and dilute sulfuric acid. The bone = zen phase is washed with water. The aqueous solutions are combined, adjusted to strongly alkaline reaction with sodium hydroxide and extracted with ether to recover (+) - ephedrine. The benzene extracts are evaporated to a total volume of approx. 550 ml and boil for 2 hours with 300 ml of 28 $ aqueous sodium hydroxide solution with stirring and refluxing. After cooling the mixture, the phases are separated. Bone aqueous phase is strongly acidified with dilute hydrochloric acid and extra = heres twice with ether. After evaporation of the solvent, 202 g of Eis-1,3-dibenzyl-2-oxo-4,5-imidazolidine-dicarboxylic acid are obtained.

Example 8.

50 g of (+) - cis-1,3-dibenzyl-hexahydro-1H-furo [3,4-d] imidazole-2,4-dione and 20 g of potassium thioacetate are stirred in 50 ml of dimethylacetamide for 30 minutes = 150 ° C C under nitrogen atmosphere. The reaction mixture is cooled and partitioned between water and benzene. Bone aqueous phase is further extracted once with benzene, and the benzene phases are washed once more with water. After evaporation of the organic extracts, the residue is recrystallized from isopropanol to give 47.4 - 48.4 g (+) - cis = -1,3-dibenzyl-hexahydro-1H-thieno [3,4-d] imidazole -2,4-dione; melting = tp point 125 - 127 ° C; [α] D = + 90.4 ° - + 92.2 ° (c = 1 in chloroform).

11.0 g of magnesium is poured with 70 ml of diethyl ether and 70 ml of toluene. To this solution, a solution of 24.9 g of 1,2-dibroromethane in 36 ml of diethyl ether is then dropped over a period of approx. 20 minutes relieves cooling. (The temperature of the reaction mixture: 20 - 28 ° C).

After 45 minutes, a solution of 16.9 g of 1,4-dichlorobutane in 36 ml of diethyl ether and 75 ml of toluene is added dropwise over 25 minutes. Stir for a further 105 minutes, after which the obtained suspension is cooled to -30 ° - 40 ° C and at this temperature a solution of 14.65 g (+) - cis-1,3-dibenzyl = -hexahydro is dropped. -thieno [3,4-d] imidazole-2,4-dione in 260 ml of toluene. Stir for an additional 1 hour at -30 - 40 ° C, then add carbon dioxide, first for 1 hour at -30 - 40 ° C and then 1 A3 100 11 for 1 hour at room temperature. The reaction mixture is then separated with ice and hydrochloric acid. The organic phase is separated, washed with water and evaporated to dryness. Shake the residue for 4-0 minutes with 150 ml of 5 $ sodium carbonate solution. Undissolved neutral proportions are extracted with ethyl acetate. The aqueous solution is adjusted to pH 5.5 with hydrochloric acid and extracted with ethyl acetate. The ethyl = acetate extracts are washed with water, dried and evaporated in vacuo.

13.28 g of crude cis-5- (1,3-dibenzyl-4-hydroxy-2-keto-hexahydro = -ΙΗ-thieno [3,4-d] imidazolyl-4) -valeric acid are obtained as a chloroform right-turning oil. 11.6 g of this oil is boiled in 60 ml of glacial acetic acid for 2 hours at reflux. The glacial acetic acid is distilled off in vacuo and the residue is dissolved in toluene and this solution is evaporated in vacuo. The residual oily, chloroform right-turning cis-1,3-dibenzyl-4- (4-carboxybutylldene) -hexahydro-1H-thieno [3,4-d] = imidazol-2-one is dissolved in 80 ml of methanol and hydrogenated in the presence of Raney nickel at 35 - 40 ° C under 38 - 40 atmospheres hydrogen pressure. The catalyst is filtered off and the filtrate is evaporated. 10.3 g of oily crude Ν, Ν-dibenzyl-biotin are obtained, which is left-turning in chloro = form.

10.3 g of crude Ν, Ν-dibenzyl-biotin are heated for 5 hours under reflux in 100 ml of 48 $ * hydrochloric acid. It is then distilled off under 60 ml of partial vacuum, after which the residual solution is diluted with 230 ml of water and refluxed for 10 minutes. The hot solution is decanted from a dark brown insoluble oil. This oil is boiled again with 80 ml of water and then decanted.

2.9 g of oil remains as insoluble residue. The aqueous solutions are combined, evaporated to 50 ml and left for 24 hours at + 5 ° C. 0.61 g of (+) - biotin crystallizes, mp 225 - 228 ° C; in [cc] jp = + 86.0 ° (c = 1.0 in 0.1N NaOH). The filtrate is evaporated to dryness and boiled another. once for 3 1/2 hours in 100 ml of 48 $ hydrochloric acid under reflux. The hydrochloric acid is removed in vacuo and the residue is taken up in 50 ml of water. After standing for 24 hours at + 5 ° C, 0.72 g of (+) - biotin crystallizes, mp 223 - 225 ° C; [.alpha.] D @ 20 = + 83.2 DEG (c = 1.0 in 0.1NaOH). The filtrate is added with 2 g of sodium carbonate and at ca. At 10 ° C, phosgene is passed to this solution until pH 1. Of this reaction mixture crystallizes overnight 0.58 g (+) - biotin, mp 224 - 226 ° C; [α] D = + 85.5 ° (c = 1.0 in 0.1N NaOH).

Claims (2)

143109 12 Patent Claims. 1. Optically active lactone for use as an intermediate in the synthesis of (+) - biotin and its derivatives and related compounds, characterized in that it is (+) - cis-1,3-dibenzylhe: x: a = hydro-1H-furo [3,4-d] imidazole-2,4-dione of formula IO A C6H5CH2-IT A 1T-CH2C6H5 w H_ / \ = o \ o / in which rings A and B are cis- related. Process for the preparation of an optically active lactone of formula I according to claim 1, characterized in that a racemic trion of formula II 0 A ο6η5οη2-ιγ * r-CH2C6H5 is converted into the corresponding semesters by means of cholesterol or cyclohexanol. with the general formulas III and IV O o AA C6H5CH2-lf! f-CH2C6H5 Vs ™! -? hCH2C6H5 HfcJ-I ^ H Ej- HOOC 000E1 E ^ OOCT AoOH III IT