DE1176635B - Process for the production of dl-ribose - Google Patents

Description

Process for the preparation of dl-ribose The invention relates to on a new process for the production of dl-ribose.

The methods by which ribose has been produced so far are: 1. a process for the production of ribose by converting monosaccharides, 2. A method of making ribose from low number monosaccharides of carbon atoms as a result of enzymatic reactions and 3. a process for the production of ribose from natural substances.

In particular, the production is described in the literature of ribose by electrolytic reduction of ribonic acid lactone (Swiss Patent Specification 258 581 and Chemical Abstracts, 50, 1956, column 41 59e), the use of alkali metal amalgams in place of electricity as the reducing agent in the aforementioned Method (USSR Patent 118 130 and Khim Nauka i Prom. 3, 1958, p. 677 and 678, reported in Chemical Abstracts, 53, 1959, column 3943a), in both cases Ribonic acid lactone is obtained from arabinose (Chemical Abstracts, 45, 1951, column 2046h), as well as the production of ribose by condensation of D-glycerose and Hydroxypyruvic acid at pH 6.8 (Japanese patent specification 2279 [59j).

It is impossible to produce ribose on a large scale afterwards, because the starting material used in these common processes difficult to obtain from natural substances.

In contrast, according to the invention, dl-ribose is produced by a method the total synthesis produced using allyl alcohol derivatives as the starting material that are easy to manufacture industrially.

Accordingly, the process according to the invention is suitable for industrial use Suitable for mass production of ribose.

The process according to the invention consists in that a compound of the general formula RO-CH2-OH = CH-R1 in which R is the 2-tetrahydropyranyl and 2-tetrahydrofuryl radical and R1 is hydrogen, an alkyl radical having 1 to 3 carbon atoms and the radicals means, oxidized in a manner known per se with ozone and the reaction mixture in a manner known per se. reduced, forming a compound of the general formula RO-CH2-CHO, in which R has the meaning given above that the last-mentioned compound with a compound of the general formula converts, in which M is an alkali metal or Mg X, in which X is a chlorine, bromine and iodine atom, and R2 is an alkyl group with 1 to 3 carbon atoms and the reaction mixture is hydrolytically - known per se to a bond of the general formula OR2 ROCH2fHC ~ CHC OH OR2 decomposed, in which R and R2 have the meaning given above, that the last-mentioned compound is partially with hydrogen in the presence of a noble metal catalyst, such as palladium, platinum or nickel, to a compound of the general formula vr 4 hydrogenated, in which R and R2 have the meaning given above, that the last-mentioned compound with permanganate, osmium tetraoxide or hydrogen peroxide to a compound of the general formula hydroxylated, in which R and R2 have the meaning given above, and that the last-mentioned compound is reacted with a dilute mineral acid to give dl-ribose.

On the basis of other work by the inventor, Chem. Pharm. Bull. (Tokyo) 9, 1961, pp.316 to 321, reported in Chemical Abstracts, 1962, column 3551h, a process for the preparation of dl-ribose by total synthesis is described. at In the process of that method, the hydroxylation takes place in the hydreoxylation stage stereospecific .1n - - - flies and it is thinned in the further process Mineral acid obtained a mixture of ribose and arabinose. As a result, .results-. a decreased yield of ribose.

In contrast to this, the hydroxylation process takes place in the process according to the invention Hydroxylation stage, namely the reaction process from compound V to compound VI in the equation given below, stereospecifically in a single Direction, so that in the later treatment with dilute mineral acid only ribose is obtained. Ribose is therefore produced in the case of the inventive method Extremely high yield process.

The reactions of the process according to the invention can be represented chemically by the following equation: Process stage la and lb Process stage 2 Process stage 3 Process stage 4 Process stage 5 RO-CH2-CH - CH-R1 t RO-CH2-CHO OR2 MC - C-HC OR2 OR2 ROCH2-CH -C --C-HC OH OR2 ROCH2 ¼? / ~ OR2 HO | t GH ROCH2OR2 1 dl ribose (Compound I) (Compound II) (Compound III) (Compound IV) (Compound V) (Compound VI) In the above formula, R, Rl, R2 and M have the same meanings as before.

In B e i s t e i n, 1, 817, it is described that glycolaldehyde is produced by carbon oxidation of allyl alcohol. It was found that the Compound (II) can be obtained in very high yield by treating the compound (I) ozone oxidation in the presence of formaldehyde subject in the event that R1 in the compound (I) is one of the above-mentioned substituents other than hydrogen atom, or in the absence of formaldehyde in the event that R1 in the formula (I) is a hydrogen atom is.

