LV15111B - Method for preparation of optically pure diethyl[4-methyl-1-nitropentan-2-yl]malonate - Google Patents

Abstract

The invention relates to a method for preparation of optically pure diethyl[4-methyl-1-nitropentan-2-yl]malonate. The present invention relates to a process for the preparation of asymmetric compounds, which includes an asymmetric dicarbonyl compounds Michael addition to nitroalkenes in the presence of chiral catalyst.

Description

The present invention relates to a process for the preparation of optically pure diethyl [4-methyl-1-nitropentan-2-yl] malonate. The present invention relates to a process for the preparation of asymmetric compounds comprising asymmetric addition of dicarbonyl compounds to nitroalkenes in the presence of a chiral catalyst according to the Michael addition reaction.

Brief Analysis of Prior Art Known to Applicant There are many compounds that are useful as intermediates in the synthesis of pharmaceutically active substances. For example, optically active nitro compounds are widely used as synthetic intermediates in the preparation of various drugs, pesticides and other complex chemicals such as rolipram, vigabatrin, pregabalin, various γ-aminobutyric acid analogues.

Asymmetric organic synthesis is very topical in pharmaceutical chemistry since most drugs contain only one of the possible enantiomers as active pharmaceutical ingredients. Asymmetric synthesis results in the formation of only one enantiomer and the possible increase of the total yield, which gives an economic effect. However, only some of the known methods of asymmetric synthesis can be used in industry. Many of the methods described in the literature are not suitable for large-scale production because they do not meet the following criteria: safety (use of hazardous materials and techniques), environmental aspect (solvents, waste), economic criteria (costs of materials and techniques), control requirements (repeatability, product purity) ).

One of the divisions of asymmetric synthesis of interest over the last 10-15 years is the stereo-controlled addition of various nucleophiles (e.g. enolates, nitronates, organometallic compounds) to activated olefins (e.g., α, β-unsaturated carbonyl compounds, nitriles, sulfones, nitroalkenes). ). The addition of stabilized active C-H nucleophiles to α, β-unsaturated electrophiles (known as Michael's reaction) usually occurs under relatively mild conditions and is applicable in the production of various types and scales. In this reaction, stereocontrol is performed using various additives (including diastereoselective), transition metal catalysis, organocatalysis, phase transition catalysis, and others. Various catalysts are used for enantioselective addition, mainly metal-ligand complexes including palladium, scandium, copper, aluminum, nickel, magnesium, iridium, ruthenium, lanthanum. Evans and co-workers (JACS, 2005, 127, 9958) have developed a Michael reaction of nickel-catalyzed malonate and nitro-olefins at ambient temperature, which requires a relatively small amount of catalyst.

Further research was needed to find a simple industrially applicable method for obtaining optically pure nitro compounds.

SUMMARY OF THE TECHNICAL PROBLEM AND A SOLUTION THEREOF The present invention relates to diethyl [(2 S) -4-methyl-1-nitropentan-2-yl] malonate (I), which is an intermediate of (S) -3-aminomethyl-5-yl. methylhexansabbe (11 -и »« »\

The method of obtaining this enzyme is <RTI ID = 0.0> ll-x1-xz-b4-T1 </RTI> ivgubaiia. The process described in the present invention is useful in obtaining pure pregabahn, does not include a chiral splitting step, is easily realized, effective and can be easily adapted for large-scale production:

Enantioselective addition of 1,3-dicarbonyl compounds to nitroalkenes in the presence of a catalyst according to Michael's addition reaction is used to obtain diethyl [(2 S) -4-methyl-1-nitropentan-2-yl] malonate (I). The enantioselective complex of nickel and S, S - (+) - N, N'-di-4,4 '- tert -butylbenzyl-1,2-diaminocyclohexane was initially selected for the preparation of the production method by analogy with literature data (JACS, 2005 , 127, 9958). In the literature, better results for enantioselective addition are obtained by reaction of malonates with conjugated aryl-containing nitroalkenes. Reactions of aliphatic β-substituted nitroalkenes require longer time, lower yields and selectivity compared to the reaction of nitrostyrol with malonates. Further studies were needed to improve the conditions of the given reaction in order to obtain compound (I) with good yield and optical purity of at least 80%.

Within the scope of the invention, the diethyl [4-methyl-1-nitro-pentan-2-yl] malonate is obtained by condensing 4-methyl-1-nitro-1-pentene (II) with malonic acid diethyl ester (III) in an organic solvent using a chiral catalyst following reaction schemes:

COOEt Catalyst <..... .....

