A method of obtaining optically active cyclobutanone and derivatives of cyclobutanone

 

(57) Abstract:

The inventive product is optically active cyclobutanone and its derivatives. BF C20H16O5so pl. 95,5 - S. Reagent 1: dibenzoate (1S, 2R)-3,3-dimethoxy-1,2-cyclobutadiene. Reagent 2: sulfuric acid. Reaction conditions: acetonitrile, 20 - 22S. 4 other

The invention relates to methods of producing optically active cyclobutanone the compounds of formula 1, where R3is a protective group.

where - R3- benzoyl

The invention relates to new intermediate compounds used in the specified manner, and to a method for producing these intermediates.

The optically active compound of cyclobutanone formula I is an intermediate compound in the synthesis of optically active similar CYCLOBUTANE-nucleoside IR(I , 2 , 2 )-2-amino-9-/2,3-bis(hydroxymethyl)cyclobutyl/-1,9-dihydro-6N-PU Rin-6-he, represented by formula 2. The specified connection and its pharmaceutically acceptable salts possess antiviral activity. Compounds 1 and 2 are optically active (if it is not specifically mentioned) and their absolute stereochemistry

presents (2S, 3S) and (1R, 2R, 3 ) in the above images.

Receiving the connection 1 in the optically inactive form (i.e., in the form of a racemic mixture) and its conversion into optically inactive compound 2 ( + ) - (1 , 2 3 ) - 2-amino-9-/2, 3-bis(hydroxymethyl)cyclobutyl/-1,9-dihydro-6N-purine-6-it is described in [2-3] .

Besides obtaining optically inactive compound (1) described in [3] , [4] .

The closest in technical essence and the achieved results is a method of obtaining optically active cyclobutanone formula 1

by interacting Allen with fluids methyl fumaric acid in the presence of a catalyst of the Lewis acid-di/lower/alkylamine chloride, where the lower alkyl contains 2-4 carbon atoms, with stirring and cooling, after which the obtained derivative containing cyclobutanone ring and fluids containing CYCLOBUTANE ring, is subjected to the repair using a metal hydride with the formation of the corresponding diol, which make the protection of the Oh-groups, and then carry out acid hydrolysis with the formation of the target product (5).

The disadvantage of this method is the complexity of the process, as well as the inaccessibility of the used substances.

Carmoly (1).

The invention is illustrated by the following scheme:

where R1is a group obtained by removing hydroxyl group from homochiral alcohol of formula R1OH, and can be replaced by cycloalkyl with 3-20 carbon atoms, R2is lower alkyl with 1-5 carbon atoms, R3is a protective group.

Compounds 5A and 5B is diastereomers with respect to each other, and on the drawings of the above reaction scheme shows the absolute stereochemistry of compounds 5A and (1S, 2R) and 5B (IR, 2S) in the I-position and 2-position CYCLOBUTANE. Compounds 6 and 7 (if it is not specifically mentioned) are optically active and their absolute stereochemistry of (1S, 2S) shown on the drawings representing the above reaction scheme.

The formation of compounds 6 and 7 in the optically inactive form was described in [2] .

The term "lower alkyl" refers to straight and branched alkyl groups containing from 1 to 5 carbon atoms. The term "lower alkoxy" refers to said lower alkyl groups, associated with oxygen. The term "halogen" refers to Br, Cl, and I.

Suitable protective groups R3can be employed silyl gr is lastnosti, suitable R1groups are groups:

< / BR>
These R1group derived from optically active alcohols, in particular (+) - or (-)-methanol.

Preferred R2groups are methyl and ethyl.

The compound of formula 5A is produced by reaction of compounds of formula 3 with a compound of formula 4 in the presence of Lewis acid. Examples of these Lewis acids are aluminum compounds such as chloride diethylamine, chloride diisobutylaluminum, dichloride ethylamine, dichloride isoproxide, trichloride aluminum, etc., Compound 3 and compound 4 is used in a ratio of 0.1 to 5 equivalents of compound 4 on one equivalent of compound 3. The Lewis acid can be used as a catalyst in the amount of 0.5-5 equivalents to one equivalent of the compound 3. The reaction is carried out in a solvent such as methylene chloride, toluene, hexane, petroleum ether, mixtures of toluene and hexane, etc., the Reaction mixture is stirred for approximately time from 1 min to 24 h, at a temperature in the range from about -100aboutWith up to 25aboutC. you must specify that if the Lewis acid is titanium tetrachloride, tin tetrachloride, Ateret TRIFLUORIDE is MIS 5A, in this reaction can be also obtained by different amounts of diastereoisomer 5V. Relative quantity 5A and 5B produced in this reaction will depend on the reactants and the reaction conditions, in particular, the relative amount 5A and 5B will depend on the absolute stereochemistry of the selected R1-group. The crude compound 5A obtained in the above reaction, may be by means of crystallization or chromatography.

