Synthesis method of (R)-4-propyl pyrrolidine-2-ketone

Abstract

The invention discloses a synthesis method of (R)-4-propyl pyrrolidine-2-ketone, which comprises the following steps: step S1, reacting (R)-3-(chloromethyl) hexanoyl chloride with ammonia gas, and carrying out post-treatment to obtain (R)-3-(chloromethyl) hexanamide; and S2, carrying out an intramolecular ring closing reaction on the (R)-3-(chloromethyl) hexanamide under an alkaline condition, and carrying out post-treatment to obtain the (R)-4-propyl pyrrolidine-2-ketone. The high-purity target product prepared by the method can be used as a standard substance for quality research of the briracetam; and the synthesis route is simple, the process is simple, the cost is low, and the operation is safe.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical industry, and specifically relates to a method for synthesizing (R)-4-propylpyrrolidone-2-one. Background Art

[0002] Brivaracetam is a third-generation anti-epileptic drug developed by UCB Ltd. of Belgium. It is suitable for the treatment of partial epileptic seizures. Its structural formula is as follows:

[0003]

[0004] Brivaracetam degrades to produce (R)-4-propylpyrrolidin-2-one and (S)-2-hydroxybutyramide. The reaction equation is as follows:

[0005]

[0006] If the relevant degradation impurities are not completely removed, the purity of the brivaracetam API will be affected. Therefore, it is necessary to control the generation of the impurity during the synthesis process, and to prepare the impurity as a standard for quality research on brivaracetam. In summary, it is particularly necessary to develop an efficient and low-cost synthesis method to synthesize the relevant degradation impurity (R)-4-propylpyrrolidin-2-one. Summary of the invention

[0007] The purpose of the present invention is to provide a method for synthesizing (R)-4-propylpyrrolidone-2-one in view of the current status of the prior art, so as to provide a standard product for the quality research of brivaracetam.

[0008] The present invention adopts the following technical solutions:

[0009] The synthesis of (R)-4-propylpyrrolidin-2-one comprises the following steps:

[0010]

[0011] Step S1: (R)-3-(chloromethyl)hexanoyl chloride reacts with ammonia gas and then undergoes post-treatment to obtain (R)-3-(chloromethyl)hexanamide;

[0012] Step S2: (R)-3-(Chloromethyl)hexanamide undergoes intramolecular ring-closure reaction under alkaline conditions and is post-treated to obtain (R)-4-propylpyrrolidin-2-one.

[0013] Furthermore, the reaction temperature in step S1 is -10°C to 30°C.

[0014] In a preferred embodiment, the reaction temperature in step S1 is 0°C to 10°C.

[0015] Furthermore, in step S1, the reaction solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether and methyl cyclopentyl ether.

[0016] In a preferred embodiment, the reaction solvent in step S1 is tetrahydrofuran.

[0017] Furthermore, the post-treatment step in step S1 is: adding n-heptane to precipitate solids, filtering to obtain a crude product, and separating through a column to obtain (R)-3-(chloromethyl)hexanamide.

[0018] Furthermore, during column separation, the eluent is n-heptane / ethyl acetate in a ratio of (1-5):1.

[0019] Furthermore, the reaction temperature in step S2 is -50°C to 50°C.

[0020] In a preferred embodiment, the reaction temperature in step S2 is -20°C to -10°C.

[0021] Furthermore, the alkali added in step S2 is one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, barium hydroxide and calcium hydroxide.

[0022] In a preferred embodiment, the alkali added in step S2 is sodium hydroxide.

[0023] Furthermore, the molar ratio of the base added in step S2 to (R)-3-(chloromethyl)hexanamide is (0.5-5):1.

[0024] In a preferred embodiment, the molar ratio of the base added in step S2 to (R)-3-(chloromethyl)hexanamide is 1.5:1.

[0025] Furthermore, the reaction solvent in step S2 is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide.

[0026] In a preferred embodiment, the reaction solvent in step S2 is N,N-dimethylformamide.

[0027] Furthermore, the post-treatment step in step S2 is: after the reaction is completed, methyl tert-butyl ether and water are added, and the liquids are separated and extracted; the organic phase is spin-dried to obtain a crude product, and the crude product is separated by column to obtain (R)-4-propylpyrrolidin-2-one.

[0028] Furthermore, during column separation, the eluent is n-heptane / ethyl acetate in a ratio of (1-5):1.