COOEt

III Using a nickel complex with S, S - (+) - N, N'-di-4,4'-tert-butylbenzyl-1,2-diaminocyclohexane as catalyst in the reaction, diethyl [(2S) -4-methyl-1] is obtained. -nitropentan-2-yl] malonate (I), but using?,? - (+) - N, N'-di-4,4'-tert-butylbenzyl-1,2-diaminocyclohexane

diethyl [(2R) -4-methyl-1-nitropentan-2-yl] malonate. In the preferred embodiment, ethyl acetate is used as a condensation solvent.

The nickel-diamine-diethyl malonate complex was studied as a chiral catalyst for the condensation of 4-methyl-1-nitro-1-pentene (II) with diethyl malonate (III). Nickel chloride or bromide, N, N'-di-4,4 '- tert -butylbenzyl-L2-diaminocyclohexane and diethyl malonate are used for the preparation of catalysts of this type. The use of said catalyst slightly improved the enantioselectivity of the reaction compared to the N, N'-di-4,4'-tert-butylbenzyl-1,2-diaminocyclohexananil complex.

[ООП] The present invention makes it possible to simplify the technological process using a catalyst without prior separation in solution. The chiral catalyst is prepared prior to use and used as a solution without releasing the complex, which greatly simplifies the process under production conditions. This ensures first the activity of the catalyst as it loses its activity when stored for a long time. Second, it facilitates the technological process (no precipitation, crystallization, filtration steps).

[0012] The catalytic reaction mechanism involves one of the N, N'-di-4,4'-tert-butylbenzyl-1,2-diaminocyclohexane ligands to act on the 1,3-dicarbonyl compound by enolization and to release the complex. Therefore, to reduce the consumption of N, N'-di-4,4'-tert-butylbenzyl-1,2-diaminocyclohexane in the given synthesis, only one equivalent of ligand was used to prepare the complex, and the other equivalent was replaced by a cheaper enolizing reagent. Triethylamine was tested as the enolizing reagent. An important improvement is the possibility of using nickel chloride hexahydrate, which is more readily available, to replace the anhydrous nickel bromide catalyst. The best results in terms of product quality and technological simplicity were obtained for the preparation of diethyl [(2S) -4-methyl-1-nitropentan-2-yl] malonate (I) using nickel chloride hexahydrate, (5S) -N as the chiral catalyst. N'-di-4,4'-tert-butylbenzylcyclohexane-1,2-diamine, diethyl malonate and triethylamine in a solution of n-butanol. All reagents for the preparation of the catalyst are taken equimolar.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS The invention is illustrated but not limited by the following examples.

Example 1. Nickel Bromide-N, N '- (+) - N, N'-di-4,4'-tert-Butylbenzyl-1,2-diaminocyclohexane-diethyl malonate complex.

304 mg (0.748 mmol) of R, R - (+) - N, N'-di-4,4'-tert-butylbenzyl-1,2-diaminocyclohexane and 164 mg (0.748 mmol) of anhydrous nickel bromide are boiled under reduced pressure. ml of tert-butanol until complete dissolution of the nickel bromide. To the resulting red solution is added a solution of diethyl malonate (120 mg; 0.749 mmol) in terobutanol (1 mL) and 84 mg (0.749 mmol) of potassium t-butylate. The reaction mixture is boiled for 1 hour, cooled and the green precipitate formed is filtered off, washed with 3 ml of diethyl ether on the filter and dried.

IS (KBr), cm ^-1 : 3276; 3026; 2856; 1458; 1149; 784; 758; 700.

Example 2. Solution of nickel chloride-N, N - (+) - N, N'-di-4,4'-tert-butylbenzene-1,2-diaminocyclohexane-diethyl malonate.

191.7 mg (0.472 mmol) of 7?, R - (+) - N, N'-di-4,4'-tert-butylbenzyl-1,2-diaminocyclohexane and 56.1 mg (0.236 mmol) of nickel chloride Hexahydrate is dissolved in 2.36 ml of t-butanol. To the resulting solution was added 37.8 mg (0.236 mmol) of diethyl malonate and stirred for 18 hours.

A solution of the nickel chlonda-S, S - (+) - N, N'-di-4,4'-tert-butylbenzyl-1,2-diaminocyclohexanediethyl malonate complex is prepared analogously.

Example 3. Solution of nickel chloride-R, N - (+) - N, N'-di-4,4'-tert-butylbenzyl-1,2-diaminocyclohexane-diethyl malonate-triethylamine.

102 mg (0.252 mmol) of N, N - (+) - N, N'-di-4,4'-tert-butylbenzyl-1,2-diaminocyclohexane and 59.8 mg (0.252 mmol) of nickel chloride hexahydrate Dissolve 2.52 ml of t-butanol. To the resulting solution is added 40.4 mg (0.252 mmol) of diethyl malonate and 25.5 mg (0.252 mmol) of triethylamine. The resulting mixture is stirred for 2 hours.

