KR101325589B1 - Process for the preparation of 1-alkyl-2-(2-aminoethyl)pyrrolidines - Google Patents

Abstract

The present invention relates to a manufacturing method of 1-alkyl-2-(2-aminoethyl)pyrrolidines indicated as formula 1, and a novel intermediate to a manufacturing method therefor which is indicated as formula 2. More particularly, the present invention relates to a novel manufacturing method of 1-alkyl-2-(2-aminoethyl)pyrrolidines into a high purity compound of 1-alkyl-2-(2-aminoethyl)pyrrolidines after producing organic and mineral salt after reduction reaction by hydriding reaction among metal catalysts after obtaining 1-alkyl-2-(2-aminoethyl)pyrrolidines after reacting nitroethane and an alcoholic alkali metal solution in a product produced after processing a halide of 1-alkyl-2-(2-aminoethyl)pyrrolidines. The new manufacturing method deals with 1-alkyl-2-(2-aminoethyl)pyrrolidines in formula 1 and an intermediate of 1-alkyl-2-(2-aminoethyl)pyrrolidines in formula 2. R1 is a methyl, a propyl, an isopropy, and an isobutyl.

Description

Process for the preparation of 1-alkyl-2- (2-aminoethyl) pyrrolidines}

The present invention provides a process for preparing 1-alkyl-2- (2-aminoethyl) pyrrolidine of formula [I], 1-alkyl-2- (2-nitroethylidene) pyrrolidine of formula [II] and A method for preparing an intermediate of 1-alkyl-2- (2-nitroethylidene) pyrrolidine of formula [II].

The 1-alkyl-2- (2-aminoethyl) pyrrolidine compound to be synthesized in the present invention is described in US Patent Publication No. 2004 / 039044A1 and Korean Patent Registration No. 10-0696187, and aminoalkyl pyrrolidine derivatives Cardiovascular, gastrointestinal diseases, neurotransmitters Vasoconstrictors (5HT) are disclosed as being used as an antagonist drug, and also has been used as an intermediate of the drug with the efficacy of the genitourinary system. Examples of manufacturing methods for these production methods are as follows.

1) US Patent Publication No. 2004 / 039044A1

[Reaction Scheme 1]

Where R ₁ is methyl

Specifically, in [Scheme 1], starting from the starting material (S) -2-hydroxymethyl pyrrolidine (1), the amine group is protected with 2-carbonate-tert-butyl, followed by molecular formula (2) The compound of (3) is prepared, separated and purified, and then reacted with sodium cyanide to reduce cyano group with lithium aluminum hydride to prepare 1-methyl-2- (2-aminoethyl) pyrrolidine.

In addition, the preparation method of [Scheme 2] below prepares the molecular formula (4) by the same method as above, and then reacts with trifluoroacetic acid and acetic anhydride to produce the molecular formula (7), reduced to lithium aluminum hydride 1- Ethyl-2-aminoethylpyrrolidine.

[Reaction Scheme 2]

Where R ₁ is Echil

2) In Korean Patent Registration No. 10-0696187

Scheme 3

In detail, the starting material (I) is reacted with dimethyl sulfuric acid to produce a reactant having the molecular formula (II), and then methylated cyanoacetate is added to the mixture to prepare a molecular formula (3) without separation, followed by crystallization and separation under basic conditions. Method of preparing 1-methyl-2- (2-aminoethyl) pyrrolidine [Formula I] by introducing hydrogen in a catalyst of palladium hydroxide in the catalyst of palladium hydroxide under the condition of organic acid after the carboxylation reaction The overall theoretical yield from the starting material is 15.12%.

The present invention relates to an intermediate of 1-alkyl-2- (2-nitroethylidene) pyrrolidine of formula [II] and a process for preparing 1-alkyl-2- (2-aminoethyl) pyrrolidine [Formula I]. It is about. In the method described in US Patent Publication No. 2004 / 039044A1, (S) -2-hydroxymethyl pyrrolidine was subjected to several steps from the starting material (S) -1-methyl-2- (aminoethyl) In order to obtain the compound of each step by the method for preparing pyrrolidine, it is necessary to separate and refine the step-by-step compound, and it is difficult to expect industrial application, and the method of preparing Korean Patent Registration No. 10-0696187 is based on the molecular formula (1). It is prepared using 1-methyl-2-pyrrolidone as starting material but is described as having a very low overall yield and also does not describe the purity of the obtained 1-methyl-2- (aminoethyl) pyrrolidine compound.