[0029] In summary, the beneficial effects of the present invention are:

[0030] The method prepares a high-purity target product, which can be used as a standard product for quality research of brivaracetam; and the method has a simple synthesis route, a simple process, low cost and safe operation. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is the HPLC spectrum of (R)-4-propylpyrrolidin-2-one obtained in Example 1 of the present invention. DETAILED DESCRIPTION

[0032] The present invention will now be further described in detail with reference to the embodiments. The application of the present invention is not limited to the following embodiments, and any modifications made to the present invention will fall within the protection scope of the present invention.

[0033] The present invention adopts the following technical solutions:

[0034] The synthesis of (R)-4-propylpyrrolidin-2-one comprises the following steps:

[0035]

[0036] Step S1: (R)-3-(chloromethyl)hexanoyl chloride reacts with ammonia gas and then undergoes post-treatment to obtain (R)-3-(chloromethyl)hexanamide;

[0037] (R)-3-(Chloromethyl)hexanoyl chloride reacts with ammonia at low temperature. Ammonia acts as a nucleophile to attack the carbonyl carbon atom in the acyl chloride, forming a transition state, and then the chloride ion acts as a leaving group to form the corresponding amide. This process is a nucleophilic substitution reaction, which is preferably carried out in a polar aprotic solvent such as tetrahydrofuran (THF) to promote the reaction.

[0038] Post-treatment step: After the reaction is completed, water is added to dissolve the unreacted raw materials or by-products in the aqueous phase, and the product in the organic phase is obtained by separation. Then, n-heptane is added to crystallize the product, which is convenient for filtration and collection. Finally, it is purified by silica gel column chromatography, using a mixed solvent of n-heptane and ethyl acetate for elution to obtain a pure target product.

[0039] The key to this step of the reaction is to control the reaction conditions: temperature, solvent, etc., to ensure the selectivity and yield of the reaction.

[0040] Step S2: (R)-3-(Chloromethyl)hexanamide undergoes intramolecular ring-closure reaction under alkaline conditions and is post-treated to obtain (R)-4-propylpyrrolidin-2-one.

[0041] Under low temperature conditions (-20 to -10°C), any one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide are added as reaction solvents, and an alkaline solution is added. The presence of an alkaline solution can promote the dehydration ring-closing reaction of the amide. The alkaline solution can deprotonate the nitrogen atom of the amide to form a very short-lived anionic intermediate. This anionic intermediate undergoes an intramolecular nucleophilic attack, in which the nitrogen atom attacks the carbon atom connected to the chlorine, resulting in cyclization and release of the chloride ion. This step forms a nitrogen-containing heterocyclic intermediate.

[0042] Post-treatment and purification:

[0043] After the reaction is completed, methyl tert-butyl ether (MTBE) and water are added for liquid separation to separate the organic product. The organic phase is washed with a large amount of water to remove residual salts and other impurities.

[0044] After removing the solvent by rotary evaporation, the obtained crude product can be further purified by column chromatography. Preferably, n-heptane and ethyl acetate in a ratio of 3:1 are used as eluent to obtain the target product (R)-4-propylpyrrolidin-2-one.

[0045] Reaction conditions: temperature, pH value, and choice of solvent are crucial to obtaining high yield and high purity products.

[0046] The above is the specific content of the present invention, which will be described in detail below in conjunction with specific embodiments of the present invention.

[0047] Example 1

[0048] Synthesis of (R)-4-propylpyrrolidin-2-one:

[0049] Step S1: Add 1.0 eq of (R)-3-(chloromethyl)hexanoyl chloride to a reaction bottle, add 5 vol of tetrahydrofuran, and react for 5 h at 0-10° C. with ammonia gas; after the reaction is completed, add 5 vol of water, separate the liquid to obtain an organic phase; add 8 vol of n-heptane to precipitate a solid, filter at room temperature to obtain a crude product, and separate the crude product through a column in a mixed solvent of n-heptane / ethyl acetate = 2:1 to obtain (R)-3-(chloromethyl)hexanamide.

[0050] Step S2: Add 4 vol of N,N-dimethylformamide to the reaction bottle, add 1.0 eq of (R)-3-(chloromethyl)hexanamide, control the internal temperature at -20 to -10°C, add 1.5 eq of potassium hydroxide and react for 6 hours. After the reaction is completed, add 5 vol of methyl tert-butyl ether and 5 vol of water, separate the liquids and extract, then wash the organic phase with water, repeat twice; spin dry the organic phase to obtain a crude product, and separate it through a column in a mixed solvent of n-heptane / ethyl acetate = 3:1 to obtain (R)-4-propylpyrrolidin-2-one (purity 99.7%).

