A preparation method of chiral (R)-4-n-propyl-dihydrofuran-2(3H)-one

Abstract

The present invention belongs to the field of medical technology and relates to a preparation method of chiral (R) 4 n-propyl dihydrofuran 2 (3H) ketone. The method first utilizes the acylation reaction of chiral oxazolidinone and n-valeryl chloride to introduce an alkyl side chain, and then reacts with diethyl oxalate under the action of sodium methoxide to introduce a chiral center, and then reduces the carbonyl group and sodium borohydride to reduce the amide to obtain a chiral side chain, and finally completes lactonization under the catalytic action of trifluoroacetic acid to obtain the target product. Compared with current synthetic methods, this route has mild reaction conditions, does not involve the use of reagents such as ultra-low temperature reaction and dangerous Grignard reagents and lithium salts, and post-processing is simple, and chiral oxazolidinone is recyclable, has the advantages of green and high efficiency, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, in particular to a method for preparing chiral (R)-4-n-propyl-dihydrofuran-2(3H)-one. Background Art

[0002] (R)-4-n-propyl-dihydrofuran-2(3H)-one is a key intermediate in the synthesis of brivaracetam. Brivaracetam, a 4-N-propyl derivative of levetiracetam, is a novel antiepileptic drug with high affinity for the SV2A receptor, exhibiting 15-30 times greater selectivity than levetiracetam. Brivaracetam is rapidly and completely absorbed after oral administration, demonstrating high bioavailability. It has weak plasma protein binding and is primarily excreted through the kidneys, with a terminal half-life of approximately 9 hours. Clinical trials have shown that brivaracetam significantly reduces the frequency of partial-onset epileptic seizures and exhibits relatively few adverse reactions, most commonly drowsiness, dizziness, and fatigue, making it well tolerated by patients. Therefore, the launch of brivaracetam provides a new treatment option for epilepsy. Global sales of brivaracetam have exceeded US$3 billion to date, demonstrating its broad market potential. As a key intermediate in the synthesis of brivaracetam, the development of a new green synthesis method for (R)-4-n-propyl-dihydrofuran-2(3H)-one is not only conducive to reducing the cost of raw materials, but also helps to alleviate the economic burden of long-term medication for patients. It is one of the hot topics in the field of drug research and development.

[0003] To date, a variety of synthetic methods for (R)-4-n-propyl-dihydrofuran-2(3H)-one have been developed, which can be roughly divided into the following three categories: (1) chiral resolution using bioenzymatic methods; (2) chiral resolution using chemical methods; and (3) using chiral raw materials to prepare optically pure target compounds. For example, CN105837535A reports that methyl valerate is used as the starting material, and an intermediate is obtained through a substitution reaction with tert-butyl bromoacetate. The optically pure intermediate is then resolved through bioenzymatic resolution, and the target compound is finally obtained through reduction and cyclization. Although this method has a short synthetic route and uses an efficient bioenzymatic resolution method, the low reaction temperature in the first step results in high energy consumption, which is not conducive to industrial production. In addition, bioenzymatic chiral resolution often requires specific reaction conditions and requires a longer reaction time than chemical resolution methods, which increases industrial production costs.

[0004]

[0005] In addition, WO2016191435A reports a synthetic method for preparing a target compound using chiral raw materials. First, R-epichlorohydrin is reacted with diethyl malonate in the presence of sodium methoxide to produce a chiral fused-ring intermediate. This intermediate is then reacted with ethylmagnesium bromide to achieve position-selective ring opening, and hydrolytic decarboxylation under the presence of lithium chloride yields the target product. This method involves the use of a Grignard reagent, requires a low-temperature environment, is somewhat hazardous, and has a low material utilization rate. The total yield reported in the literature is 27.5%, further limiting its application in industrial scale-up.

[0006]

[0007] CN109134406A reports a relatively mild reaction route, which uses glyoxylic acid and n-valeraldehyde as raw materials. Under the synergistic effect of morpholine and concentrated hydrochloric acid, a [3+2] cycloaddition reaction is performed to generate a five-membered lactone ring intermediate. After reduction with sodium borohydride and Raney nickel, a racemic intermediate is obtained. Finally, the target product is obtained through sodium hydroxide hydrolysis ring opening, S-1-phenylethylamine chiral resolution, and concentrated sulfuric acid lactone cyclization reaction. Although this route reaction conditions are mild and utilizes the means of chemical resolution, the yield is low, and the other chiral byproduct is not effectively recovered, resulting in certain waste and significantly increasing industrial costs.