Preferably, if R1group for compound 3 comes from (-)-methanol, i.e., R1is

and the Lewis acid is di(lower alkyl) aluminum chloride, especially if each group of the lower alkyl contains from 2 to 4 carbon atoms. If R1-group 3 connection comes from (-)-methanol, and the Lewis acid is di(lower alkyl) aluminum chloride, in this reaction, the amount used of the compound 4 is preferably 1-2 equivalents per 1 equivalent of compound 3, and the used amount of the Lewis acid is preferably 1.5 to 2.5 equivalents per 1 equivalent of 3, while the reaction mixture is stirred preferably from about 5 minutes to 2 hours at a temperature preferably in the range of from about -80aboutC to -40about2is stands. For example, if the connection 3, in which R1group is derived from (-)-methanol reacts with 1.1 equivalents of compound 4, in which R2is stands, in the presence of 2 equivalents of chloride diisobutylaluminum at a temperature of about -78aboutC for 30 min in toluene, compound 5A can be obtained with high yield and in substantial excess relative to its diastereoisomer 5V. The resulting crude compound 5B purify by chromatography on silica gel or by crystallization from methanol or mixtures of methanol with water.

The compound of formula 3 in which R1the group defined above, can be obtained in the form of commercial off the shelf product (for example, compound 3, where R1is a group derived from optically active alcohol (-)-methanol, supplied by the firm Oldrich Chemical Company) or can be easily obtained by standard methods (see, for example, Heatheock C. H. other I. Med. Chem. 1989, 32, 197-202, H. D. Scharf, and other Chem. Bex. 1086, 119, 3492-3497, Helmchen, G. et al, DE 3702084). The compound of formula 4 in which R2has the values defined above, is also commercially available (for example, supplied by the firm Wiley Organic Inx. or it can be obtained standard spoletta commercially available or they can be obtained by standard methods, well-known to experts.

The compound of formula 6 obtained by reaction of compounds of formula 5A with a reducing agent such as alumalite lithium, borohydride lithium, etc. in a solvent such as tetrahydrofuran, diethyl ether, etc., the Reaction mixture was stirred for 30 min to 4 h at a temperature in the range of 0aboutWith temperatures of distillation of the solvent. Compound 6 is then isolated and purified by standard methods.

The compound of formula 7, in which R3is a protective group, obtained by reaction of compound 6 with an appropriate precursor of the protective group. In particular, the compound of formula 7, where R3is an acyl group such as acetyl or benzoyl, obtained by treatment of compounds of formula 6 corresponding allamerica or allelochemical, preferably, benzoyl chloride or anhydride of benzoic acid in a solvent such as pyridine tetrahydrofuran (tritylated) triethylamine, preferably ethyl acetate/triethylamine. Optional to the reaction mixture may be added to the catalyst, such as 4,4-dimethylaminopyridine. The benzoylation reaction is carried out at-10-35aboutAnd predpochtitelnei stir, the resulting product is extracted and optionally purified, for example by means of chromatography.

The compound of formula 1 is obtained by treatment of compounds of formula 7 acid catalyst such as sulfuric acid, hydrochloric acid, etc. , preferably sulfuric acid, in a solvent or mixture of solvents, for example water, mixtures of water and acetonitrile, water and dioxane, acetone, etc., and preferably in a mixture of water and acetonitrile. The reaction mixture was stirred at 0-60aboutWith, and preferably at 15-30aboutWith over 1/2 h - 48 h, and preferably within 2-24 hours Then the reaction mixture is neutralized, and the resulting product is extracted and optionally purified, for example by chromatography or crystallization.

P R I m e R 1. (1S, 2R)-3,3-dimethoxy-1,2-CYCLOBUTANE-dicarboxylic acid, di-(-)-metalowy ester.

