RU2384577C2 - Method of producing 2-(oxiran-2-yl)-ethanol - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method of producing 2-(oxiran-2-yl)-ethanol of formula

(1) which is a valuable intermediate product for production of different biologically active substances, including in entantiomerically pure form. The said method involves esterification of apple acid, nucleophilic substitution of the hydroxyl group of dialkylmalate with a chlorine or bromine atom, reduction of dialkyl halosuccinate and solvolysis of halogendiol to 2-(oxiran-2-yl)-ethanol.

EFFECT: method enables obtaining the desired product with at least 99% retention of enantiomeric excess and total output of up to 49% per initial apple acid.

1 cl, 12 ex

Description

The invention relates to organic synthesis, specifically to a new method for producing 2- (oxiran-2-yl) ethanol of the formula (1) (Scheme 1)

which is used in fine organic synthesis to produce various biologically active substances [Frick, JA, Klassen, JB, Bathe, A., Abramson, JM, Rapoport, H. An efficient synthesis of enantiomerically pure (R) - (2-benzyloxyethyl) oxirane from (S) -aspartic acid. // Synthesis - 1992 - N.7. - P.621-623].

Several methods are known for the preparation of (S) -2- (oxiran-2-yl) ethanol (S-1), some of which involve the enantioselective epoxidation of 3-butene-1-ol (3) [Okachi, T., Murai, N., Onaka, M. Catalytic enantioselective epoxidation of homoallylic alcohols by chiral zirconium complexes. // Organic Letters. 2003. - Vol. 5. - No.l. - P.85-87; Karjalainen, J.K., Hormi, O.E.O., Sherrington, D.C. An improved heterogeneous asymmetric epoxidation of homoallylic alcohols using polymer-supported Ti (IV) catalysts. // Tetrahedron: Asymmetry. - 1998 - Vol.9 - N.21 - P.3895-3902] (Scheme 2)

These methods require reactions at low temperatures (-40 ° C) and, accordingly, the use of cryogenic equipment. Due to the low reaction rates, a long time is needed to obtain a product with at least a small yield - from a day to 2 weeks. The maximum yield of the product does not exceed 55%, and the enantiomeric excess is 78% [Okachi, T., Murai, N., Onaka, M. Catalytic enantioselective epoxidation of homoallylic alcohols by chiral zirconium complexes. // Organic Letters. 2003. - Vol. 5. - N.l. - P.85-87].

Another method uses the reactions of deamination of (R) -partic acid (R-4), reduction of (R) -bromosuccinic (R-5) acid, and solvolysis of bromdiol (R-6) to (S) -2- (oxiran-2- yl) ethanol (S-1) [Frick, J., Klassen, J. B., Bathe, A., Abramson, J, Rapoport, H. An efficient synthesis of enantiomerically pure (R) - (2-benzyloxyethyl) oxirane from (S) -aspartic acid. // Synthesis - 1992 - N.7. - P.621-623] (Scheme 3)

The first stage is characterized by a small yield of the deamination reaction (70%) and the danger of its uncontrolled flow, which requires precise observance of the reaction conditions, in particular, control of the temperature of the reaction medium. In addition, in the second stage, an explosive reducing agent is used, and in the last stage, an expensive base is cesium carbonate. The circuit has a low total output. It is also doubtful that the stereo configuration is preserved during the nucleophilic substitution reaction (racemization in a strongly acidic medium is possible) and the possibility of obtaining a product with high enantiomeric purity by this method.

In addition to the above, we found in the literature two methods that are similar to each other with the preparation of benzyloxyepoxide (7) with a similar structure from (S) malic acid (S-2). The first method involves the recovery of malic acid (S-2) to 1,2,4-butanetriol, the ketal protection of the vic-diol group, the protection of the 4-hydroxyl group, the removal of the ketal protective group, the formation of a mixture of methanesulfonic acid esters (mesylates 8, 9) and their solvolysis [M. Majewski, D. Clive, P. Anderson. Synthetic studies related to compactin and mevinolin: a new synthesis of the lactone system. // Tetrahedron Letters. - 1984 - Vol.25. - N.20 - P.2101-2104] (Scheme 4)