[0008]

[0009] Patent WO2020148787A optimizes the aforementioned reaction, achieving efficient preparation of the target product through the use of asymmetric reduction catalysis. However, the use of metal catalysts and chiral ligands results in high costs and creates certain environmental impacts, making it unsuitable for industrial production.

[0010]

[0011] CN105837535A utilizes chiral oxazolidinone to induce the formation of a chiral intermediate. First, an alkyl side chain is introduced through an acylation reaction. Subsequently, a chiral center is introduced by reacting with bromoacetonitrile under the catalytic effect of n-butyl lithium and the induction effect of the chiral oxazolidinone. After sodium borohydride reduction, cyano group hydrolysis, and lactone cyclization, the target compound is obtained. Although this reaction route can efficiently prepare the target product, the reaction process involves the use of n-butyl lithium, the reaction temperature is low, and inert gas protection is required. The final ring-closure reaction involves an acid-base neutralization reaction, which produces a large amount of wastewater and has further room for improvement.

[0012]

[0013] In summary, existing synthesis methods all have certain limitations, such as ultra-low temperature reaction environment, the use of hazardous chemicals such as Grignard reagents and butyl lithium reagents, and the waste of materials with another configuration caused by splitting. These problems make the development of new (R)-4-n-propyl-dihydrofuran-2(3H)-one synthesis process imminent. Summary of the Invention

[0014] The present invention aims to provide a new process for synthesizing (R)-4-n-propyl-dihydrofuran-2(3H)-one, which does not require an ultra-low temperature environment and inert gas protection, has mild reaction conditions, simple post-processing, and achieves efficient and green preparation of the target compound.

[0015] To achieve the purpose of the present invention, the present invention first introduces an alkyl side chain by an acylation reaction of a chiral oxazolidinone with n-valeryl chloride, then reacts with diethyl oxalate under the action of sodium methoxide to introduce a chiral center, then reduces the carbonyl group with Huang Minglong and reduces the amide with sodium borohydride to obtain a chiral side chain, and finally completes a lactonization reaction under the catalytic action of an acid to obtain the target product.

[0016] The specific technical solutions are as follows:

[0017]

[0018] (1) Synthesis of Intermediate II: Chiral oxazolidinone I was added to a flask, followed by solvent and base to dissolve it. N-valeryl chloride was then added dropwise to the system for reaction. After the reaction was completed, the reaction was quenched, and the organic phase was collected and dried to obtain crude product II, which was directly used in the next reaction.

[0019] (2) Synthesis of Intermediate III: Add the crude product II obtained in the previous step to a flask, add a solvent and a base to dissolve it, and then add diethyl oxalate dropwise to the system for reaction. After the reaction is completed, quench the reaction, collect the organic phase, and dry it to obtain the crude product III, which is directly used in the next reaction.

[0020] (3) Synthesis of Intermediate IV: The crude product III obtained in the previous step was added to a flask, and hydrazine hydrate solution and sodium hydroxide solution were added. The reaction system was heated to react. After the reaction was completed, the reaction was quenched, the organic phase was collected, and the crude product was obtained by drying. Subsequently, a mixed solvent of tetrahydrofuran and water (1-20V, 1:1-10:1) was added, and sodium borohydride was added in batches to react. After the reaction was completed, the organic phase was extracted, collected, filtered, and dried to obtain the crude product IV, which was directly used in the next reaction.

[0021] (4) Synthesis of Final Product V: The crude product IV obtained in the previous step was added to a flask, and a solvent and an acid were added for reaction. After the reaction, the crude product V was obtained by extraction, and the organic phase was collected, filtered, and dried to obtain the crude product V. The purified compound V was obtained after extraction, concentration, and drying.

[0022] The solvent involved in the reaction is dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, n-hexane, dioxane or water.

[0023] The base in step (1) includes triethylamine, N,N-diisopropylethylamine, sodium methoxide, sodium ethoxide or sodium hydride; the base is preferably triethylamine, and the solvent is preferably chloroform;

[0024] In the reaction of step (2), the base is preferably sodium methoxide, and the solvent is preferably methanol;

[0025] The acid in step (4) is hydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid; the acid is preferably trifluoroacetic acid, and the solvent is preferably dichloromethane.