Di-(-)-gentilhombre (100 g) was dissolved in 400 ml of anhydrous toluene and cooled to -75aboutIn the presence of argon. To this solution, stirring, for 15 min was added chloride diisobutylaluminum (99.5 ml). The obtained orange mixture stirred for 15 min at -75aboutC and for 15 min was added 1,1-dimethoxyethane (24,7 g). After a 10-minute ramashiva is 0 minutes Then for 5 min was added hexane (250 ml) and then added for 15 min at (-60) - (-40aboutC) 20% aqueous sodium hydroxide (40 ml). Then the reaction mixture was left slowly (over 45 minutes) to warm up to 10aboutWith, and then was added anhydrous magnesium sulfate (40 g). The mixture was left to warm to room temperature, then filtered, and the filtrate was concentrated in vacuo, resulting in the obtained oily product (119,5), which was subjected to curing in a vacuum. The crude product containing a mixture of (1S, 2R)- and (1R, 2S)-TRANS-3,3-dimethoxy-1,2-cyclobutanedicarboxylic acid, di-(-)-mentolovogo of ester was recrystallized from a mixture of methanol and water (95: 5) and received 102 g of target compound (isometrically clean, which was confirmed by HPLC), in the form of a white solid substance, so pl. 89aboutWITH ( )D= -28,5o(C = 1, CHCl3).

Alternative target compound can be obtained using chloride diethylamine instead chloride diisobutylaluminum, as described below.

The chloride solution diethylaluminum (1M in hexane, 5.1 ml) drop by drop) was added to a stirred solution of di-(-)-gentilhombre (1.0 g) in 5 ml of toluene and in the presence of nitrogen at -78aboutaboutWith, then carefully added to a mixture of 50 ml of hexane and 20 ml saturated aqueous sodium bicarbonate solution. The organic phase was washed with additional solution of magnesium bicarbonate and concentrated in vacuo, resulting in a received 1,23 g thick oily substance. The crude mixture containing (1S, 2R)- and (1R, 2S)-TRANS-3,3-dimethoxy-1,2-cyclobutanedicarboxylic acid, di-(-)-mentolovogo complex ether, recrystallized from a mixture of methanol and water (95: 5) and received 0,98 g of target compound, the purity of which was confirmed by HPLC and NMR.

P R I m m e R 2. (1S, 2R)-3,3-Dimethoxy-1,2-cyclobutylmethyl.

A solution of (1S, 2R)-3,3-dimethoxy-1,2-cyclobutanedicarboxylic acid di-(-)-mentolovogo of ester (3.5 g) in 15 ml of anhydrous tetrahydrofuran drop for 5 min was added to a suspension of 420 mg of lithium aluminum hydride in 73 ml of anhydrous tetrahydrofuran at room temperature and in an atmosphere of argon. The mixture was heated for 1 h at 55aboutWith, and then conducted the analysis using thin-layer chromatography, which has not detected the presence of the source material. To the reaction mixture, cooled to 5aboutWith sequentially added 420 ál of water, 420 μl of 15% aqueous solution of hydrochlo 5 g of anhydrous magnesium sulfate and stirred for another 0.5 hours The solid product was removed by filtration through celite and the clear, colorless filtrate was concentrated to obtain a semi-solid residue (3.7 g) (mixture of target compound and (-)-methanol). The residue was dissolved in a mixture of 35 ml of water, 3.5 ml of methanol and 20 ml of heptane. The organic layer was separated, and the aqueous layer was extracted with additional heptane (3x10 ml). The combined aqueous fractions were concentrated in vacuo to obtain 5 ml residue, which was saturated with sodium chloride, and was extracted with ethyl acetate (2x20 ml). The combined ethyl acetate extracts were dried with anhydrous magnesium sulfate and concentrated to obtain 1,33 g of target compound in the form of pure colorless oily substance.

IH-NMR (CDCl3): 1,69 (DDD, IH, I = 1,2, 7,8, 12.3 Hz, H-4), 2,1 (m, IH, H-3), to 2.35 (M, 2H, H-2 and H-4), of 2.64 (s, 2H, hon), 3,184 (s, 3H, och3), 3,188 (s, 3H, och3), 3,51 (DD, IH, I = = 8,8; 10,5 Hz) and 3.75 (m, 3H/hon2).

Alternative, described crude semi-solid mixture of target compound and (-)-methanol can be processed as follows.

The crude mixture resulting from the recovery of 17.5 g of di-(-)-mentolovogo of ester (1S, 2R)-to 333.3-dimethoxy-1,2-cyclobutanedicarboxylic acid using alumoweld, saturated ammonium sulfate (45 g) and was extracted with ethyl acetate (4x50 ml). United an ethyl acetate extracts were dried with anhydrous magnesium sulfate and concentrated to obtain 6.3 g of the target compound as colorless oily substance.

P R I m e R 3. (1S, 2R)-3,3-dimethoxy-1,2-cyclobutanediyl, complex dibenzoate.