In the first stage, an explosive reducing agent is used. The next three stages are used to selectively protect the 4-hydroxyl group of 1,2,4-butanetriol, and their presence dramatically affects the total yield of the synthetic scheme. The reaction of the formation of mesylates (8, 9) occurs at a low temperature (-30 ° С, this requires the use of cryogenic equipment or cooling baths with CO ₂ ) with low selectivity for the formation of the required primary mesylate (9). This leads to a noticeable loss in optical yield (the ratio of enantiomers after the epoxide production S: R = 2.3: 1) and the need to separate the primary and secondary mesylates (8, 9) by HPLC, which, however, does not allow complete separation of the isomers (8, 9) (Scheme 4).

The second method (prototype) is similar to the previous one and differs from it by using the reaction with a complex of triphenylphosphine with tetrachlomethane to obtain a benzyl-protected at the 4-hydroxyl group derivative of 2- (oxiran-2-yl) ethanol (S-7) [C. Liu , J. Coward. A facile and highly stereoselective synthesis of (R) - and (S) - (2- (phenylmethoxy) ethyl) oxirane. // J. Org. Chem. - 1991 - N.56. - P.2262-2264] (Scheme 5)

This method, in addition to a large number of stages and the use of reactions with low atomic efficiency (setting and removing protective groups), has an even lower total yield.

The objective of the invention is to provide a simple safe method for producing 2- (oxiran-2-yl) -ethanol (1) in high yield and optical purity.

The problem is solved by a method that includes an esterification reaction of malic acid (2), nucleophilic substitution in an ester (12, 16, 17), reduction of an ester (13, 15, 18-21) to a halogenated diol (6, 14) and solvolysis of halogenated in the basic medium with the formation of compound (1) according to the following scheme (scheme 6):

It was found that it is possible to selectively and with high optical purity 2-halogen-1,4-butanediol (6, 14) using a sequence of nucleophilic substitution and reduction reactions without the use of protective groups. 2-halogen-1,4-butanediol (6, 14), in turn, is easily solvolized with available and cheap bases to form the target compound (1). It was found that the reaction of esterification of malic acid can be carried out without acid catalysis, which reduces the risk of racemization of compounds to zero. It has been established that the use of nitrites in an acidic medium at the stage of nucleophilic substitution requires precise control of temperature and pH; therefore, it can be replaced by simpler, more technologically advanced and safer reactions with triphenylphosphine complexes with carbon tetrachloride or bromine. In this case, the need for a strongly acidic environment disappears, which also eliminates the risk of racemization of the compounds. It has been established that instead of boranes at the reduction stage, more fireproof and less active reducing agents (lithium and sodium borohydrides) can be used, while the processing of reaction mixtures is significantly accelerated. Instead of free acids, their diesters can be reduced, which is advantageous from the point of view of saving a reducing agent. This leads to the obtaining of the target compound (1) with a yield exceeding the literature by 1.2-3.5 times, as well as to a significant simplification of the procedures. Comparison with published data on the rotation of the polarization angle shows that at all stages of this synthetic path a high degree of optical purity of products is maintained (at least 99%).

Thus, the patented method has the following advantages:

- simplicity of operations and the availability of reagents;

- lack of fire, explosive and toxic reagents;

- faster reactions;

- a high degree of preservation of the optical purity of the compounds along the entire synthetic route (99%);

- high atomic efficiency and the absence of the need for the use of protective groups;

- a higher total yield of the final product.

The method for producing 2- (oxiran-2-yl) ethanol (1) is illustrated by the following examples.

Example 1. Obtaining (S) -2- (oxiran-2-yl) ethanol (S-1) from (S) malic acid (S-2)

Stage I. The esterification of (S) malic acid (S-2) (Scheme 7)

The synthesis is carried out in a plant consisting of a reactor and a stirrer. 300 ml of methanol are charged to the reactor and 15.5 ml of acetyl chloride are added dropwise. After stirring for 15 minutes, 47 g of solid (S) malic acid (S-2) was added and stirred for 18 hours. The solution was evaporated. This yields a yellow oil, which is further purified by silica gel chromatography, eluting with a mixture of dichloromethane and methanol (95: 5). (S) -dimethylmalate (S-12) is obtained in 86% yield. ¹ H NMR spectrum (CDCl ₃ ) (δ, ppm): 2.70-3.00 (m, 2H), 3.50 (s, 3H), 3.60 (s, 3H), 4.45 (m, 1H). [α] _D -8.2, (c 1.0, CH ₃ OH).