[0051] The corresponding spectrogram of the product of Example 1 after testing is attached. Figure 1 , Figure 1 The purity of (R)-4-propylpyrrolidin-2-one reaches 99.7%, which meets the purity requirement of the raw material drug impurity reference substance, proving that this embodiment is feasible.

[0052] The NMR data of (R)-4-propylpyrrolidin-2-one are as follows: 1 HNMR (400MHz, CD3CN): δ6.51(s,1H),6.18(s,1H),4.39(dd,1H),3.45(dd,1H),3.04(dd,1H),2.45(dd,1H),2.33~2.29(m, 1H),2.02(dd,1H),1.88~1.81(m,1H),1.68~1.60(m,1H),1.43~1.38(m,2H),1.34~1.29(m,2H),0.90(t,3H),0.83(t,3H).

[0053] Example 2

[0054] Synthesis of (R)-4-propylpyrrolidin-2-one:

[0055] Step S1: Add 1.0 eq of (R)-3-(chloromethyl)hexanoyl chloride to a reaction bottle, add 5 vol of 2-methyltetrahydrofuran, and react for 5 hours at 0-10° C. with ammonia gas; after the reaction is completed, add 5 vol of water, separate the liquid to obtain an organic phase; add 8 vol of n-heptane to precipitate a solid, filter at room temperature to obtain a crude product, and separate the crude product through a column in a mixed solvent of n-heptane / ethyl acetate = 2:1 to obtain (R)-3-(chloromethyl)hexanamide.

[0056] Step S2: Add 4 vol of N,N-dimethylformamide to the reaction bottle, add 1.0 eq of (R)-3-(chloromethyl)hexanamide, control the internal temperature at -20 to -10°C, add 1.5 eq of potassium hydroxide and react for 6 hours. After the reaction is completed, add 5 vol of methyl tert-butyl ether and 5 vol of water, separate the liquids and extract, then wash the organic phase with water, repeat twice; spin dry the organic phase to obtain a crude product, and separate it through a column in a mixed solvent of n-heptane / ethyl acetate = 3:1 to obtain (R)-4-propylpyrrolidin-2-one.

[0057] Example 3

[0058] Synthesis of (R)-4-propylpyrrolidin-2-one:

[0059] Step S1: Add 1.0 eq of (R)-3-(chloromethyl)hexanoyl chloride to a reaction bottle, add 5 vol of tetrahydrofuran, and react for 5 h at 0-10° C. with ammonia gas; after the reaction is completed, add 5 vol of water, separate the liquid to obtain an organic phase; add 8 vol of n-heptane to precipitate a solid, filter at room temperature to obtain a crude product, and separate the crude product through a column in a mixed solvent of n-heptane / ethyl acetate = 2:1 to obtain (R)-3-(chloromethyl)hexanamide.

[0060] Step S2: Add 4 vol of N,N-dimethylacetamide to the reaction bottle, add 1.0 eq of (R)-3-(chloromethyl)hexanamide, control the internal temperature at -20 to -10°C, add 1.5 eq of potassium hydroxide and react for 6 hours. After the reaction is completed, add 5 vol of methyl tert-butyl ether and 5 vol of water, separate the liquids and extract, then wash the organic phase with water, repeat twice; spin dry the organic phase to obtain a crude product, and separate it through a column in a mixed solvent of n-heptane / ethyl acetate = 3:1 to obtain (R)-4-propylpyrrolidin-2-one.

[0061] Example 4

[0062] Synthesis of (R)-4-propylpyrrolidin-2-one:

[0063] Step S1: Add 1.0 eq of (R)-3-(chloromethyl)hexanoyl chloride to a reaction bottle, add 5 vol of tetrahydrofuran, and react for 5 h at 0-10° C. with ammonia gas; after the reaction is completed, add 5 vol of water, separate the liquid to obtain an organic phase; add 8 vol of n-heptane to precipitate a solid, filter at room temperature to obtain a crude product, and separate the crude product through a column in a mixed solvent of n-heptane / ethyl acetate = 2:1 to obtain (R)-3-(chloromethyl)hexanamide.

