KR0127750B1 - Process for preparing pyrroli donone derivatie - Google Patents

Abstract

Halolactone compound(II) was reacted with NH2CH2R at 40-200deg.C for 4-30 hours in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, ethyl alcohol and dimethylsulfoxide in the presence of a strong base such as sodium hydride, potassium hydride, triethylamine, and N,N-dimethylamine to give an intermediate compound(IV), which was refined with silica gel column chromatography or a cationic resin to obtain the pharmaceutically useful title compound (I), where R is alkoxy, substituted or nonsubstituted phenoxy, benzyl, or COR2; R2 is alkoxy, amine, diisopropyl ethylene amine, alkyl or alkoxyamine; R1 is H or OH-protectable tetrahydrofuran or acetyl; X is a halogen atom such as Cl, Br or I.

Description

Method for preparing pitolidon derivative

The present invention relates to a new method for producing a pitolidon derivative represented by the following general formula (I).

Wherein R is alkoxy, substituted or unsubstituted phenoxy, 1-2 are substituted or unsubstituted benzyl or COR _{2 and the like and} R ₂ is alkoxy, amine, diisopropylethylenediamine, alkyl or alkoxyamine and the like and R ₁ is hydrogen or hydroxyl group Protectable tetrahydropy is an acetyl column.

Known methods for producing pitolidon derivatives

First, a method of using a five-step process using ethyliminodiacetate and 2-carbooxyoxyacetyl chloride as a raw material (US Patent No. 4118395)

Secondly, a method of preparing gamma-amino-beta-hydroxy butyric acid by three steps after reacting with nucleomethyldisilazane (US Patent No. 441769)

Third, a method of preparing diketene after bromine treatment in five steps (US Patent No. 4529797)

Fourth, the method of manufacturing in 5-step after epoxidation of 2-methylfurophyl-3 buteneate

Fifth, a method of producing in two steps by reacting epichlorohydrinol methane with methylchloro-3-hydroxy butyrate and glycineamide hydrochloride prepared by the high pressure present (Japanese Patent Laid-Open No. 62-185069 number)

Sixth, there is a method of epoxidizing methylbutyrate and treating it with glycine amide hydrochloride (Japanese Patent Laid-Open No. 62-185069).

However, these methods are generally low in yield, relatively long in process, expensive in production of starting materials and intermediates, difficult in production process, and difficult to purify by generation of by-products.

The present invention uses 4-brom-3-hydroxy-beta-butyrolactone which can be easily prepared as a starting material of vinyl acetate, which is very inexpensive, and is obtained by reacting with alkylamine under a strong base. It is a very economical method with high production yield, low by-product generation, simple process and easy purification.

If this is expressed in detail step by step as follows.

1) The starting material is prepared by the method described in, for example, Japanese Patent Application Laid-Open No. 74-219, etc.

X is a halogen atom such as chlorine, bromine, iodine.

2) The halolactone (II) compound is reacted with the structural formula (III) in the presence of a strong base to prepare the target compound as the structural formula (I).

Where R and R are as described above.

At this time, all of the reaction solvents, such as tetrahydrofuran, acetonitrile, dimethylformamide, ethyl alcohol, dimethylsulfoxide, acetone, etc. can be reacted satisfactorily. Preferred within.

The reaction time is 4 to 30 hours and preferably about 12 hours.

Examples of the base used may include metal hydrides such as sodium hydride, potassium-hydride, organic bases such as trimethylamine, triethylamine, N, N-diethylamine, inorganic bases, alkali metals, and hydroxides thereof and sodium. Hydroxide, potassium potassium hydroxide, metal carbonates such as sodium carbonate, potassium potassium hydroxide, metal carbonates such as sodium carbonate, potassium carbonate and the like can be used, and metal hydride is preferred.

In addition, when the structural formula (II) and the structural formula (III) are reacted, the structural compound (IV) can be obtained as an intermediate.

The compound can be reacted without being separated to obtain the desired compound (I). Compounds of the general formula (I) and salts thereof are prepared by purification using silica gel column separation or cationic resin in a conventional manner.

It will be described in detail in the following Examples.

Example 1

Preparation of 4-brom-3-hydroxy-beta-butyrolactone

After dissolving 4.3 g (0.05 mol) of scale acetic acid in 30 ml of tetrahydrofuran, the mixture was stirred for a while at room temperature, and slowly added dropwise a solution of 4.2 g of sodium bicarbonate dissolved in 20 ml of water in advance.