[0026] Advantages of the present invention: A new method for synthesizing (R)-4-n-propyl-dihydrofuran-2(3H)-one has been developed. Compared with the published synthetic routes, this route has mild reaction conditions, does not involve ultra-low temperature reaction and the use of hazardous reagents such as Grignard reagents and lithium salts, is simple to post-process, and the chiral oxazolidinone can be recovered with a yield of more than 95%. It has the advantages of being green and efficient and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is the H NMR spectrum of (R)-4-n-propyl-dihydrofuran-2(3H)-one prepared in the present invention;

[0028] Figure 2 This is the nuclear magnetic carbon spectrum of (R)-4-n-propyl-dihydrofuran-2(3H)-one prepared in the present invention. DETAILED DESCRIPTION

[0029] The present invention will be described in more detail below through examples, but the scope of protection of the present invention is not limited thereto.

[0030] Example 1

[0031]

[0032] (1) Synthesis of intermediate II-1: Chiral oxazolidinone I-1 (3.55 g, 20 mmol) was added to a round-bottom flask, followed by addition of chloroform (35 mL) and triethylamine (5.55 mL, 40 mmol) to dissolve it. The reaction system was cooled to 0°C and kept warm for 10-15 minutes. N-valeryl chloride (2.66 g, 22 mmol) was added dropwise to the system. After the addition was complete, the temperature was raised to 35°C and the reaction was continued for 2 hours. After TLC plate monitoring showed that the reaction raw material I-1 was completely consumed, 35 mL of water was added to the system to quench the reaction. The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was concentrated and dried to obtain crude II-1 (5.18 g) with a yield of 99%. 1 H NMR(400MHz, CDCl3), δ7.34(t,J=7.3Hz,2H),7.30(d,J=7.2Hz,1H),7.21(d,J =7.2Hz,2H),4.71(ddd,J=10.7,7.2,3.7Hz,1H),4.27-4.09(m,2H),3.31(dd,J =13.5,3.2Hz,1H),3.05-2.85(m,2H),2.77(dd,J=13.4,9.7Hz,1H),1.68(ddd, J=16.8,10.9,6.2Hz,2H),1.42(dt,J=15.1,7.8Hz,2H),0.96(t,J=7.3Hz,3H).

[0033]

[0034] (2) Synthesis of intermediate III-1: The crude product II-1 (5.23 g, 20 mmol) obtained in the previous step was added to a round-bottom flask, followed by methanol (25 mL) and sodium methoxide (1.62 g, 30 mmol). The reaction system was cooled to 0°C and kept warm for 10-15 minutes. Diethyl oxalate (3.22 g, 22 mmol) was added dropwise to the system. After the temperature was raised to 35°C, the reaction was continued for 16 hours. After TLC plate monitoring, the reaction material II-1 was completely consumed, 25 mL of water was added to the system to quench the reaction. The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was concentrated and dried to obtain the crude product III-1 (6.87 g). The yield was 95%. 1H NMR(400MHz, CDCl3), δ7.34(t,J=7.2Hz,2H),7.31-7.26(m,1H),7.23(d,J=7.1Hz,2H),4.68(qd,J=6.9 ,3.5Hz,1H),4.33-4.20(m,2H),4.19-4.08(m,1H),4.07-3.99(m,2H),3.33(dd,J=13.5,3.0Hz,1H),2.8 3(dd,J=13.4,9.6Hz,1H),2.73(dd,J=16.8,7.8Hz,1H),2.61(dd,J=16.8,5.5Hz,1H),1.81(ddd,J=20. 2,11.7,7.1Hz,1H),1.69-1.50(m,1H),1.49-1.30(m,2H),1.09(t,J=7.4Hz,3H),0.98(t,J=7.3Hz,3H).

[0035]