Stage II. Obtaining (R) -dimethylchlorosuccinate (R-13) (Scheme 8)

The synthesis is carried out in a plant consisting of a reactor, a stirrer and a water-cooled reflux condenser. 50 ml of carbon tetrachloride and 13.96 g (0.053 mol) of triphenylphosphine are charged to the reactor. Stir until complete dissolution of triphenylphosphine. Then, (S) -badic acid dimethyl ester (S-12) (5.13 g, 0.031 mol) in 10 ml of carbon tetrachloride is added. The reaction mixture is refluxed for 2 hours. The solvent is distilled off on a rotary evaporator. The remaining precipitate was washed thoroughly on a porous filter with a mixture of hexane and diethyl ether (1: 1, 5 × 30 ml). The mother liquor is collected and evaporated, the residue as a brown mobile oil is chromatographed on silica gel. The elution fraction with a 1: 1 hexane-diethyl ether mixture was evaporated and evacuated, leaving a light yellow mobile oil - dimethyl ether (R) -chlorosuccinic acid (R-13) weighing 4.57 g (82%). ¹ H NMR spectrum (CDCl ₃ ) (δ, ppm): 2.70-3.00 (m, 2H), 3.50 (s, 3H), 3.60 (s, 3H), 4.45 (m, 1H). [α] _D +42.8, (c 1.0, CHCl ₃ ).

Stage III. Recovery of (R) -dimethylchlorosuccinate (R-13) (Scheme 9)

The synthesis is carried out in a plant consisting of a reactor, a stirrer, a dropping funnel and a water-cooled reflux condenser. To a suspension of 0.46 g of LiBH ₄ (0.021 mol) in 100 ml of tetrahydrofuran (THF) is added dropwise a solution of 2.55 g (0.014 mol) of (R) -dimethylchlorosuccinate (R-13) and 0.67 g (0.021 mol) of methanol in 10 ml of THF. The mixture is refluxed for 4 hours. After cooling, 3 ml of methanol or water are added with stirring. After further stirring for 20 minutes, dilute phosphoric acid is added dropwise to a neutral reaction according to the universal indicator. The precipitate was filtered off with suction and washed with acetone (3 × 10 ml). The mother liquor was evaporated, yielding a light yellow viscous oil - (2R) -2-chloro-1,4-butanediol (R-14) weighing 1.32 g (81%). ¹ H NMR spectrum (DMSO d ₆ ) (δ, ppm): 1.40-1.90 (m, 2H), 3.50-3.95 (m, 4H), 4.10 (m, 1H), 6.00 (br s, 2H ) [α] _D +36.5, (c 1.2, CH ₃ OH).

Stage IV. Solvolysis of (R) -2-chloro-1,4-butanediol (R-14) (Scheme 10)

To a solution of 1.74 g of (R) -2-chloro-1,4-butanediol (R-14) in 20 ml of THF was added 0.94 g (0.017 mol) of solid KOH. Stirred for 7 hours. The suspension is filtered on a vacuum filter, the precipitate is washed with dichloromethane (3 × 10 ml). The mother liquor is evaporated, the oily residue is passed through a silica gel column (5 cm) (dichloromethane eluent) to obtain a light yellow oil - (S) -2- (oxiran-2-yl) -ethanol (S-1) weighing 0.86 g ( 70%). ¹ H NMR spectrum (CDCl ₃ ) (δ, ppm): 1.50-1.60 (m, 1H), 1.70-1.80 (m, 1H), 2.40 (m, 1H), 2.60-3.00 (m, 2H) 3.60 (m, 2H); 4.20 (br s, 1H). [α] _D -30.7, (c 1.0, CH ₂ Cl ₂ ).