At this time, the carbon dioxide is badly generated.

Subsequently, it cools to 0 degreeC, and 8 g of bromines are dripped slowly.

After finishing, the mixture was warmed up to room temperature, stirred for 7 hours, and allowed to stand at room temperature overnight.

After confirming the completion state of reaction with pesticide chromatograph, the reaction solution was concentrated under reduced pressure, the organic solvent was removed and extracted with ethyl acetate. .

(1) TLC (GF 254) R / F = 0.75 (AN: H ₂ O = 4: 1)

(2) NMR (CDCl ₃ ); 3.3 to 3.9 (4H) 4.6 (1H)

Example 2

Preparation of 1-Ethyl-2- (4-hydroxypyrrolidin-2-one-1-yl) acetate

Dissolve 2 grams of 4-brom-3-hydroxy-betabutyrolactone in 18 milliliters of tetrahydrofuran, add 1.69 grams of glycineethylesdel hydrochloride, and then suspend at room temperature for a while.

0.58 grams of sodium hydride was slowly added at 10 DEG C, heated to reflux for 12 hours. The reaction solution is cooled to room temperature, the insolubles are filtered off, the filtrate is concentrated, separated using a silica gel column and developed with ethyl acetate.

Identify the fractions by TLC, collect the desired product, concentrate and remove the organic solvent, and dry in vacuo to give 1-ethyl-2- (4-hydroxy phytolidin-2-one-1-yl) -acetate as a colorless liquid. Get

(1) TLC (GF 254) R / F = 0.2) EA)

(2) IR (KBr) cm ^-1 : 3400 (OH), 1740 (ester), 1680 (Lactam), 1200

(3) NMR (CDCl ₃ ): 1.3 (t, 3H)

2.2 (m, 2H)

3.1 (m, C ₅ 2H)

3.4 (s, 2H, CH ₂ COO)

4.1 (m, C ₄ 1H)

4.2 (q, 2H)

(4) BP (2.0 mmHg): 182 ° C

Example 3

Preparation of 4-Hydroxy-2-oxo-pyrrolidine acetamide 1-ethyl-2- (4-hydroxy-pyrrolidin-2-one-1-yl) -acetate 1 gram of methanol at 10 ° C. 20 In milliliters, a solution containing ammonia (about 1.8 grams of ammonia) is added, sealed, and reacted at room temperature overnight.

The reaction solution is concentrated, suspended in a small amount of ethanol, and excess acetone is added to the mixture, which is then sufficiently stirred at room temperature to crystallize.

The resulting crystals were filtered and dried in vacuo to yield 0.76 g of 4-hydroxy-2-oxo-pyrrolidine acetamide as a white powder.

(1) MP: 162-164 degreeC

(2) TLC (GF 254) R / F = 0.32 (AN: H ₂ O = 4: 1)

(3) IR (KBr) cm ^-1 : 3,400, 3300, 3250, 1660

(4) NMR (DMSO) = 2.3 (2H)

3.4 (2H)

3.8 (2H)

4.3 (1H)

5.2 (1H)

7.1 and 7.3 (1 H)

(5) Elemental analysis: as C ₆ H ₁₀ N ₂ O ₃

Theoretic: C: 45.5% H: 6.28% N = 17.71%

Measured value: C: 45.8% H: 6.29% N = 17.88%

(6) Purity (%): 99.5%

Example 4

Preparation of 1-Ethyl-2- (4-hydroxy-pyrrolidin-on-1-yl) -acetate

5 grams of 4-brom-3-hydroxy-beta-butyrolactone are dissolved in 40 milliliters of dimethylformamide and 4.23 grams of glycine estylhydrocride are added and suspended. 6 milliliters of triethylamine is added at room temperature, the mixture is stirred at the same temperature for 4 hours, the resulting crystals are filtered off, and the filtrate is concentrated under reduced pressure.

5.4 g of gamma-aminoaceticethylester-beta-hydroxy-beta-butyrolactone as an oily residue is obtained.

It was used for the next reaction without further purification.

[TLC R / F = 0.66 (EA)]

Subsequently, 3 milliliters of triethylamine and 30 milliliters of dimethylformamide were added thereto, dissolved, and warmed to reflux for 20 hours. Then, the solvent was concentrated under reduced pressure. The distilled liquid at 186 DEG C) is collected to give 4.45 g of the target product as colorless title.