[0036] (3) Synthesis of intermediate IV-1: The crude product III-1 (7.23 g, 20 mmol) obtained in the previous step was added to a round-bottom flask, followed by the addition of hydrazine hydrate solution (1.1 g, 22 mol) and 1N sodium hydroxide solution (35 mL). The reaction system was heated to 150°C for 3 hours. After the reaction raw material III-1 was completely consumed as monitored by TLC, an equal volume of ethyl acetate was added to the system. The organic phase was collected and dried over anhydrous magnesium sulfate. The crude product after concentration and drying was added to a round-bottom flask. A mixed solvent of tetrahydrofuran and water (40 mL, 3:1) was then added. The system was cooled to 0°C, and sodium borohydride (1.51 g, 40 mmol) was added in batches. The reaction temperature was then raised to 35°C and kept for 6 hours. After the reaction was complete as monitored by TLC, a saturated ammonium chloride solution (40 mL) was added dropwise to the reaction system. The aqueous phase was extracted with methyl tert-butyl ether (40 mL), and the organic phases were collected and combined. To the concentrate was added methyl tert-butyl ether / n-hexane (10 mL, 3:1), cooled to 0°C, filtered, and filter cake I (3.5 g) was recovered as a white powder with a recovery rate of 98%. The filtrate was distilled under reduced pressure, concentrated and dried to obtain crude product IV-1 as a colorless oil with a yield of 90%. 1H NMR(400MHz, CDCl3), δ3.9(t,J=7.1Hz,2H),3.72(dd,J=10.7,4.3Hz,1H),3.55(dd,J=10.7,4.3Hz,1H),2.51(d ,J=5.9Hz,2H),2.02(s,1H),1.96-1.88(m,1H),1.52-1.33(m,4H),0.99(t,J=7.1Hz,3H),0.95(t,J=7.5Hz,3H).

[0037]

[0038] (4) Synthesis of final product V-1: The crude product IV-1 (5.23 g, 30 mmol) obtained in the previous step was added to a round-bottom flask, followed by addition of dichloromethane (25 mL) and trifluoroacetic acid (10.3 g, 90 mmol), and the reaction system was placed at 35°C for 6 hours. After TLC monitoring showed that the reaction of the raw materials was complete, an equal volume of water was added to the system, the organic phases were collected and combined, and dried over anhydrous magnesium sulfate. The organic phases were concentrated and dried to obtain the crude product V-1. V-1 was extracted with an equal volume of water and n-hexane (30 mL), the organic phases were collected and combined, and dried over anhydrous magnesium sulfate. The organic phases were concentrated and dried to obtain the refined V-1 (3.5 g), which was a colorless oil with a yield of 91%. 1 H NMR (400MHz, DMSO-d6) δ4.38(t,J=7.8Hz,1H),3.89(t,J=7.7Hz,1H),2.59(dd,J=16.3,8.2Hz,1H),2.49(d,J=7 .7Hz,1H),2.20(dd,J=16.1,7.1Hz,1H),1.47-1.35(m,2H),1.29(dd,J=14.9,8.1Hz,2H),0.90(t,J=7.1Hz,3H). 13 CNMR(100MHz,DMSO-d6)δ177.67,73.27,35.30,34.88,34.37,20.47,14.35.

[0039] Comparative Example 1

[0040] (1) Add chiral oxazolidinone I-1 (3.55 g) to a round-bottom flask, then add anhydrous tetrahydrofuran (35 mL), cool the reaction system to -78 ° C, keep warm for 10-15 minutes, add n-butyl lithium (1.0 eq) dropwise to the system, then add acid chloride (2.66 g, 22 mmol) dropwise, raise the temperature to 35 ° C after the addition is complete, and continue the reaction for 3 hours. After TLC plate monitoring, the reaction material I is completely consumed, add 35 mL of water to the system to quench the reaction, collect the organic phase, and dry it with anhydrous sodium sulfate. After the organic phase is concentrated and dried, the crude product II-1 is obtained with a yield of 98%. This comparative example involves the use of hazardous chemical n-butyl lithium, and requires ultra-low temperature reaction to proceed normally.

[0041] (2) Intermediate II-1 (1 g) was added to a round-bottom flask, followed by anhydrous tetrahydrofuran (10 mL), and the reaction system was cooled to -78 ° C. and kept warm for 10-15 minutes. Under nitrogen protection, lithium bis(trimethylsilyl)amide was added. After the addition was complete, the reaction was continued for 30 minutes. Subsequently, bromoacetonitrile (3 eq) was added dropwise to the system and kept warm for 3 hours. After the reaction was completed, 25 mL of saturated ammonium chloride was added to the system to quench the reaction, extracted with dichloromethane, and the organic phase was collected and combined and dried over anhydrous sodium sulfate. The organic phase was concentrated and dried to obtain crude III-1 with a yield of 81%. Although this comparative example can effectively introduce a chiral center, it involves the use of lithium bis(trimethylsilyl)amide, which requires inert gas protection and ultra-low temperature environment. Bromoacetonitrile is used in excess and has no obvious advantage in yield, which does not conform to the characteristics of green chemistry and atom economy.