To a solution of 300 mg of (1S, 2R)-3,3-dimethoxy-1,2-cyclobutadiene in 3.4 ml of anhydrous pyridine in 5aboutC in argon atmosphere for one drop was added 494 μl of benzoyl chloride. The mixture is stirred while cooling another 1.5 h, then was added 100 μl of water. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous hydrochloric acid, brine, saturated bicarbonate and again with saline. The organic solution was dried with anhydrous magnesium sulfate and concentrated to obtain 642 mg of target compound in the form of a colorless transparent oil. An analytical sample of the target compounds were obtained using prepreparation HPLC, [ ]D= = 54,3about(C = 0,94, CCl3).

Alternatively, the solution of 147.7 g of (1S, 2R)-3,3-dimethoxy-1,2-cyclobutadiene in 900 ml of ethyl acetate, cooled in an ice bath until the internal temperature 8aboutWith, obrabatyvali to warm to room temperature for 15 hours Then this mixture was treated with 45 ml of water and stirred at room temperature for 6 hours After which the mixture was diluted with 1 l of ethyl acetate and washed with water (2x1 l), IH, HCl (2x0,5 l), water (0.5 l) and 10% sodium bicarbonate (2x0,5 l), and brine (0.5 l). The organic solution was dried with anhydrous magnesium sulfate and concentrated, resulting in a received 309,2 g of target compound.

P R I m e R 4. (2S, 3S)-2,3-bis/(benzoyloxy)methyl/cyclobutanone.

The solution of complex dibenzalacetone (1S, 2R)-3,3-dimethoxy-1,2-cyclobutadiene (312 mg) and 12 ml of acetonitrile and 3.8 ml of 0.5 N. the aqueous sulfuric acid is stirred at room temperature overnight. After which was added to 1.9 ml of 0.5 N. aqueous sulfuric acid and the mixture continued to stir for another 6 hours Thin layer chromatography carried out after the above procedures have not found the source material. The solution was diluted with ethyl acetate and washed with salt solution, saturated aqueous sodium bicarbonate and saline. The organic solution was dried with anhydrous magnesium sulfate and concentrated, resulting in a received 245 g of target compound as a white solid. An analytical sample of target compound was recrystallized from CME the teachings of optically active cyclobutanone formula I

< / BR>
by the interaction of two unsaturated compounds in the presence of a catalyst of the Lewis-di (lower) alkylhalogenide, where the lower alkyl contains 2 to 4 carbon atoms, with stirring and cooling using phase recovery diapir using a metal hydride with the formation of the corresponding diol, the introduction of the protection of hydroxyl groups and followed by hydrolysis, characterized in that, to simplify the process, as the unsaturated compounds used as a compound of General formula II

R1O2C

and the compound of General formula III

H2CC

and the process is carried out in the range -80 . . . -40oC, and the compound of General formula III is present in amounts of 1 to 2 equivalents per equivalent of compound of General formula II, and the catalyst Lewis - in the amount of 1.5 to 2.5 equivalents per equivalent of compound of General formula II with a mixture of diastereoisomers General formula IV and IVC

< / BR>
where R1group obtained by removing hydroxyl group from homochiral alcohol of formula R1OH, and represents a substituted C3- C10-cycloalkyl:

R2the lowest C1- C5-alkyl;

followed crystallizes formula V

< / BR>
then protect the hydroxyl groups of the compounds of General formula V R3with the formation of compounds of General formula VI

< / BR>
where

R

and hydrolysis of the compounds of General formula VI is carried out in the presence of a mineral acid to obtain compounds of General formula I.

2. The method according to p. 1, wherein R1is the rest

< / BR>
3. The method according to p. 1, wherein R1the balance of (-)-menthol, R2- methyl, an acid catalyst Lewis is diethylaluminium or diisobutylaluminium, the compound of General formula III is used in the amount of 11 equivalent per 1 equivalent of the compound of General formula II, the process is carried out at -78oAnd restore using sociallyengaged

4. The compound of General formula

< / BR>
where the absolute stereochemistry at CYCLOBUTANE is a (1S, 2R), and R1is a group obtained by removing hydroxyl group from homochiral alcohol of General formula R1OH, and represents a substituted C3- C10-cycloalkyl, and R2the lowest C1- C5-alkyl, as intermediate compounds for obtaining optically active CYCLOBUTANE formulazone compound is a di(-) metalowy ether (1S, 2R)-3,3-dimethoxy-1,2-cyclobutanedicarboxylic acid, as an intermediate compound for obtaining optically active CYCLOBUTANE formula I.

 

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