Example 2

The esterification of (S) malic acid is carried out by reaction with diazomethane (Scheme 11)

The synthesis is carried out in a facility consisting of a reactor, a cooling bath (ice) and a stirrer. (S) -Malic acid (S-2) of purity 98 +% by weight of 5.91 g is loaded into the reactor, diethyl ether is added and stirred until complete dissolution. While cooling in the bath, an ether solution of diazomethane is added dropwise until a non-fading yellow color of the solution appears. The solution is stirred for 20 minutes, after which the bath is removed and the excess diazomethane is eliminated by adding dropwise a 10% solution of acetic acid in water until discoloration. The solution was evaporated and the residue was treated as described in Example 1. The mass of the product was (S) -Malic acid dimethyl ester (S-12) 6.64 g (93%). Stage II-IV are performed as described in Example 1.

Example 3

The esterification of (S) malic acid (S-2) is carried out by reaction with dimethyl sulfate (Scheme 12). The synthesis is carried out in a plant consisting of a reactor and a stirrer. (S) -Malic acid (S-2) with a purity of 98 +% by weight of 5.91 g is loaded into the reactor, 10 ml of methanol are added and 4.2 g of sodium hydroxide are added with stirring, stirred for 10 minutes. Then add 13.3 g of dimethyl sulfate. The reaction mixture is stirred for 2 hours. The reaction mixture was evaporated, diluted with 20 ml of water and extracted with dimethyl malate (S-12) or ethyl acetate (3 times 30 ml). After the organic phase was dried over sodium sulfate, the solution was evaporated. In this case, the residue is obtained - a yellowish oil, which is further processed as described in Example 1. The mass of the product is (S) -Malic acid dimethyl ester (S-12) 6.64 g (85%). Stage II-IV are performed as described in Example 1.

Example 4

As the methylating agent, 15 g of methyl iodide are used (Scheme 12). Triethylamine (10.7 g) was used as the base. The synthesis procedure is similar to that in Example 3. The yield of dimethyl ester of (S) malic acid (S-12) for the method with methyl iodide is 83%. Stage II-IV are performed as described in Example 1.

Example 5. Stage I is performed according to one of the methods described in Examples 1-4. In stage II, a bromo-triphenylphosphine complex is used to produce (R) -dimethyl bromosuccinate (R-15) (Scheme 13)

The synthesis is carried out in a plant consisting of a reactor, a stirrer, a bath with ice and salt, and a water-cooled reflux condenser. 25 ml of dichloromethane and 14.56 g (0.056 mol) of triphenylphosphine are charged to the reactor. After complete dissolution of triphenylphosphine, the solution is cooled with ice and salt, and a solution of 9.0 g (0.054 mol) of bromine in 20 ml of dichloromethane is added dropwise. After complete addition, mix for another 10 minutes. Then, malic acid dimethyl ether (S-12) (5.03 g, 0.031 mol) in 10 ml of dichloromethane is added. Immediately after complete addition, the previously precipitated precipitate is completely dissolved. The solution was refluxed for 2 hours. After cooling, the solvent is distilled off on a rotary evaporator. The remaining precipitate was washed thoroughly on a porous filter with a mixture of hexane and diethyl ether (1: 1, 5 × 30 ml). The mother liquor was collected and evaporated, the residue was chromatographed on silica gel as a yellow mobile oil. The elution fraction with a 1: 1 hexane-diethyl ether mixture was evaporated and evacuated, leaving a light yellow mobile oil - (R) -dimethylbromosuccinate (R-15) weighing 6.0 g (85%). ¹ H NMR spectrum (CDCl ₃ ) (δ, ppm): 2.70-3.00 (m, 2H), 3.50 (s, 3H), 3.60 (s, 3H), 4.45 (m, 1H). [α] _D +70.3, (c 1.16, C ₆ H ₆ )

In step III, (R) -dimethyl bromosuccinate (R-15) is reduced (Scheme 14)

