A method for preparing a boceprevir intermediate

Abstract

The key intermediate of brivaracetam was synthesized by the ruthenium-catalyzed asymmetric hydrogenation of unsaturated cyclobutanone esters, which features high yield, high ee value, mild reaction conditions, low catalyst dosage, and can be scaled up to gram scale, showing great potential application value.

Description

Technical Field

[0001] The present invention relates to the technical fields of medicine and organic chemical synthesis, and particularly relates to a preparation method of a brivaracetam intermediate. Background Art

[0002] Brivaracetam, with the chemical name of (S)-2-((R)-2-oxo-4-propylpyrrolidin-1-yl)butyramide, has the following structure:

[0003]

[0004] Brivaracetam was developed by UCB and was approved for marketing by the European Medicines Agency (EMA) on January 14, 2016, and by the US Food and Drug Administration (FDA) on February 18, 2016. This drug is used for the adjunctive treatment of partial seizures in adults and adolescents aged 16 and above, with or without secondary generalized seizures, and was approved by the US Food and Drug Administration (FDA) in 2021 for patients as young as 1 month old for the treatment of partial-onset epilepsy. It is also the only type-IV preparation approved by the FDA in the past 7 years for the treatment of partial-onset epilepsy in pediatric patients aged 1 month and above.

[0005] Brivaracetam has a high affinity and can selectively bind to synaptic vesicle protein 2A (SV2A), which is the action site of the AED levetiracetam. SV2A is located on the presynaptic membrane and is involved in mediating the release of neurotransmitters and vesicle recycling, thereby maintaining the normal function of synaptic vesicles. The binding of AED to SV2A can reduce the release of excitatory neurotransmitters and control epileptic seizures by regulating the balance of excitatory and inhibitory neurotransmitters in the brain.

[0006] (R)-4-n-propyldihydrofuran-2-one is a key intermediate in the synthesis of brivaracetam. Arnaud Schule (Org. Process Res. Dev. 2016, 20, 1566 - 1575) reported the following reaction route:

[0007]

[0008] Patent CN 108503610 A published the following reaction route:

[0009]

[0010] Patent CN 108530402 A published the following reaction route:

[0011]

[0012] Patent CN 109134406 A discloses the following reaction route:

[0013]

[0014] Sinai-Zingde, G., (J. Org. Chem. 1987, 52, 719.) reported the following reaction route:

[0015]

[0016] In the above synthesis routes, both Route 1 and Route 4 involve chiral resolution to obtain products with a single configuration. These methods have long routes, low yields, and cumbersome operations; Routes 2, 3, and 5 use chiral substrates as starting materials to directly construct products with chiral centers. Although these methods can avoid problems such as low yields caused by chiral resolution, the chiral substrate raw materials are expensive, increasing the production cost. Summary of the Invention

[0017] In order to overcome the shortcomings and deficiencies of the prior art, the purpose of the present invention is to provide a preparation method for a boceprevir intermediate. This method has mild reaction conditions, high yield, good enantioselectivity, simple operation, does not require chiral resolution, does not require chiral starting materials, and has low cost.

[0018] The technical solution adopted by the present invention to solve the above technical problems is: A preparation method for a boceprevir intermediate, using 4-n-propylfuran-2(5H)-one as a substrate, reacting under the action of hydrogen and a chiral catalyst, including the following steps:

[0019] 1) Prepare an unsaturated cyclobutane lactone compound shown in formula (Ⅲ):

[0020] 2) The compound of formula (Ⅲ) undergoes asymmetric hydrogenation in the presence of a chiral catalyst to obtain an optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one shown in formula (Ⅰ):

[0021]

[0022] The chiral catalyst used in the asymmetric hydrogenation is a complex of ruthenium acetate and a bisphosphine ligand.