The first step in the process of the present invention is carried out by ozonizing the compound (I) conveniently in one inert Solvents such as methylene chloride, ethyl acetate, petroleum ether, chloroform, carbon tetrachloride at a low temperature, for example at about 0 to about -70 "C, and by reduction of the ozonated product by means of an ozonide-decomposing agent, for example Acetic acid and zinc, or catalytic reduction, where the compound (11) results.

After the reaction has ended, the reaction product, the compound (II), can be separated from the reaction mixture by one of the customary methods. For example, after the reaction has ended, the solid substance is filtered off and washed with an organic solvent.

The combined organic solvents are washed successively with sodium bicarbonate solution and water and then over anhydrous sodium sulfate dried. The solvent is distilled off from the dried solution, and the residue is distilled under reduced pressure, whereby the desired Compound (II) results.

The second stage of the process of the invention, which is the conversion of the compound (II) in the compound (IV) is carried out by Reaction of the compound (II) with the compound (III) expediently in an inert Solvent. Examples of organic solvents are liquid ammonia, lower alkyl ethers with 1 to 5 carbon atoms in each alkyl radical, for example Diethyl ether, alicyclic ethers, for example tetrahydrofuran, aromatic hydrocarbons, for example benzene. Liquid ammonia, diethyl ether and tetrahydrofuran are suitable inert solvents. The reaction temperature is between about -60 and about 100 OC and particularly expediently at about room temperature.

After completion of the reaction, the reaction product can be removed from the reaction mixture be separated by one of the known methods. For example, the solvent removed from the reaction mixture and the residue from distillation or recrystallization from ethanol or diethyl ether subjected to the desired compound (IV) receives.

The partial hydrogenation, which is the third stage of the invention Process is carried out by hydrogenating the compound (IV) with Hydrogen in the presence of a noble metal catalyst such as palladium, platinum or Nickel, with or without suitable inert solvents. When an inert solvent should be used, then examples of inert solvents are: ethyl acetate, Chloroform, lower alcohols with 1 to 5 carbon atoms, petroleum ether, glacial acetic acid, Pyridine.

The fourth stage, hydroxylation, is accomplished by hydroxylation the compound (V) obtained in the third step described above, with the help of permanganate, for example potassium permanganate, hydrogen peroxide or osmium tetraoxide, expediently in an inert solvent such as water, aqueous Alcohols, lower alcohols with 1 to 5 carbon atoms, aqueous acetone, acetone. The reaction is carried out at a low temperature, for example from about 0 to about -30 "C. After the reaction has ended, the reaction product can be obtained from the Reaction mixture through one of the usual methods can be removed. For example the solid substance is filtered off after completion of the reaction and with ether washed, then the filtrate is also extracted with the same solvent, and the combined organic solutions are dried and evaporated, whereby a residue is obtained which, by distillation under reduced pressure, the desired compound (VI) results.

The final stage, treatment with mineral acid, is through treatment the compound (VI) with a dilute mineral acid such as dilute hydrochloric acid and sulfuric acid. After the reaction has ended, the reaction product, which is dl-ribose, from the reaction mixture by one of the known methods be separated. For example, the reaction mixture is treated with a suitable ion exchange resin to remove the related mineral acid, and the filtrate is concentrated under reduced pressure to leave a residue results, which contains dl-ribose in the raw state. Pure dl-ribose is obtained by Acylation of the crude dl-ribose with an acylating agent, for example propionic anhydride, and distillation of the resulting dl-ribose tetraacylate.

The allyl alcohol derivatives of formula (I) used as starting material were used are manufactured in a manner not claimed as follows: the Allyl alcohol derivatives of the formula (I) in which R1 represents a hydrogen atom obtained by reacting allyl alcohol with dihydropyran or dihydrofuran in the presence of traces of a mineral acid. The allyl alcohol derivatives of the formula (I) in which R1 represents any of the above-mentioned substituents other than hydrogen atom are prepared by reacting butynediol with dihydropyran and / or dihydrofuran in the presence of traces of a mineral acid, and partial hydrogenation of the resulting compound.

The invention is explained in more detail using an exemplary embodiment.