(1) TLC (GF254) R / F = 0.2

(2) IR (KBr) cm ^-1 : 3400, 1740, 1680, 1200

Example 5

Preparation of 1- (4-methoxyphenethyl) -4-hydroxypyrrolidin-2-one

Dissolve 2 grams of 4-brom-3-hydroxy-beta-butyrolactone in 20 milliliters of ethanol, add 1.78 ml of 4-methoxy phenethylamine at room temperature, and add 1.7 g of anhydrous potassium carbonate.

The mixture was heated to reflux for 14 hours, cooled to room temperature, and the insolubles were filtered off.

The filtrate was concentrated under reduced pressure, dried, and then dissolved in a small amount of methanol. The silica gel column was separated, and the mixture was mixed with 5: 1 mixture of methylene chloride and methanol, and fractionated by TLC. The target product was collected and concentrated. 1.84 g of phosphorus 1-N- (4-methoxyphenethyl) -4-hydroxy pyrrolidin-2-one is obtained.

(1) TLC (GF254) R / F = 0.3 (MC: MeOH = 3: 1)

(2) Elemental Analysis C ₁₃ H ₁₇ NO ₃ as

C H N

Theory 83.37% 9.15% 7.48%

Found 82.98% 8.79% 7.56%

Example 6

Preparation of N- (2-diisopropylaminoethyl) -4-hydroxy-2-oxo-1-pyrrolidine acetamide

Dissolve 1 gram of 4-brom-3-hydroxy-beta-butyrolactone in 8 milliliters of dimethformamide, add 1.22 grams of 1-aminoacetinoyl-2-N-diisopropyl-ethanediamine, and stir at room temperature. Then, 0.29 grams of sodium hydride is added thereto.

After heating and reflux cooling for 22 hours, the insolubles were filtered off through celite, the filtrate was concentrated under reduced pressure, and treated in the same manner as in Example 4 to obtain en- (2-diisopropylaminoethyl). 0.96 g of 4-hydroxy-2-oxo-1-pyrrolidine acetamide is obtained.

Elemental Analysis: As C ₁₄ H ₂₇ N ₃ O ₃

C H N

Theoretical 58.29% 9.53% 14.72%

Found 59.05% 9.68% 14.58%

Example 7

Preparation of 4-hydroxy-2-oxo-pyrrolidine acetamide

5 grams of 4-brom-3-hydroxy-beta-butyrolactone are dissolved in 40 milliliters of tetrahydrofuran, and 3.35 g of glycineamide hydrochloride is added at room temperature, followed by stirring for a while.

After adjusting to 10 ° C, 1.4 g of sodium hydride was added several times.

After stirring for 1 hour at room temperature and refluxed for 26 hours to terminate the reaction.

The insolubles are filtered off, the filtrate is concentrated and blown off. The residue is dissolved in a small amount of water, carefully placed in a column filled with Ambrite IR120H ^+, and passed through with water.

The mixture was collected by TLC, concentrated to dryness, dissolved in a small amount of methanol, poured into acetone excess, and stirred for a long time to obtain 3.9 grams of 4-hydroxy-2-oxo-pyrrolidine acetamide.

(1) MP 163-165 deg.

(2) TLC (GF 254) R / F = 0.32 (AN: H ₂ O = 4: 1)

(3) IR (KBr) cm ^-1 = 3400, 3300, 3250, 1660

Claims (4)

The halolactone compound of the following formula (II) and the alkylamine of the following formula (III) are reacted under an infectious group to prepare the compound of the following formula (IV), and the protecting group is removed to form a pyrrolidone derivative or pharmaceutical composition of the following formula (I). To prepare a phase effective non-toxic salt.

Wherein R is alkoxy, substituted or unsubstituted phenoxy, 1-2 substituted or unsubstituted benzyl or -COR ₂ (where R ₂ is alkoxyamine, diisopropyl, ethylenediamine, alkylamine) , R ₁ is hydrogen, tetrahydropyran, acetyl or benzoyl carbonyl, and X is chlorine, bromine or iodine. The process for producing the compound of formula (I) according to claim 1, wherein the compound of formula (II) is 4-brom-3-hydroxy-betabutyrolactone. The process according to claim 1, wherein sodium carbonate or potassium carbonate is used as treatment for the hydrogen halide liberated in the reaction. The method according to claim 1, wherein tetrahydrofuran, dimethylformamide, ethanol, water, or a mixed solvent thereof is used as the reaction solvent.