[0023] The diphosphine ligand of the chiral catalyst is (S)-(-)-2,2'-bis(di-3,5-dimethylphenyl)phosphino-1,1'-binaphthalene, (S)-(+)-2,2'-bis[bis(3,5-di-tert-butylphenyl)phosphino]-6,6'-dimethoxy-1,1'-biphenyl, (S)-(+)-2,2'-bis[di-(4-methylphenyl)phosphino]-1,1'-binaphthalene, (S)-(6,6′-dimethoxybiphenyl-2,2'-diyl)bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphine], (S)-5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole, (S)-(-)-2,2'-bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-1,1'-binaphthalene, preferably (S)-(+)-2,2'-bis[bis(3,5-di-tert-butylphenyl)phosphino]-6,6'-dimethoxy-1,1'-biphenyl.

[0024] The temperature of the asymmetric hydrogenation reaction is 25°C to 60°C, preferably 25°C.

[0025] The pressure of the asymmetric hydrogenation reaction is 300 kPa to 1600 kPa, preferably 500 kPa.

[0026] The solvent for the asymmetric hydrogenation reaction is trifluoroethanol, methanol, ethanol, isopropanol, tert-butanol, cyclohexanol, benzyl alcohol, ethyl acetate, tetrahydrofuran, ethylbenzene, toluene, mesitylene, trifluorotoluene, benzene, anisole, preferably trifluoroethanol.

[0027] The method for preparing the compound of formula (III) in step (1) is that the compound shown in formula (II) is used to prepare 4-n-propylfuran-2(5H)-one shown in formula (III) in the presence of a reducing agent.

[0028] The reducing agent is sodium borohydride.

[0029] The molar ratio of the compound of formula (II) to the reducing agent is 1:1.

[0030] The reaction solvent for the reduction of the compound of formula (II) is toluene, and the reaction temperature is 25°C.

[0031] The preparation method of the compound of formula (II) includes the following steps:

[0032] Commercially available n-valeraldehyde and glyoxylic acid hydrate are provided as substrates,

[0033] N-valeraldehyde and glyoxylic acid hydrate are reacted in a solvent containing a basic reagent to form the compound shown in formula (II).

[0034] Among them,

[0035] The basic reagent used in the reaction is morpholine.

[0036] In step B), the molar ratio of n-valeraldehyde to glyoxylic acid hydrate is 1:1.3, and the molar ratio of n-valeraldehyde to morpholine is 1:1.1.

[0037] The solvent for the reaction is n-hexane, and the reaction temperature is 48 °C.

[0038] In the present invention, prochiral 4-n-propylfuran-2(5H)-one is used to obtain the target product of the present invention by asymmetric hydrogenation in the presence of a chiral catalyst. The overall reaction process is as follows:

[0039] Step (1): React n-valeraldehyde with glyoxylic acid hydrate in the presence of a basic reagent to form a compound represented by formula (II).

[0040]

[0041] Step (2): Prepare a compound represented by formula (III) from the compound represented by formula (II) obtained in step (1) in the presence of a reducing agent.

[0042]

[0043] Step (3): Perform an asymmetric hydrogenation reaction on the compound represented by formula (III) obtained in step (2) in the presence of a chiral catalyst to prepare optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one.

[0044] The entire synthetic route is as follows:

[0045]

[0046] The method of the present invention is suitable for preparing (R)-4-n-propyl-dihydrofuran-2(3H)-one. The term (R) used herein refers to a compound having an enantiomeric composition of more than 95%.

[0047] Compared with the prior art, the beneficial technical effects brought by the technical solution adopted in the present invention are as follows:

[0048] The method of the present invention solves the problems of long synthetic route, low yield and high cost in the existing synthetic route of boceprevir intermediate by catalytically chiral reducing 4-n-propylfuran-2(5H)-one to (R)-4-n-propyl-dihydrofuran-2(3H)-one with a chiral catalyst. This method has mild reaction conditions, high reaction efficiency, simple operation, good enantioselectivity, improves the efficiency of preparing (R)-4-n-propyl-dihydrofuran-2(3H)-one and reduces the production cost, and has industrial value. Description of the Drawings

[0049] Figure 1 It is the 1H NMR spectrum of the product obtained in Example 1

[0050] Figure 2 It is the 13C NMR spectrum of the product obtained in Example 1

[0051] Figure 3 It is the 1H NMR spectrum of the product obtained in Example 2

[0052] Figure 4 It is the 1H NMR spectrum of the product obtained in Example 2

[0053] Figure 5 It is the 1H NMR spectrum of the product obtained in Example 3

[0054] Figure 6 It is the 1H NMR spectrum of the product obtained in Example 3

[0055] Figure 7 It is the gas chromatogram of the product obtained in Example 3

[0056] Figure 8 It is the gas chromatogram integration result diagram of the product obtained in Example 3 Embodiment

[0057] The present invention will be further described in detail below with reference to specific embodiments, but the embodiments of the present invention are not limited thereto.