Example process stage la: Production of 2- (2'-tetrahydropyranyloxy) ethanol from 1,4-di- (2'-tetrahydropyranyloxy) -butene formaldehyde, which is obtained by heating 75 g of paraformaldehyde is formed in 1.3 l of methylene chloride with ice cooling given. After adding 128 g of 1,4-di- (2'-tetrahydropyranyloxy) -butene to the obtained solution is a theoretical amount of ozone at -50 0C through the solution conducted (ozone concentration: 6.098geh). After the ozonization is complete, this will be Transfer the reaction mixture to a three-necked round bottom flask and add 130 g of zinc. A mixture of 75 ml of acetic acid and 3.8 ml of water is added to the resulting mixture added with ice cooling at such a rate that the temperature of the Contents are kept at about 15 to 19 "C. When the addition is complete, add the contents of the flask were stirred at room temperature for an additional 30 minutes. Upon termination upon stirring, the resulting mixture gives a negative ozonide reaction on iodine starch paper. The solid substance is filtered off and washed thoroughly with methylene chloride. The United organic solutions are successively mixed with sodium bicarbonate solution and water and then dried over anhydrous sodium sulfate. The methylene chloride is distilled off from the dried solution, and the residue is distilled, 9.5 g (63.50 / 0 of the theoretical amount) of 2- (2'-tetrahydropyranyloxy) -ethanol that boils at 77 to 79 "C at 10 mm Hg.

Analysis values for C7H1203: Calculated ... C 58.250 / 0, H 8.490 / 0; found . C 5X, 310 / o, H 8.390 / o.

Process stage 1b: production of 2- (2'-tetrahydropyranyloxy) -ethanol from 3- (2'-tetrahydropyranyloxy) -propene- (1) a theoretical amount of ozone becomes by a solution of 14.2 g of 3- (2'-tetrahydropyranyloxy) -propen- (l) in 100 ml of methylene chloride passed through at -500C. After the ozonization is complete, the reaction mixture becomes transferred to a three-necked round bottom flask and 26 g of zinc is added to the solution, to which a mixture of 15 ml of acetic acid and 0.7 ml of water was added while cooling with ice is run at such a rate that the solution is maintained at 15-19 "C will. After the addition is complete, the solution becomes additional at room temperature Stirred for 30 minutes.

After stirring, the solution reacts negatively with iodine starch paper. the Solution is treated in the same way as described in Example 1, 10.5 g (730/0 of the theoretical amount) of 2- (2'-tetrahydropyranyloxy) -ethanol that boil at 77 to 79 "C at 10 mm Hg.

Analysis values for C7H1203: Calculated ... C 58.390 / o, H 8.210 / o; found ... C 58.310 / o, H 8.39w0.

Process stage 2: Preparation of 1,1-diethoxy-542'-tetrahydropyranylpoxypent-2-inffiol A solution of 11.8 g of ethyl bromide in 30 ml of tetrahydrofuran is slowly added dropwise to a solution of 2.62 g of metallic magnesium in 50 ml of tetrahydrofuran added vigorous stirring. After dissolving all of the added magnesium the solution is stirred for an additional 30 minutes. Add dropwise to the solution a solution of 12.8 g of propargyl diethyl acetal in 30 ml of tetrahydrofuran in about 15 Minutes added, during which time there is a violent development of ethane. After the addition is complete, the reaction mixture becomes additional at room temperature Stirred for 1 hour. A solution of 12 g of 2- (2'-tetrahydropyranyloxy) ethanol in 30 ml Tetrahydrofuran is added dropwise to the resulting mixture, whereby the temperature of the mixture is kept below 35 "C. The mixture is further Stirred for 2 hours and then left to stand for 24 hours. The reaction mixture obtained is poured into saturated aqueous ammonium chloride solution, and it becomes the organic Layer separated and dried over anhydrous sodium sulfate. The solvent is distilled off from the dried solution, and the Residue is reduced under reduced Distilled pressure, resulting in a fraction that at 141 to 142C at 0.1 mm Hg boils. There are 14 g of I, l-diethoxy-5- (2'-tetrahydropyranyl) -oxypes t-2-yn-4-ol obtain.

Analysis values for C4H: S} 05: calculated ... C 61.74 "10, H 8.88%; found ... C 61.52in. H 8.880 / 0.

Process stage 3: Production of 2-ethoxy-5- (2'-tetrahydropyranyl) -oxymethyl-2,5-dihydrofuran 49.5 g of Lindlar's catalyst (palladium on calcium carbonate) are added to a solution of 148 g of 1,1-diethoxy-5- (2'-tetrahydropyranyl) -oxypent-2-yn-4-ol in 950 ml of ethyl acetate, and the mixture is shaken under a hydrogen atmosphere, to 930 are absorbed in the theoretical amount of hydrogen. After completion the reaction mixture is filtered to remove the catalyst, which is washed with a small amount of diethyl ether. Filtrate and wash water are combined and then distilled to remove the solvent. The residue is distilled under reduced pressure, with 78 g of 2-ethoxy-5- (2'-tetrahydropyranyl) oxymethyl-2,5-dihydrofuran that boils at 80 to 90 "C at 0.15 mm Hg.

