RU2555370C1 - Method for enanthioselective synthesis of diethyl[3-methyl-(1s)-(nitromethyl)butyl]malonate of formula i - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention refers to a method for producing diethyl[3-methyl-(1S)-(nitromethyl)butyl]malonate of formula I by enanthioselective attachment of diethylmalonate to 4-methyl-1-nitropent-1-ene in accordance with the scheme below. A reaction of diethylmalonate and 4-methyl-1-nitropent-1-ene is carried out in the presence of a catalyst system representing a nickel chloride hexahydrate solution, (S,S)-N,N'-dibenzylcyclohexane-1,2-diamine and triethylamine in molar ratio 1:1:1 in methanol. Preferentially, the catalyst system components are used in ratio 0.05-1 mole % in relation to 4-methyl-1-nitropent-1-ene. The method enables producing diethyl[3-methyl-(1S)-(nitromethyl)butyl]malonate with an enanthiomeric excess of 96.6-97.2% with the use of the catalyst system generated from nickel chloride hexahydrate, (S,S)-N,N'-dibenzylcyclohexane-1,2-diamine and triethylamine, avoiding the stage of individual complex recovery.

EFFECT: considerable cost-cutting and simplification of the technological process.

2 cl, 5 ex

Description

The present invention relates to the field of organic chemistry, and in particular to a method for producing diethyl [3-methyl- (1S) - (nitromethyl) butyl] malonate.

Diethyl [3-methyl- (1S) - (nitromethyl) butyl] malonate is a synthetic precursor of (S) -pregabalin - a drug used in the treatment of a number of neuropathic diseases and disorders, including neuropathic pain, epilepsy, fibromyalgia, migraine, syndrome restless legs, sleep disturbances, etc. (Pat. WO 2006/110783 A2. Process for making (S) -pregabalin (published date 10/19/2006)).

This invention solves the problem of enantioselective synthesis of diethyl [3-methyl- (1S) - (nitromethyl) butyl] malonate using an readily available and cheap catalytic system used in the form of a solution, which eliminates the need for a stage of separation of the catalytic complex as an individual compound and provides significant cost reduction and simplification of the process.

A number of methods are known for producing diethyl [3-methyl- (1S) - (nitromethyl) butyl] malonate based on the use of organocatalysts (Hoashy Y., Okino T., Takemoto YJ Am. Chem. Soc. 2003, Vol.125, N 42 , P.12672-12673; Furukawa T., Hoashy Y., Okino T., Takemoto Y., Xu XJ Am. Chem. Soc. 2005, Vol.127, N 1, P.119-125; Liu J.- M., Wang X., Ge Z.-M., Sun Q., Cheng J.-M., Li R.-T. Tetrahedron. 2011, Vol. 67, No. 3, P.636-640). A common disadvantage of these methods is the complexity of the structure of organocatalysts, their inaccessibility and high cost, as well as the high consumption of organocatalysts required to achieve a catalytic effect.

Diethyl [3-methyl- (1R) - (nitromethyl) butyl] malonate was obtained from diethyl malonate and 4-methyl-1-nitropent-1-ene in the presence of 5.5% chiral bis-oxazoline, 5% magnesium triflate, 6 mol. % N-methylmorpholine and molecular sieves (Bames DM, Ji J., Fickes MG et al. J. Am. Chem. Soc. 2002. Vol.124. N 44. P.13097) with a yield of 88% and an enantiomeric excess of 90% .

The (R) -isomer of diethyl [3-methyl-1- (nitromethyl) butyl] malonate was obtained with a yield of 94% and an enantiomeric excess of 88% by the interaction of a double excess of diethyl malonate with 4-methyl-1-nitropent-1-ene in the presence of 2 mol . % dibromobis [(R, R) -N, N′-dibenzylcyclohexane-1,2-diamine] nickel (II) (Evans DA, Mito S., Seidel DJ Am. Chem. Soc. 2007. Vol.129. N 37 P.11583).

In both cases, the (R) -isomer of diethyl [3-methyl-1- (nitromethyl) butyl] malonate is obtained, while the synthesis of the pharmaceutically active substance pregabalin requires the (S) -isomer. In addition, the high consumption of chiral ligands (from 2 to 6 mol%) and the need for additional steps for the preparation and isolation of the nickel (II) complex (Evans DA, Mito S., Seidel DJ Am. Chem. Soc. 2007. Vol.129. N 37. P.11583) make these methods unsuitable for technological implementation.

