A novel process for the preparation of brivaracetam

Abstract

The application relates to the technical field of organic synthesis, in particular to a new method for preparing brivaracetam, which takes (S)-2-aminobutyramide as raw material, forms compound 1 through docking with (R)-2-propyl oxirane, further reacts with methacrylic acid, directly constructs a chiral five-membered ring through decarboxylation acylation, and obtains brivaracetam. Compared with the scheme disclosed in the prior art, the preparation process of the application is shortened, material transfer is reduced, the yield is higher, and the cost is lower.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, particularly the field of organic drug synthesis, and more specifically, to a new method for preparing buvastan. Background Technology

[0002] Brivaceran is an analogue of the antiepileptic drug levetiracetam. Its chemical name is (2S)-2-(4R)-2-oxo-4-propyl-pyrrolidine-1-yl-butyramide, CAS number: 357336-20-0, and its structure is shown below:

[0003]

[0004] Brivaceran has a high affinity and selectively binds to synaptic vesicle protein 2A (SV2A). SV2A is located on the presynaptic membrane and participates in regulating neurotransmitter release and vesicle circulation, thereby maintaining the normal function of synaptic vesicles. By binding to SV2A, brivaceran reduces the release of excitatory neurotransmitters and controls epileptic seizures by regulating the balance of excitatory and inhibitory neurotransmitters in the brain.

[0005] The typical preparation method in the current technology is the preparation method of buvaciran reported in the original research company's patent WO2001062726:

[0006]

[0007] In this method, glyoxylic acid is first cyclically bonded to pentanal to form a furanone compound, then (S)-2-aminobutyramide is added, and the double bond is reduced to obtain a racemic product. Finally, chiral resolution yields brivacertan. This method has two significant disadvantages: first, the glyoxylic acid used is unstable and easily deteriorates, making it difficult to control; second, it requires liquid-phase chiral resolution to obtain the target compound, which greatly hinders its industrial-scale production and promotion. Summary of the Invention

[0008] This invention addresses the problems of difficult chiral resolution and unstable raw materials in existing synthetic techniques by providing a novel method for preparing buvastan, comprising the following steps:

[0009] (1) (S)-2-aminobutyramide and (R)-2-propyl ethylene oxide were first docked to obtain compound 1;

[0010] (2) Compound 1 was docked with McFarland acid under the action of an azo reagent and trialkylphosphine to obtain compound 2;

[0011] (3) After decarboxylation, compound 2 was cyclically closed under sulfuric acid catalysis to give compound 3;

[0012] Its synthetic route is as follows:

[0013]

[0014] More preferably, in step (1), the molar ratio of (S)-2-aminobutyramide to (R)-2-propyl ethylene oxide is 1:1 to 1.3.

[0015] More preferably, in step (2), the molar ratio of compound 1, McFarland acid, azo reagent, and trialkylphosphine is 1:1 to 1.3:1 to 1.5:1 to 1.5.

[0016] More preferably, in step (2), the azo reagent is R1 is any alkyl group selected from C1 to C6.

[0017] More preferably, in step (2), the trialkylphosphine is P(R2)3, where R2 is any alkyl or aryl group selected from C1 to C6.

[0018] More preferably, in step (3), the decarboxylation reaction is carried out directly in the same reactor.

[0019] More preferably, in step (3), the molar ratio of compound 2 to concentrated sulfuric acid is 1:0.1 to 0.3.

[0020] This invention departs from traditional preparation methods. Using (S)-2-aminobutyramide as a raw material, it forms compound 1 by docking with (R)-2-propylethylene oxide. This compound is then further reacted with McLaurel acid, directly constructing a chiral five-membered ring via decarboxylation and acylation. This eliminates the need for chiral purification, simplifying the reaction process. Furthermore, compound 2 can react continuously to yield the target compound without separation, improving material conversion efficiency. The technical solution disclosed in this invention significantly improves product yield, greatly simplifies process steps, increases raw material utilization, reduces losses during preparation, and lowers production costs. Detailed Implementation

[0021] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that the following specific embodiments are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0022] Example 1

[0023] Synthesis of Compound 1

[0024]

[0025] Add (S)-2-aminobutyramide (50g, 0.490mol) and ethanol (250ml) to the reactor, mix and stir, then slowly add (R)-2-propylethylene oxide (42.16g, 0.490mol). After the addition is complete, maintain the reaction at 25-35℃ and stir for 4-5 hours.

[0026] After the reaction was completed, the ethanol was concentrated under reduced pressure to give compound 1 (89.3 g, 0.474 mol) 76.73 g BV-1, yield: 96.8%.

[0027] Example 2

[0028] Synthesis of Compound 2

[0029]

[0030] Compound 1 (50 g, 0.266 mol), McFarland acid (38.29 g, 0.266 mol), triphenylphosphine (76.86 g, 0.293 mol), and toluene (250 ml) were added to the reactor. The mixture was stirred until dissolved and cooled to 0 °C. DIAD (49.42 g, 0.293 mol) was added dropwise. After the addition was complete, the temperature was allowed to return to 20–25 °C and the mixture was stirred for 1–2 h.