The synthesis is carried out in a plant consisting of a reactor, a stirrer, a dropping funnel and a water-cooled reflux condenser. To a suspension of 0.53 g LiBH ₄ (0.024 mol) in 60 ml THF, a solution of 3.67 g (0.016 mol) dimethyl bromosuccinate (R-15) and 0.78 g (0.024 mol) methanol in 10 ml THF are added dropwise. The mixture is refluxed for 4 hours. Cool the mixture and add 5 ml of methanol or water with stirring. After gas evolution ceases with stirring, dilute phosphoric acid is added dropwise until neutral according to the universal indicator. The precipitate was filtered off in vacuo and washed with acetone (3 × 10 ml). The mother liquor was evaporated to give a light yellow viscous oil - (2R) -2-bromo-1,4-butanediol (R-6) weighing 2.2 g (80%). ¹ H NMR spectrum (DMSO d ₆ ) (δ, ppm): 1.90-2.15 (m, 2H), 3.70-3.90 (m, 4H), 4.20-4.40 (m, 1H), 5.50 (br s , 2H). [α] _D +31.6, (c 15, CHCl ₃ ).

In stage IV, 0.94 g (0.017 mol) of solid KOH is added to a solution of 2.37 g of (2R) -2-bromo-1,4-butanediol (R-6) in 20 ml of THF (Scheme 15)

Stirred for 7 hours. It is filtered off with suction and the precipitate is washed with dichloromethane (3 × 10 ml). The mother liquor is evaporated, the oily residue is passed through a silica gel column (5 cm) (dichloromethane eluent) to give a light yellow oil - (S) -2- (oxiran-2-yl) -ethanol (S-1) weighing 0.92 g ( 75%). ¹ H NMR spectrum (CDCl ₃ ) (δ, ppm): 1.50-1.60 (m, 1H), 1.70-1.80 (m, 1H), 2.40 (m, 1H), 2.60-3.00 (m, 2H) 3.60 (m, 2H); 4.20 (br s, 1H). [α] _D -30.6, (c 1.0, CH ₂ Cl ₂ ).

Example 6. Stage I is performed according to one of the methods described in Examples 1-4. Stage II is carried out according to one of the methods described in Examples 1, 5. In stage III, the reduction is carried out using a mixture of sodium borohydride and lithium chloride taken in a 1.5-fold excess (in moles) relative to the ester (13) or (15 ) As a result, (2R) -2-chloro-1,4-butanediol (R-14) and (2R) -2-bromo-1,4-butanediol (R-6) are obtained in yields of 80 and 78%, respectively. Stage IV is performed according to one of the methods described in Examples 1, 5.

Example 7. Stage I is performed according to one of the methods described in Examples 1-4. Stage II is carried out according to one of the methods described in Examples 1, 5. In stage III, the reduction is carried out using 1 g of ethanol instead of methanol. Sulfur ether is used as a solvent instead of tetrahydrofuran. As a result, (2R) -2-chloro-1,4-butanediol (R-14) and (2R) -2-bromo-1,4-butanediol (R-6) are obtained in yields of 75 and 71%, respectively. Stage IV is performed according to one of the methods described in Examples 1, 5.

Example 8. Stage I is performed according to one of the methods described in Examples 1-4. Stage II is performed according to one of the methods described in Examples 1.5. Stage III is performed according to one of the methods described in Examples 1, 5-7. In step IV, an equal amount of sodium hydroxide is used instead of potassium hydroxide. As a result, from (2R) -2-chloro-1,4-butanediol (R-14) and (2R) -2-bromo-1,4-butanediol (R-6) (S) -2- (oxiran-2 -yl) -ethanol (S-1) is obtained with yields of 68 and 70%, respectively.

Example 9. Stage I is performed according to one of the methods described in Examples 1-4. Stage II is performed according to one of the methods described in Examples 1, 5. Stage III is performed according to one of the methods described in Examples 1, 5, -7. In stage IV, instead of tetrahydrofuran, 20 ml of a mixture of dimethyl sulfoxide and water in a ratio of 3: 1 (by volume) can be used as a solvent. In this case, the reaction mixture after dilution is diluted with 20 ml of water and 2- (oxiran-2-yl) ethanol (1) is extracted with diethyl ether (three times in 20 ml). The ethereal solution was dried over sodium sulfate, filtered and evaporated. The yield of (S) -2- (oxiran-2-yl) ethanol (S-1) from (2R) -2-chloro-1,4-butanediol (R-14) and (2R) -2-bromo-1 4-butanediol (R-6) 70 and 72%, respectively.