Analysis values for C12Hs, 04: Calculated ... C 63.20 ozone H 8.730 / o; found ... C 63.21 ° / o, H 8.62 ° / o.

Process stage 4: preparation of 2-ethoxy-3,4-dihydroxy-5- (2'-tetrahydropyranyl ) -oxymethyl-tetrahydrofuran 12.5 g of 2-ethoxy-5- (2'-tetrahydropyranyl) -oxymethyl-2,5-dihydrofuran, those obtained in the third process stage are added to one Mixture of 65 ml of acetone and 42 ml of water, and 7.0 g of crystalline potassium permanganate are added in portions to the solution at 15 to 20 ° C. in the course of 2 hours with stirring. After the addition is complete, the mixture is stirred for an additional 30 minutes. After completion of the reaction, the reaction mixture is centrifuged to obtain colloidal Remove manganese dioxide washed with a small amount of diethyl ether.

On the other hand, the mother liquor is concentrated under reduced pressure, and the remaining aqueous solution is extracted with diethyl ether. The extract is combined with the above wash water and the combined solutions are dried. The removal of the solvent from the solution and the distillation of the residue under reduced pressure give 7.6 g of a viscous oil, which at 150 to 160 "C (Bath temperature) boils at 5 10-4 mm Hg.

Analysis values for C12H2206: Calculated ... C 54,950 / 0, H 8,450 / o; found ... C 54.960 / o, H 8.010 / 0.

Process stage 5: production of dl-ribose A suspension of 5.3 g of 2-ethoxy-3,4-dihydroxy-5 - (2'-tetrahydropyranyl) -oxymethyl-tetrahydrofuran in 50 ml of 60 / above hydrochloric acid is 3 days at room temperature ditched. The reaction mixture is treated with an ion exchanger to remove the acid, and the filtrate is concentrated under reduced pressure to give 2.5 g of a syrupy substance. The syrupy substance is cleaned with 13.1 g of propionic anhydride and 18 g of pyridine reacted, and the reaction mixture is under reduced pressure distilled, resulting in 5.3 g of dl-ribose tetrapropionate, which at 155 to 165 "C (Bath temperature) boil at 3 10-4 mm Hg.

Analysis values for C17H2609: Calculated ... C 54.60 solos H 6.950 / 0; found ... C 54.710 / 0, H 7.03 ° lo.

Claims (1)

Claim: A process for the preparation of dl-ribose, characterized in that a compound of the general formula RO-CH2-CH = CH-R1 in which R is the 2-tetrahydropyranyl and 2-tetrahydrofuryl radical and R1 is hydrogen, an alkyl radical with 1 to 3 carbon atoms as well as the remainders means, oxidized in a manner known per se with ozone and the reaction mixture is reduced in a manner known per se, a compound of the general formula RO-CH2-CHO being formed, in which R has the meaning given above that the last-mentioned compound is also formed a compound of the general formula converts, in which M is an alkali metal or Mg X, in which X is a chlorine, bromine and iodine atom, and R2 is an alkyl group with 1 to 3 carbon atoms, and the reaction mixture hydrolytically in a manner known per se to a compound of general formula decomposed, in which R and R2 have the meaning given above, that the last-mentioned compound is partially with hydrogen in the presence of a noble metal catalyst, such as palladium, platinum or nickel, to a compound of the general formula hydrogenated, in which R and R2 have the meaning given above, that the last-mentioned compound with permanganate, osmium tetroxide or hydrogen peroxide to a compound of the general formula hydroxylated, in which R and R2 have the meaning given above, and that the last-mentioned compound is reacted with a dilute mineral acid to give dl-ribose. Publications considered: Swiss patent specification No. 258 581; USSR Patent No. 118,130; Japanese Patent Publication No. 2279 ('59); Chemical Abstracts 45, 1951, column 2046h, 50, 1956, column 4159e; 53, 1959, Column 3943a; Chem. Pharm. Bull. (Tokyo) 9, 1961, pp. 316 to 321, reported in Chemical Abstracts, 1962, column 3551h; Khim Nauka i Prom. 3, 1958, pp. 677 and 678.