[0058] Example

[0059] Preparation of 5-hydroxy-4-n-propyl-2-furanone:

[0060] Morpholine (110 mmol, 9.6800 g, 1.1 eq.) was dissolved in n-hexane (30 mL), and 50% aqueous glyoxylic acid solution (130 mmol, 19.2504 g, 1.3 eq.) was slowly added dropwise at 0 °C. After reacting at 30 °C for 2 hours, n-valeraldehyde (100 mmol, 8.7888 g) was added dropwise, and the reaction was carried out at 48 °C for 20 hours. TLC was used to monitor until the reaction was complete. The temperature was lowered to room temperature, and concentrated hydrochloric acid (15 mL) was slowly added dropwise to quench the reaction, and stirring was continued for 2 hours. The aqueous phase was separated, washed first with n-hexane (30 mL × 3), then extracted with methyl tert-butyl ether (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. 10.7225 g of the target compound was obtained through a silica gel column, which was a colorless transparent liquid with a yield of 75%.

[0061] 1 H NMR (400 MHz, CDCl3) δ 6.04 (s, 1H), 5.84 (s, 1H), 2.48–2.32 (t, 2H), 1.72–1.56 (m, 2H), 1.01 (t, J = 5.3 Hz, 3H). 1313C NMR (101 MHz, CDCl3) δ 73.58, 35.61, 35.33, 34.64, 20.71, 14.08.

[0062] Based on the above data, the structure of the obtained product is as follows:

[0063]

[0064] Example 2

[0065] Preparation of 4-n-propylfuran-2(5H)-one:

[0066] Under nitrogen protection, 5-hydroxy-4-n-propyl-2-furanone (11.0803 g, 78 mmol) was dissolved in toluene (86 mL). An aqueous solution of sodium borohydride (78 mmol, 3.0420 g, 1.0 eq.) was slowly added dropwise at 0 °C. After reacting at room temperature for 4 hours, acetic acid was added dropwise to quench the reaction. The mixture was extracted with toluene (30 mL × 3), washed with 10% aqueous sodium bicarbonate solution (10 mL × 3), saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and 4.2518 g of the target compound was obtained through a silica gel column. It was a colorless transparent liquid with a yield of 43%.

[0067] 1 1H NMR (400 MHz, CDCl3) δ 5.84 (s, 1H), 4.74 (s, 2H), 2.39 (t, J = 6.0 Hz, 2H), 1.67–1.59 (m, 2H), 1.00 (t, J = 9.0 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 73.58, 35.61, 35.33, 34.64, 20.71, 14.08.

[0068] Based on the above data, the structure of the obtained product is as follows:

[0069]

[0070] Example 3

[0071] Preparation of (R)-4-n-propyl-dihydrofuran-2(3H)-one (milligram-scale reaction):

[0072] Under a nitrogen atmosphere, a chiral catalyst (0.006 mmol, 6.2 mg) was placed in a reaction kettle, trifluoroethanol (0.25 mL) was added, and the mixture was stirred at room temperature for 20 minutes. Then, 4-propylfuran-2(5H)-one (1 mmol, 126.2 mg) dissolved in trifluoroethanol (0.5 mL) was slowly added. Nitrogen was replaced with hydrogen (500 kPa × 7 times), and the reaction was carried out at 500 kPa and 25 °C for 20 hours. After the reaction was monitored by GC-MS to be complete, it was filtered through diatomaceous earth and silica gel, washed with dichloromethane, and the filtrate was concentrated under reduced pressure and distilled to obtain 96.2 mg of the target compound, which was a colorless transparent liquid. The GC yield was 99%, the isolation yield was 75%, and the ee value was 96%.