Example 10. To obtain (R) -2- (oxiran-2-yl) ethanol (R-1), (R) -Malic acid (R-2) is used (Scheme 16). In stage I, (R) -dimethylmalate (R-12) ([α] _D + 8.1 (s, 1.0, CH ₃ OH)) was obtained in 94% yield by the procedure of Example 2. In stage II, (S) -dimethylchlorosuccinate ( S-13) ([α] _D -42.8 (s, 1.0, CHCl ₃ )) was obtained with a yield of 81% according to the procedure from Example 1. In stage III (2S) -2-chloro-1,4-butanediol (S- 14) ([α] _D -36.2 (s, 1.2, CH ₃ OH)) was obtained with a yield of 83% according to the procedure from Example 1. (S) -dimethyl bromosuccinate (S-15) ([α] _D -69.7 (s, 1.16, C ₆ H ₆ )) and (2S) -2-bromo-1,4-butanediode (S-6) ([α] _D -31.7 (s, 15, CHCl ₃ )) were obtained by the method of Example 5 ( stages II and III) with yields of 85 and 80%, respectively. In step IV, (R) -2- (oxiran-2-yl) ethanol (R-1) ([α] _D +31.0 (s, 1.0, CH ₂ Cl ₂ )) is obtained from (S-14) and ( S-6) according to the methods of Examples 1 and 5 with yields of 75 and 70%, respectively. The spectral characteristics of all intermediate products and (R) -2- (oxiran-2-yl) ethanol (R-1) coincide with those given in Examples 1, 5 for antipodes

Example 11. To obtain the intermediate products - 2-chloro-1,4-butanediol (14) and 2-bromo-1,4-butanediol (6), the restoration of diethyl ether, respectively, of chlorosuccinic and bromosuccinic acids obtained from diethyl malate is used (Scheme 17) . In stage I, diethyl malate (16) was obtained with a yield of 82% by a method similar to that described in Example 1. In stage II, diethyl chlorosuccinate (18) was obtained with a yield of 80% by a method similar to that described in Example 1; diethyl bromosuccinate (20) was obtained in 85% yield by a method similar to that described in Example 5. In step III, 2-chloro-1,4-butanediol (14) was obtained by the method of Example 1 with a yield of 73%, 2-bromo-1 , 4-butanediol (6) was obtained by the method of Example 5 with a yield of 70%. The specific rotation of the polarization angle of the halide diols (6, 14) coincides with the data given in Examples 1, 5 and 10.

Example 12. To obtain the intermediate products 2-chloro-1,4-butanediol (14) and 2-bromo-1,4-butanediol (6), di-n-propyl ether is reduced, respectively, of chlorosuccinic and bromosuccinic acids obtained from di n-propylmalate (Scheme 17). In stage I, di-n-propylmalate (17) was obtained in 75% yield by a method similar to that described in Example 1. In stage II, diethyl chlorosuccinate (19) was obtained in 75% yield by a method similar to that described in Example 1; diethylbromosuccinate (21) was obtained in 73% yield by a method similar to that described in Example 5. In step III, 2-chloro-1,4-butanediol (14) was obtained by the method of Example 1 with a yield of 65%, 2-bromo-1 , 4-butanediol (6) was obtained by the method of Example 5 with a yield of 61%. The specific rotation of the polarization angle of the halide diols (6, 14) coincides with the data given in Examples 1, 5 and 10

Claims (1)

The method of obtaining 2- (oxiran-2-yl) ethanol of the formula (1)

by esterification of malic acid, nucleophilic substitution of the hydroxyl group of the obtained malic acid dialkyl ester with a chlorine or bromine atom, reduction of the obtained dimethylgalosuccinate and subsequent solvolysis of halogenated