[0064] Step S2: Add 4 vol of N,N-dimethylformamide to the reaction bottle, add 1.0 eq of (R)-3-(chloromethyl)hexanamide, control the internal temperature at -20 to -10°C, add 1.5 eq of sodium hydroxide and react for 6 hours. After the reaction is completed, add 5 vol of methyl tert-butyl ether and 5 vol of water, separate the liquids and extract, then wash the organic phase with water, repeat twice; spin dry the organic phase to obtain a crude product, and separate it through a column in a mixed solvent of n-heptane / ethyl acetate = 3:1 to obtain (R)-4-propylpyrrolidin-2-one.

[0065] Example 5

[0066] Synthesis of (R)-4-propylpyrrolidin-2-one:

[0067] Step S1: Add 1.0 eq of (R)-3-(chloromethyl)hexanoyl chloride to a reaction bottle, add 5 vol of tetrahydrofuran, and react for 5 h at 0-10° C. with ammonia gas; after the reaction is completed, add 5 vol of water, separate the liquid to obtain an organic phase; add 8 vol of n-heptane to precipitate a solid, filter at room temperature to obtain a crude product, and separate the crude product through a column in a mixed solvent of n-heptane / ethyl acetate = 2:1 to obtain (R)-3-(chloromethyl)hexanamide.

[0068] Step S2: Add 4 vol of N,N-dimethylformamide to the reaction bottle, add 1.0 eq of (R)-3-(chloromethyl)hexanamide, control the internal temperature at -20 to -10°C, add 1.8 eq of potassium hydroxide and react for 6 hours. After the reaction is completed, add 5 vol of methyl tert-butyl ether and 5 vol of water, separate the liquids and extract, then wash the organic phase with water, repeat twice; spin dry the organic phase to obtain a crude product, and separate it through a column in a mixed solvent of n-heptane / ethyl acetate = 3:1 to obtain (R)-4-propylpyrrolidin-2-one.

[0069] The above description is only a preferred embodiment of the present invention, and does not limit the patent scope of the present invention. All equivalent changes made using the present invention are within the patent protection scope of the present invention.

Claims

1. A method for synthesizing (R)-4-propylpyrrolidin-2-one, characterized in that: The following steps are involved: Step S1: (R)-3-(chloromethyl)hexanoyl chloride reacts with ammonia gas, and then post-processes to obtain (R)-3-(chloromethyl)hexanamide; Step S2: (R)-3-(Chloromethyl)hexanamide undergoes an intramolecular ring-closing reaction under alkaline conditions, and is post-treated to obtain (R)-4-propylpyrrolidin-2-one.

2. The method for synthesizing (R)-4-propylpyrrolidin-2-one according to claim 1, wherein the reaction temperature in step S1 is -10°C to 30°C.

3. The method for synthesizing (R)-4-propylpyrrolidin-2-one according to claim 1, characterized in that: The reaction solvent in step S1 is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether and methyl cyclopentyl ether.

4. The method for synthesizing (R)-4-propylpyrrolidin-2-one according to claim 1, characterized in that: The post-treatment step in step S1 is: adding n-heptane to precipitate solids, filtering to obtain a crude product, and separating through a column to obtain (R)-3-(chloromethyl)hexanamide.

5. The method for synthesizing (R)-4-propylpyrrolidin-2-one according to claim 4, characterized in that: During column separation, the eluent is a mixed solvent of n-heptane and ethyl acetate in a ratio of (1-5):

1.

6. The method for synthesizing (R)-4-propylpyrrolidin-2-one according to claim 1, characterized in that: The reaction temperature in step S2 is -50°C to 50°C.

7. The method for synthesizing (R)-4-propylpyrrolidin-2-one according to claim 1, characterized in that: The alkali added in step S2 is one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, barium hydroxide and calcium hydroxide.

8. The method for synthesizing (R)-4-propylpyrrolidin-2-one according to claim 1, characterized in that: The reaction solvent in step S2 is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide.

9. The method for synthesizing (R)-4-propylpyrrolidin-2-one according to claim 1, characterized in that: The post-treatment step in step S2 is: after the reaction is completed, methyl tert-butyl ether and water are added, and the liquids are separated and extracted; the organic phase is spin-dried to obtain a crude product, and the crude product is separated by column to obtain (R)-4-propylpyrrolidin-2-one.

10. The method for synthesizing (R)-4-propylpyrrolidin-2-one according to claim 9, characterized in that: During column separation, the eluent is a mixed solvent of n-heptane and ethyl acetate in a ratio of (1-5):1.

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