The method to be solved of the present invention is a cumbersome and effective method of carrying out the process with a suitable manufacturing method which is industrially easy to produce and has economic and productive value. Namely, 1-methyl-2-pyrrolidone represented by the formula (1-a) was reacted with sodium borohydride at a temperature of 0 ° C. to 50 ° C. as a starting material, thereby reacting 1-methyl-2- of formula (1-b). Hydroxypyrrolidine is obtained almost quantitatively, and halogenated with a halogenating agent at a temperature of 0 ° C. to −20 ° C. to give the result of the halide of formula (1-c), which is reacted with an alkoxide of an alkali metal to give a formula ( 1-d) to obtain a compound of formula [II] to react with nitroethane to give 1-alkyl-2- (2-nitroethylidene) pyrrolidine of formula [II], which reduces the compound of formula [II] To prepare 1-alkyl-2- (2-aminoethyl) pyrrolidine of formula [I].

In the manufacturing process described by the continuous reaction of the present invention, in order to prepare [Formula I], 1-methyl-2-pyrrolidone is reacted with bromine or phosgene to obtain an intermediate product, and an alcoholic alkali metal solution and nitroethane Compound (4) obtained by the reaction is maintained at room temperature to 35 ℃ in the metal catalyst, the reaction pressure is 1-alkyl-2- (2-aminoethyl) pyrrolidine through the hydrogenation reaction at normal pressure to 5kg / ㎠ To obtain 5).

Purification of the obtained crude product, 1-alkyl-2- (2-aminoethyl) pyrrolidine, after formation of an inorganic salt in the selected solvent yields a high overall yield and very high purity.

The present invention uses a compound of formula [II], a novel intermediate compound, and can continuously proceed the reaction without separating and purifying the process compound of each step, and has a high yield and high purity of final formula [Formula I]. Has the advantage to get

The preparation method of the present invention is formula (1-a) which is 1-alkyl-2-pyrrolidone to prepare 1-methyl-2- (2-aminoethyl) pyrrolidine of [Formula I] in the following scheme. Was reacted with sodium borohydride at 0 ° C. to 50 ° C. to prepare 1-alkyl-2-hydroxy pyrrolidine [Formula (1-b)], and at −5 ° C. to 10 ° C. under a medium of a halide and a reaction solvent. [Formula (1-c)] produced by the reaction can be separated and purified before adding the alcoholic alkali metal solution (alkoxide of alkali metal). In addition, alcoholic alkali metal solution can be added at 0 ° C to -20 ° C without separation, followed by reaction of nitroethane at room temperature. Treatment with alcoholic alkali metal solution at low temperature gives the compound of formula Lose. Here, the reaction with nitroethane is carried out at room temperature, and 1-methyl-2- (2-nitroethylidene) pyrrolidine of [Formula II] may be separated and purified before the hydrogenation reaction, and not purified. The hydrogenation reaction may be carried out without. The hydrogenation reaction may be performed by generating hydrogen in-situ, preferably by injecting hydrogen in the presence of a metal catalyst or by adding acid to the metal. In the former case, a suitable metal of iron or zinc may be used, and may be carried out by heating in hydrochloric acid or acetic acid serving as a solvent. The catalyzed hydrogen reaction is platinum black, rhodium, palladium carbon, Raney nickel, and the reaction is carried out in an inert solvent. The solvent may be water, methanol, ethanol, butanol, tetrahydrofuran or dioxane in a single solvent or a mixed solvent. The pressure at the time of reaction is atmospheric pressure or 5-6 kg / cm <2>. If there is no absorption of hydrogen, the catalyst is filtered off and the solvent is concentrated in vacuo. To this, inorganic acids such as hydrochloric acid and bromic acid are added, or organic acids such as picric acid, maleic acid, tartaric acid, and oxalic acid are added to form and purify the salt to obtain high purity 1-methyl-2- (2-aminoethyl) pyrrolidine. The reaction process is as follows.

[Reaction Scheme 4]

R ₁ is a lower alkyl group having ₁ to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl and isobutyl group, and X is a halogen atom such as chlorine, bromine and iodine.

Halogenating agents are thionyl chloride, phosphorus pentachloride, phosgene, bromine, O-phenylenephosphorochloridite. Reaction solvents are benzene, toluene and xylene.

In the above scheme, M is an alkali metal such as sodium, potassium, lithium, and R ₂ is a lower alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, and butyl groups.

Description of the manufacturing method of the present invention is described by the following examples, the scope of the invention is not limited by the examples.