[0031] After the reaction was completed, the toluene was concentrated and dried, and methanol (150 ml) was added and heated to 40-45 °C to dissolve it. Then the temperature was slowly lowered to 0-5 °C for recrystallization. The mixture was filtered and dried to give compound 3 (71.16 g, 0.226 mol), yield: 85.1%.

[0032] Example 3

[0033] Synthesis of Compound 3

[0034]

[0035] Add compound 2 (30g, 0.095mol) to the reactor, add acetonitrile (180ml), control the temperature at 25-35℃, add 1N hydrochloric acid (19ml) dropwise over about 40 minutes, and then keep the temperature at 30-35℃ for 1-2 hours.

[0036] After the reaction was completed, the pH was adjusted to about 8 with 10% sodium carbonate solution, the acetonitrile was concentrated under reduced pressure, and toluene (150 ml) and water (150 ml) were added for extraction and separation. The aqueous phase was extracted once with toluene (150 ml), the toluene layers were combined, and the mixture was washed once with water (150 ml).

[0037] The toluene layer was collected and refluxed for 4–5 h. After the reaction was complete, the toluene layer was concentrated to dryness under reduced pressure to obtain an intermediate product. Methanol (180 ml) and concentrated sulfuric acid (1.9 g, 0.019 mol) were added to the intermediate product, and the mixture was refluxed for 3–4 h. After the reaction was complete, the methanol was concentrated to dryness under reduced pressure, sodium carbonate was added to adjust the pH to approximately 8, and toluene (150 ml) was added for extraction. After separation to obtain the toluene phase, the mixture was refluxed for another 15–18 h. After the reaction was complete, the toluene layer was concentrated to dryness under reduced pressure to obtain compound 3 (18.23 g, 0.0859 mol), yield: 90.4%.

[0038] Example 5

[0039] Other conditions are the same as in Example 1, except for the different molar ratios of (S)-2-aminobutyramide and (R)-2-propylethylene oxide. The reaction conditions and yields of Examples 1 and 5 are detailed in Table 1.

[0040] Table 1. Different conditions and results for Examples 1 and 5

[0041] 1 1:1 96.8％ 5 1:1.3 95.1％

[0042] Examples 6-9

[0043] Other conditions are the same as in Example 2, except for the different molar ratios of compound 1, McFarland acid, azo reagent, and trialkylphosphine, the types of azo reagent and trialkylphosphine. The reaction conditions and yields of Examples 2 and 6-9 are detailed in Table 2.

[0044] Table 2. Results under different conditions in Examples 2 and 6-9

[0045] 2 1:1:1.1:1.1 DIAD Triphenylphosphine 85.1％ 6 1:1:1:1 DIAD Triphenylphosphine 84.6％ 7 1:1.3:1.5:1.5 DIAD Triphenylphosphine 83.5％ 8 1:1:1.1:1.1 DEAD Triphenylphosphine 81.8％ 9 1:1:1.1:1.1 DIAD Tributylphosphine 82.7％

[0046] Examples 10-11

[0047] Other conditions are the same as in Example 3, except for the different molar ratios of compound 2 and concentrated sulfuric acid. The reaction conditions and yields of Examples 3 and 10-11 are detailed in Table 3.

[0048] Table 3. Results under different conditions in Examples 3 and 10-11

[0049] 3 1:0.2 90.4％ 10 1:0.1 87.2％ 11 1:0.3 88.9％

[0050] It should be noted that the above content merely illustrates the technical concept of the present invention and should not be construed as limiting the scope of protection of the present invention. For those skilled in the art, various improvements and modifications can be made without departing from the principle of the present invention, and all such improvements and modifications fall within the scope of protection of the claims of the present invention.

Claims

1. A novel method for preparing buvastan, characterized in that, Includes the following steps: (1) (S)-2-aminobutyramide and (R)-2-propyl ethylene oxide were first docked to obtain compound 1; (2) Compound 1 was docked with McMurray acid in the presence of the azo reagent DIAD azodicarboxylic acid diisopropyl ester and triphenylphosphine Ph3P to obtain compound 2; (3) After decarboxylation, compound 2 undergoes cyclization under sulfuric acid catalysis to give compound 3; Its synthetic route is as follows: 。 2. The novel method for preparing buvastan according to claim 1, characterized in that, In step (1), the molar ratio of (S)-2-aminobutyramide and (R)-2-propyl ethylene oxide is 1:1~1.

3.

3. The novel method for preparing buvastan according to claim 1, characterized in that, In step (2), the molar ratio of compound 1, McFarland acid, azo reagent and triphenylphosphine is 1:1~1.3:1~1.5:1~1.

5.

4. The novel method for preparing buvastan according to claim 1, characterized in that, In step (3), the molar ratio of compound 2 to sulfuric acid is 1:0.1~0.3.

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