Example 4. Solution of nickel chloride-S, S '- (+) - N, N'-di-4,4'-tert-butylbenzyl-1,2-diaminocyclohexane-diethyl malonate-triethylamine.

To n-butanol (400 mL), add 55 g (0.109 mol) of S ', S' - (+) - N, N'-di-4,4 ^, - tert -butylbenzyl-1,2-diaminocyclohexane and stir. about 10 minutes. 26.1 g (0.109 mol) of nickel chloride hexahydrate are then added and the mixture is stirred for another 30 minutes. To the resulting solution is added 17.7 g (0.109 mol) of diethyl malonate, 11.1 g (0.109 mol) of triethylamine and stirred for 2 hours at room temperature. Obtain approximately 460 ml of butanolic solution of the nickel chiral complex catalyst.

Example 5. Preparation of diethyl [(2S) -4-methyl-1-nitropentan-2-yl] malonate.

117 g (0.90 mol) of 4-methyl-1-nitro-1-pentene are charged into a three-necked round bottom flask, 500 ml of ethyl acetate and 138 ml (0.90 mol) of malonic acid diethyl ester are added. The reaction mixture is heated to 70 ° C and about 460 ml of freshly prepared catalyst (~ 12 mol%, Example 4) is added. The reaction mixture is stirred at 70 ° C for 18-22 hours. After completion of the reaction, the mixture is cooled to 20-25 ^G and extracted twice with 150 ml of hydrochloric acid solution (30 ml of concentrated hydrochloric acid is diluted with 270 ml of water). The organic layer is washed with 100 ml of water, 150 ml of sodium bicarbonate solution (7.5 g of sodium bicarbonate is dissolved in 150 ml of water, twice more with 150 ml of water and the solvent is distilled off in vacuo. 250 g (96% of theory) (20) -4-Methyl-nitro-pentan-2-yl] -malonate as a viscous liquid containing 11.21% diethyl [(2 R) -4-methyl-nitro-pentan-2-yl] -malonate. -4-methyl-1-nitropentan-2-yl] malonate The optical purity is above 88%.

Example 6. Preparation of diethyl [(2R) -4-methyl-1-nitropentan-2-yl] malonate.

35 g (0.274 mol) of 4-methyl-1-nitro-1-pentene, 42 ml (0.274 mol) of malonic acid diethyl ester and 150 ml of ethyl acetate are charged in a 0.5 L three-necked round bottom flask with stirrer, condenser and thermometer. Bring the reaction mixture to 70 ° C and add about 95 ml of freshly prepared catalyst (~ 8 mol%, Example 3). The reaction mixture is stirred for 18-22 hours at 70 ° C. After completion of the reaction, the mixture is cooled to 20-25 ° C, washed with 2x50 ml hydrochloric acid (15 ml concentrated hydrochloric acid dissolved in 85 ml water), 50 ml water, 50 ml sodium bicarbonate solution (2.6 g sodium bicarbonate dissolved in 50 ml water) ) and 50 ml of water. Evaporate the resulting solution in vacuo. 75 g (95% of theory) of diethyl [(2 R) -4-methyl-1-nitropentan-2-yl] malonate are obtained. The resulting product has an optical purity above 85%.

Claims (4)

A process for the preparation of an optically pure 2S or 2R diethyl [4-methyl-1-nitropentan-2-yl] malonate, comprising: reacting 4-methyl-1-nitro-1-pentene with diethyl malonate in the presence of a chiral catalyst; , wherein the chiral catalyst is a mixture of nickel chloride hexahydrate, (S, S) or (Λ, Λ) -Ν, Ν'di-4,4'-tert-butylbenzylcyclohexane-1,2-diamine, diethyl malonate and triethylamine. Process for the preparation of diethyl [(2S) -4-methyl-1-nitropentan-2-yl] malonate according to claim 1, characterized in that the chiral catalyst is nickel chloride hexahydrate, (5S) -N, N'di-4,4'-tert-butylbenzylcyclohexane-1,2-diamine, diethyl malonate and triethylamine in n-butanol. A process according to claim 1 for the preparation of diethyl [(2 R) -4-methyl-1-nitropentan-2-yl] malonate, wherein the chiral catalyst is nickel chloride hexahydrate, (R, R) -N , A solution of N'di-4,4'-tert-butylbenzylcyclohexane-1,2-diamine, diethyl malonate and triethylamine in t-butanol. The process according to claim 1, wherein the resulting diethyl [4-methyl-1-nitropentan-2-yl] malonate has an optical purity of at least 80%.