Example 1

Preparation of 1-methyl-2-hydroxy pyrrolidine

1-methyl-pyrrolidone (20.95 g, 0.21 mole) was added to 120 ml of methyl alcohol, and dissolved at room temperature. Sodium borohydride (4 g, 0.105 mole) was slowly added with stirring while maintaining the temperature below 50 ° C., and then brought to 25 ° C. Cool and react for 1 hour at the same temperature. After the reaction was completed, the solvent was evaporated under reduced pressure, 50 ml of water and 200 ml of methylene chloride were added to the residue and stirred for 30 minutes. After standing, the water layer was separated and removed. Anhydrous sodium sulfate was added to the organic layer, stirred, dried, filtered and concentrated under reduced pressure to obtain the title crude product quantitatively (21.37 g, 99.9%).

¹ HNMR (400 MHz, CDCl ₃ ) δ: 4.5 (1H, s), 2.89 (OH.s), 2.43-2.90 (CH2, m), 2.25 (N-CH3, s),

1.55-1.662.5 (CH2, m), 1.86-1.92 (CH2, m)

Example 2

Preparation of 1-methyl-2- (2-nitroethylidene) pyrrolidine

Dissolve 1-methyl-2-hydroxypyrrolidine (23.5 g, 0.232 moles) in 100 ml of anhydrous toluene, cool to 0 ° C., and bromine (40 g, 0.25 moles) in 150 ml of benzene while maintaining 0 ° C. to 5 ° C. Dilute and slowly add dropwise with stirring for 1 hour. After the addition was completed, the mixture was stirred for 3 hours while maintaining 0 ° C, and then cooled to minus 15 ° C, and a solution of metal sodium (11.9g, 0.5 mol) in 150ml of ethanol was kept at minus 5 ° C to 15 ° C for 15 minutes. Add. The addition is exothermic, producing sodium bromide, and when the reaction is complete, it is stirred until it reaches room temperature. Nitroethane (24.06 g, 0.32 mol) is added at room temperature for 20 minutes. After the addition was completed, the mixture was stirred at the same temperature for 2 hours, and then 1000 ml of water was added thereto, stirred, and left to separate an organic layer. The aqueous layer was extracted twice with 150 ml of chloroform, the organic layers were mixed, filtered through dryness with sodium sulfate, and the solvent was concentrated in vacuo to obtain a crystallized residue. M is sodium, potassium and R ₂ is methyl, ethyl.

100 ml of ether was added thereto, stirred for 1 hour, and then filtered and dried to yield the title compound (30.8 g, 85%).

¹ HNMR (400 MHz, CDCl ₃ ) δ: 5.03 (2H, d), 4.8 (= CH.triplet), 3.37-3.45 (CH2, m),

2.9 (N-CH3, s), 2.42-2.5 (CH2, m), 1.97-2.03 (CH2, m)

Example 3

Preparation of 1-methyl-2- (2-nitroethylidene) pyrrolidine

1-methyl-2-hydroxypyrrolidine (23.5 g, 0.23 mol) was dissolved in 100 ml of anhydrous toluene, cooled to 0 ° C., and then maintained at 0 ° C. to 5 ° C. toluene solution containing 20% of phosgene instead of bromine. Dilute 250 mL (24.7 g, 0.23 mole) and add dropwise while slowly stirring for 1 hour. After the addition was completed, the mixture was stirred for 3 hours while maintaining 0 ° C, and then cooled to -15 ° C, and a solution of metal sodium (11.9g, 0.5 mol) in 150ml of ethanol was kept at -5 ° C to -15 ° C for 15 minutes. Add. The addition is exothermic and sodium chloride is produced. When the reaction is complete, it is stirred until it reaches room temperature. Nitroethane (24.06 g, 0.32 mol) is added at room temperature for 20 minutes. After the addition was completed, the mixture was stirred at the same temperature for 2 hours, and then 1000 ml of water was added thereto, stirred, and left to separate an organic layer. The aqueous layer was extracted twice with 150 ml of chloroform, the organic layers were mixed, filtered through dryness with sodium sulfate, and the solvent was concentrated in vacuo to obtain a crystallized residue. 100 ml of ether was added thereto, stirred for 1 hour, and then filtered and dried to yield the title compound (31.5 g, 87%).