[0042] Comparative Example 2

[0043] Referring to the last step of patent CN105837535A, (R)-3-(hydroxymethyl)hexanenitrile (0.9g) was taken, tetrahydrofuran (2mL) and 4N sodium hydroxide (8mL) were added, and the reaction was heated to 75°C for 5 hours. TLC monitored the disappearance of the raw material, stopped heating, the reaction was cooled to room temperature, the organic phase was extracted with methyl tert-butyl ether (5mL*2), and the organic phase was discarded. Concentrated hydrochloric acid (15mL) was added to the aqueous phase and heated to 40°C for 1 hour. The reaction was stopped, cooled to room temperature, and methyl tert-butyl ether was added for extraction (5mL*2). The organic phases were combined, washed once, dried with 2g of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 0.85g of the target product with a yield of 93.4%. Compared with the patent of the present invention, the yield of this comparative example is slightly improved, but the reaction process involves the use of a large amount of acid and alkali, which will produce a lot of wastewater and put great pressure on the environment.

[0044] Application Example 1

[0045] Brivaracetam was prepared using the key intermediate V-1 prepared in Example 1 of the present invention according to the following synthetic route:

[0046]

[0047] (1) Synthesis of Compound VI-1: (R)-4-n-propyl-dihydrofuran-2(3H)-one (3.85 g), hydrobromic acid (2.92 g), and acetic acid (2.71 g) were added to a round-bottom flask and reacted at 0°C for 6 hours. The excess solvent was removed by distillation under reduced pressure to obtain the intermediate of Formula VI-1.

[0048] (2) Synthesis of Compound VII-1: The chiral acid (4.18 g), hydrochloric acid (3.64 g), and ethanol (20 mL) of Formula VI-1 were added to a round-bottom flask, heated at 80°C for 6 hours, and then the excess solvent was removed by distillation under reduced pressure to obtain the intermediate of Formula VII-1.

[0049] (3) Synthesis of compound VIII-1: Chiral ethyl ester (4.75 g), (2S)-2-aminobutyramide (2.25 g) and tetrabutylammonium iodide (0.74 g) of formula VII-1 were added to a round-bottom flask. After reacting at 80°C for 12 hours, the compound with the structure shown in VIII-1 was obtained by extraction. This compound is the brivaracetam raw material.

Claims

1. A method for preparing chiral (R)-4-n-propyl-dihydrofuran-2(3H)-one, characterized in that: This is achieved by: (1) Synthesis of Intermediate II: Chiral oxazolidinone I was added to a flask, followed by addition of a solvent and a base to dissolve it, and n-valeryl chloride was added dropwise to the system for reaction; after the reaction was completed, the reaction was quenched, the organic phase was collected, and the crude product II was obtained by drying, which was directly used in the next reaction; (2) Synthesis of Intermediate III: The crude product II obtained in the previous step was added to a flask, and a solvent and a base were added to dissolve it. Then, diethyl oxalate was added dropwise to the system for reaction. After the reaction was completed, the reaction was quenched, and the organic phase was collected and dried to obtain the crude product III, which was directly used in the next reaction. (3) Synthesis of intermediate IV: The crude product III obtained in the previous step was added to a flask, and hydrazine hydrate solution and sodium hydroxide solution were added, and the reaction system was heated to react; after the reaction was completed, the reaction was quenched, the organic phase was collected, and the crude product was obtained by drying; then a mixed solvent of tetrahydrofuran and water was added, and sodium borohydride was added in batches to react; after the reaction was completed, the organic phase was extracted, collected, filtered, and dried to obtain the crude product IV, which was directly used in the next reaction; (4) Synthesis of final product V: The crude product IV obtained in the previous step was added to a flask, and a solvent and an acid were added for reaction; after the reaction was completed, the organic phase was extracted, collected, filtered, and dried to obtain the crude product V; after extraction, concentration, and drying, the refined compound V was obtained.

2. The method for preparing chiral (R)-4-n-propyl-dihydrofuran-2(3H)-one according to claim 1, wherein: The solvent involved in the reaction is dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, n-hexane, dioxane or water.

3. The method for preparing chiral (R)-4-n-propyl-dihydrofuran-2(3H)-one according to claim 1, wherein: In the reaction of step (1), the base is selected from triethylamine, N,N-diisopropylethylamine, sodium methoxide, sodium ethoxide or sodium hydride; In step (2), the base is selected from sodium methoxide; The acid in the reaction of step (4) is selected from hydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid.

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