[0073] 1 1H NMR (400 MHz, CDCl3) δ 4.42 (dd, J = 8.6, 7.7 Hz, 1H), 3.93 (dd, J = 8.7, 7.4 Hz, 1H), 2.67–2.51 (m, 2H), 2.19 (dd, J = 16.5, 7.5 Hz, 1H), 1.49–1.42 (m, 2H), 1.40–1.30 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 73.58, 35.61, 35.33, 34.64, 20.71, 14.08. [α] D 17 +4.08° (c = 0.02646 g / mL, CH2Cl2).

[0074] Based on the above data, the structure of the obtained product is as follows:

[0075]

[0076] Example 4

[0077] (R)-4-Propyl-dihydrofuran-2(3H)-one Preparation (Gram-scale Reaction):

[0078] Under a nitrogen atmosphere, a chiral catalyst (0.016 mmol, 16.5 mg) was placed in a reaction kettle, trifluoroethanol (0.67 mL) was added, and the mixture was stirred at room temperature for 20 minutes. Then, 4-propylfuran-2(5H)-one (8.0 mmol, 1.000 g) dissolved in trifluoroethanol (4.0 mL) was slowly added. Nitrogen was replaced with hydrogen (500 kPa × 7 times), and the reaction was carried out at 1000 kPa and 25 °C for 20 hours. After the reaction was monitored by GC-MS to be complete, it was filtered through diatomaceous earth and silica gel, washed with dichloromethane, and the filtrate was concentrated under reduced pressure and distilled to obtain 0.7867 g of the target compound, which was a colorless transparent liquid. The GC yield was 99%, the isolation yield was 78%, and the ee value was 96%.

[0079] The above chiral catalyst and solvents are all commercially available. Among them, trifluoroethanol is used after impurity removal by the freeze-thaw method, and the remaining solvents are used after standard treatment.

Claims

1. A method for preparing a boceprevir intermediate: Using 4-n-propyl-2(5H)-furanone as a substrate, reacting under the action of a chiral catalyst, specifically including: 1) Preparing an unsaturated cyclobutane lactone compound shown in formula (Ⅲ): 2) The compound of formula (Ⅲ) undergoes asymmetric hydrogenation in the presence of a chiral catalyst to obtain the optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one shown in formula (Ⅰ): The chiral catalyst used in the asymmetric hydrogenation is a complex of ruthenium acetate and a bisphosphine ligand; The bisphosphine ligand of the chiral catalyst is (S)-(+)-2,2'-bis[bis(3,5-di-tert-butylphenyl)phosphino]-6,6'-dimethoxy-1,1'-biphenyl.

2. The method according to claim 1, characterized in that, The temperature of the asymmetric hydrogenation reaction is 25 °C.

3. The method according to claim 1, wherein The pressure of the asymmetric hydrogenation reaction is 500 kPa.

4. The method according to claim 1, characterized in that, The solvent for the asymmetric hydrogenation reaction is trifluoroethanol.

5. According to the method of claim 1, the method for preparing the compound of formula (Ⅲ) in step 1) is to prepare 4-n-propylfuran-2(5H)-one shown in formula (Ⅲ) from the compound shown in formula (Ⅱ) in the presence of a reducing agent 6. According to the method of claim 5, the reducing agent is sodium borohydride.

7. According to the method of claim 5, the reaction solvent for reducing the compound of formula (Ⅱ) is toluene, the reaction temperature is 25 °C, and the molar ratio of the compound of formula (Ⅱ) to the reducing agent is 1:

1.

8. According to the method of claim 5, the method for preparing the compound of formula (Ⅱ) includes the following steps: A) Providing commercially available n-valeraldehyde and glyoxylic acid hydrate as substrates, B) Reacting n-valeraldehyde and glyoxylic acid hydrate in a solvent containing a basic reagent to generate the compound shown in formula (Ⅱ).

9. According to the method of claim 8, the basic reagent used in the reaction is morpholine.

10. According to the method of claim 8, the reaction solvent is n-hexane, and the reaction temperature is 25 °C.

11. According to the method of claim 8, in step B), the molar ratio of n-valeraldehyde to glyoxylic acid hydrate is 1:1.3, and the molar ratio of n-valeraldehyde to morpholine is 1:1.1.

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