¹ HNMR (400 MHz, CDCl ₃ ) δ: 5.03 (2H, d), 4.8 (= CH.triplet), 3.37-3.45 (CH2, m),

2.9 (N-CH3, s), 2.42-2.5 (CH2, m), 1.97-2.03 (CH2, m)

Example 4

Preparation of 1-methyl-2- (2-aminoethyl) pyrrolidine

Dissolve 1-methyl-2- (2-nitroethylidene) pyrrolidine (27.5 g, 0.17 mole) in 500 ml of ethanol, add 6 g of Raney Nickel, and inject about 4 molar equivalents of hydrogen gas under normal pressure for 5 hours. Absorb and filter off the reaction to complete the catalyst. The filtrate is evaporated under reduced pressure, 500 ml of hexane is added thereto and dissolved, and then hydrochloric acid of the title compound is filtered by adding hydrogen chloride. It is dissolved in 250 ml of the obtained methylene chloride and brought to pH 9 or more with dilute ammonia water. The layers were separated, the aqueous layer was extracted three times with 150 ml of methylene chloride, the organic layers were combined, and the filtrate was dried over sodium sulfate, and the solvent was concentrated in vacuo. Distillation of the residue gave 16.3 g of a high-purity liquid 1-methyl-2- (2-aminoethyl) pyrrolidine (bp: 100-105 ° C., 60 mm Hg. Density: 0.885. Moisture: 0.1%. Purity) : 99.5%, colorless liquid.Yield 74.8%)

¹ HNMR (400 MHz, CDCl ₃ ) δ: 3.10-3.09 (1H, m), 2.80-2.62 (2H.m), 2.31 (3H, s), 2.15- 2.00 (2H, m), 1.97-1.63 (4H, m), 1.53-1.35 (4H. m).

Example 5

Preparation of 1-methyl-2- (2-aminoethyl) pyrrolidine

Dissolve 1-methyl-2- (2-nitroethylidene) pyrrolidine (13.75Kg, 85mol) in 250ℓ of ethanol, add 3kg of Raney Nickel, and inject about 4 molar equivalents of hydrogen gas under normal pressure for 5 hours to absorb. When the reaction is complete, the catalyst is separated by filtration. The filtrate is evaporated under reduced pressure, 250 liters of hexane is added thereto and dissolved, and then hydrochloric acid of the title compound is filtered by adding hydrogen chloride. It is dissolved in 125 l of methylene chloride obtained and brought to pH 9 or more with dilute ammonia water. The layers were separated, the aqueous layer was extracted three times with 75 l of methylene chloride, the organic layers were collected, and the filtrate was dried over sodium sulfate, and the solvent was concentrated in vacuo. Distillation of the residue gave 8.15 Kg of high-purity liquid 1-methyl-2- (2-aminoethyl) pyrrolidine (bp: 100-105 DEG C, 60 mmHg. Density: 0.885. Moisture: 0.1%. Purity) : 99.5%, colorless liquid.Yield 75.0%)

¹ HNMR (400 MHz, CDCl ₃ ) δ: 3.10-3.09 (1H, m), 2.80-2.62 (2H.m), 2.31 (3H, s), 2.15- 2.00 (2H, m), 1.97-1.63 (4H, m), 1.53-1.35 (4H. m).

Claims (6)

The following 1-alkyl-2- (2-nitroethylidene) pyrrolidine of the formula [II] was subjected to hydrogenation in the presence of a metal catalyst in an inert solvent to give 1-alkyl-2- ( 2-Aminoethyl) Pyrrolidine.

Where R1 is methyl, ethyl, propyl, isopropyl and isobutyl group The method of claim 1, wherein the metal catalyst uses a catalyst selected from platinum black, rhodium, palladium carbon, raninickel.
1-alkyl-2- (2-nitroethylidene) pyrrolidine of the formula [II].

Wherein R 1 is a methyl, ethyl, propyl, isopropyl and isobutyl group.
1-alkyl-2-pyrrolidone of formula [1-a] is reacted with sodium borohydride to prepare 1-alkyl-2-hydroxy pyrrolidine of formula [1-b], which is formula [1- a compound of formula [1-c] is prepared by reacting a compound of b] with a halogenating agent, and a compound of formula [1-d] is prepared by reacting a compound of formula [1-c] with an alkoxide of an alkali metal. Next, the compound of formula [1-d] is reacted with nitroethane to prepare 1-alkyl-2- (2-nitroethylidene) pyrrolidine of formula [II].

Wherein R1 is methyl, ethyl, propyl, isopropyl and isobutyl groups, and X is a halogen atom such as chlorine, bromine or iodine.
The process of claim 4 wherein the halogenating agent uses a compound selected from chlorine, bromine, iodine, thionyl chloride, phosgene, phosphorus pentachloride and O-phenylenephosphorochlorid.
The alkoxide of the alkali metal according to claim 4, wherein the alkoxide of the alkali metal is sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium butoxide, lithium methoxide, lithium A process using an alkoxide of an alkali metal selected from ethoxide, lithium propoxide and lithium butoxide.