The closest in technical essence to the claimed method is a method for producing diethyl [3-methyl- (1S) - (nitromethyl) butyl] malonate from 4-methyl-1-nitropent-1-ene and diethyl malonate in the presence of an organocatalyst described in Pat. EP 1640361 (A2) Asymmetric urea compound and process for producing asymmetric compound by asymmetric conjugate addition reaction with the same as catalyst (published date March 29, 2006).

Described in Pat. EP 1640361 (A2) a method for the production of diethyl [3-methyl- (1S) - (nitromethyl) butyl] malonate consists in adding to the solution of nitroalkene (0.20 mmol) and diethyl malonate (0.40 mmol) as a catalyst (R, R) -trans-1- [3,5-bis (trifluoromethyl) phenyl] -3- [2- (N, N-dimethylamino) cyclohexyl] thiourea (0.02 mmol) at room temperature under argon atmosphere. After 48 hours, the reaction mixture was concentrated in vacuo. The reaction product is isolated by column chromatography using eluent hexane-diethyl ether. The expected product is isolated in 88% yield and an enantiomeric excess of the (S) -isomer 81%.

The specified method has a number of significant disadvantages:

1. Low enantiomeric purity of the reaction product (81%).

2. The need to use large quantities of expensive organocatalyst (10 mol.% In relation to nitroalkene).

3. The need to use a large amount of solvent (toluene).

4. The need for isolation of the reaction product by column chromatography.

EFFECT: economical and safe process for producing diethyl [3-methyl- (1S) - (nitromethyl) butyl] malonate with an enantiomeric excess of 96.6-97.2%, using an easily accessible and cheap catalytic system generated from nickel (II) chloride hexahydrate , (S, S) -N, N′-dibenzylcyclohexane-1,2-diamine and triethylamine.

The technical result is achieved by the fact that diethyl [3-methyl- (1S) - (nitromethyl) butyl] malonate of the formula I

obtained by enantioselective addition of diethyl malonate to 4-methyl-1-nitropent-1-ene in accordance with scheme 1

the reaction is carried out by adding a catalytic system, which is a solution of nickel chloride hexahydrate, (S, S) -N, N′-dibenzylcyclohexane-1,2-diamine and triethylamine in a 1: 1: 1 molar ratio in methanol, the chiral ligand consumption can be reduced to 0.05 mol. % in relation to 4-methyl-1-nitropent-1-ene.

Features:

1. The reaction of diethyl malonate with 4-methyl-1-nitropent-1-ene in the presence of a catalytic system that is a solution of nickel chloride hexahydrate, (S, S) -N, N′-dibenzylcyclohexane-1,2-diamine and triethylamine 1: 1: 1 molar ratio in methanol.

2. The components of the catalytic system are used in a ratio of 0.05-1 mol. % in relation to 4-methyl-1-nitropent-1-ene.

The claimed invention has the following advantages:

Cheaper production due to the use of enantioselective addition of diethyl malonate to 4-methyl-1-nitropent-1-ene as a catalytic system, a solution of the components of the catalytic system in low concentration (0.05-1 mol%) and the rejection of the use of expensive organocatalysts - derivatives of thiourea.

The simplification of the process due to the use of a catalytic system in the form of a solution (without additional stages of separation of an individual complex) and the absence of the need for chromatographic isolation of the reaction product.

Ensuring environmental safety of the process due to the rejection of the use of large quantities of solvents.

Examples of the method

NMR spectra were recorded on a Jeol JNM-ECX400 instrument using CDCl ₃ solvent [399.78 ( ¹ H) and 100.53 MHz ( ¹³ C)]. The measurements were carried out without the use of additional standards with reference to the frequency of the signal of the deuterated solvent.

Mass spectra were obtained on a Finnigan Trace DCQ gas chromatography mass spectrometer using a SGE capillary column BPX-5 30 × 0.32 at an ionizing electron energy of 70 eV.

The enantiomeric composition of the reaction product was determined by HPLC on a Waters liquid chromatograph equipped with a Waters 2487 spectrophotometric detector and a Waters 2414 refractometric detector. Analysis conditions for diethyl [(2S) -4-methyl-1-nitropent-2-yl] malonate: Chiralcel AD column; mobile phase: hexane: isopropanol (95: 5), flow rate 1.0 ml / min.

A 0.1 M solution of each of the components of the catalytic system in methanol was used to catalyze the reaction of 4-methyl-1-nitropent-1-ene with diethyl malonate.

Example 1

Catalytic System Preparation

To 740 mg (2.52 mmol) of (S, S) -N, N′-dibenzylcyclohexane-1,2-diamine and 598 mg (2.52 mmol) of nickel (II) chloride hexahydrate, 25.2 ml of methanol was added and stirred until the reagents were completely dissolved; then, 0.350 ml (255 mg, 2.52 mmol) of triethylamine was added to the resulting solution. The resulting solution was used in the reaction.

Diethyl [3-methyl- (1S) - (nitromethyl) butyl] malonate

Example 2

To 12.1 g (93.5 mmol) of 4-methyl-1-nitropent-1-ene and 30.0 g (187 mmol) of diethyl malonate was added 9.35 ml of a catalytic solution (0.935 mmol, 1 mol% Ni) obtained by the procedure described in Example 1 The reaction mass was kept at a temperature of 50 ° C for 5 hours. The excess diethyl malonate was distilled off in vacuo at a residual pressure of 20 mm Hg. Yield: 27.1 g (quantitative). NMR ¹ H (CDCl ₃ ), δ, ppm: 0.85-0.87 m. (6Н), 1.20-1.29 m (8Н), 1.57-1.63 m (1Н), 2.87-2.92 m (1Н), 3.55 d (1H, J _HH 5.6 Hz), 4.13-4.19 m (4H), 4.46 dd (1H, J _HH 13.2, 6.4 Hz), 4.65 dts (1H, J _HH 13.2, 4.8 Hz). δ _C , ppm: 13.8, 13.9, 22.1, 22.2, 25.0, 34.7, 38.9, 52.6, 61.6, 61.7, 76.8, 167.7, 167.9. GC-MS, m / z (I _Rel ,%): 243 (6, M ⁺ - NO ₂ ), 215 (10), 169 (25), 160 (100), 133 (30), 55 (35). HPLC: exit time of the (R) -isomer 6.4 min, (S) -isomer 8.8 min. According to HPLC, the enantiomeric excess of the (S) -isomer is 97.2%.

Example 3

To 12.1 g (93.5 mmol) of 4-methyl-1-nitropent-1-ene and 30.0 g (187 mmol) of diethyl malonate was added 1.87 ml of a catalytic solution (0.187 mmol, 0.2 mol% Ni) obtained by the procedure described in Example 1 The reaction mass was kept at a temperature of 50 ° C for 15 hours. The excess diethyl malonate was distilled off in vacuo at a residual pressure of 20 mm Hg. Yield: 27.1 g (quantitative). Enantiomeric excess of (S) -isomer 96.8%.

Example 4

To 25.7 g (199 mmol) of 4-methyl-1-nitropent-1-ene and 63.7 g (398 mmol) of diethyl malonate were added 1.00 ml of a catalytic solution (0.100 mmol, 0.05 mol% Ni) obtained by the procedure described in Example 1 The reaction mass was kept at a temperature of 50 ° C for 15 hours. The excess diethyl malonate was distilled off in vacuo at a residual pressure of 20 mm Hg. Yield: 57.6 g (quantitative). Enantiomeric excess of (S) -isomer 96.6%.

Example 5

To 258 g (2.00 mol) of 4-methyl-1-nitropent-1-ene and 641 g (4.00 mmol) of diethyl malonate were added 10 ml of a catalytic solution (1 mmol, 0.05 mol% Ni) obtained by the procedure described in Example 1 The reaction mass was kept at a temperature of 50 ° C for 15 hours. The excess diethyl malonate was distilled off in vacuo at a residual pressure of 20 mm Hg. Yield: 579 g (quantitative). Enantiomeric excess of (S) -isomer 96.6%.

Claims (2)

1. The method of obtaining diethyl [3-methyl- (1S) - (nitromethyl) butyl] malonate of the formula I

by enantioselective addition of diethyl malonate to 4-methyl-1-nitropent-1-ene according to the scheme

,
characterized in that the reaction of diethyl malonate with 4-methyl-1-nitropent-1-ene is carried out in the presence of a catalytic system that is a solution of nickel chloride hexahydrate, (S, S) -N, N′-dibenzylcyclohexane-1,2-diamine and triethylamine in a molar ratio of 1: 1: 1 in methanol. 2. The production method according to claim 1, characterized in that the components of the catalytic system are used in a ratio of 0.05-1 mol% with respect to 4-methyl-1-nitropent-1-ene.