A method for synthesizing chiral δ-caprolactam compounds

Abstract

This invention discloses a method for synthesizing chiral δ-caprolactam compounds. Using N-Boc-L-pyroglutamate as a starting material, intermediate II is obtained through nucleophilic ring-opening with a Grignard reagent. This intermediate is then subjected to enamidation of a ketone and cyclization with a lactam to form intermediate III. Halogenation of intermediate III yields intermediate IV, which is then coupled with a metal-catalyzed reaction to obtain intermediate V. By controlling the chirality at the C-3 position of intermediate V and catalytically reducing the C5-C6 carbon-carbon double bond, chiral intermediate VI is obtained. Intermediate VI undergoes trifluoroethylation and crystallization-induced diastereomeric transformation to prepare the key aminolactam intermediate A for the drug ubrogepant. This invention avoids the chiral resolution by high-performance liquid chromatography, the high technical barriers of transaminase catalysis, and the cumbersome salt-forming resolution process, thus improving the synthetic efficiency of chiral δ-caprolactam compounds and possessing significant industrial application value.

Description

Technical Field

[0001] This invention belongs to the field of organic compound (advanced pharmaceutical intermediate) synthesis, and relates to a method for synthesizing chiral δ-caprolactam compounds, particularly a method for synthesizing a key aminolactam intermediate (compound A) of the drug ubrogepant. Background Technology

[0002] Calcitonin gene-related peptide (CGRP) is a 37-amino acid vasodilatory neuropeptide primarily expressed in the central and peripheral nervous systems, involved in pain transmission within the nervous system. During a migraine attack, CGRP levels rise and are positively correlated with headache severity. Although the underlying pathogenesis of migraine is complex and not fully understood, with ongoing research in pathophysiology, the important role of CGRP in migraine has been recognized, and it is considered an important target for migraine treatment.

[0003] In recent years, four small-molecule CGRP receptor antagonists have been launched for the acute treatment or preventative treatment of migraines. Compared to triptans (i.e., 5-HT4 receptor antagonists)... 1B / 1D CGRP receptor antagonists (agonists) offer greater cardiovascular safety and more significant therapeutic effects. Among them, ubrogepant is an orally administered, highly selective, and potent competitive CGRP receptor antagonist, approved by the FDA on December 23, 2019 (trade name: Uprelvy). TM It became the world's first small molecule CGRP receptor antagonist to be marketed and is used clinically for the acute treatment of migraines in adults.

[0004] Ubrogepant is obtained by a condensation reaction of an aminolactam fragment and a spiro acid fragment. Among them, the aminolactam fragment (compound A) is more difficult to synthesize due to the presence of three chiral carbon atoms in its molecule.

[0005]

[0006] Typically, the construction strategies for compound A fall into the following categories.

[0007] Strategy 1 involves using ketone ester compound 1 as a starting material, followed by reductive amination and cyclization under basic conditions to obtain lactam compound 2. However, the configurations of the chiral centers at positions C-3, C-5, and C-6 of compound 2 are uncertain, requiring chiral resolution by high-performance liquid chromatography (HPLC) and removal of the Boc compound to obtain compound A. The drawback of this route is the low stereoselectivity during reductive amination and cyclization, resulting in extremely low yields of the target compound.

[0008]

[0009] Strategy 2: Starting with 2-nitro-5-bromo-6-methylpyridin-2-(1H)-one (compound 3), compound 4 is obtained via N-trifluoroethylation and nitration. Subsequently, it is linked to a phenyl group via a palladium-catalyzed Suzuki coupling reaction, followed by noble metal-catalyzed hydrogenation reduction to obtain the cis-predominant 3-aminopiperidinone enantiomer. Chiral resolution yields compound A. The disadvantage of this route is the need for expensive metal reagents, and the highest yield of chiral resolution does not exceed 50%.

[0010]

[0011] Strategy 3: Using compound 5 as a starting material, a chiral center was constructed using enzymatic catalysis. In 2017, Merck, in collaboration with Codexis, obtained the kinetically resolving transaminase ATA-426 through protein engineering mutation, achieving chiral control at the C-5 and C-6 positions. The resulting compound 6, after N-trifluoroethylation, was then salted via crystallization-induced diastereomeric transformation (CIDT) to obtain compound A with high chiral purity (Org Process Res Dev. 2017, 21, 1851). The advantage of this strategy is the efficient control of chirality through transaminase catalysis, but the disadvantages are the long development cycle and high R&D costs required to introduce or develop substrate-specific transaminases. Furthermore, enzyme-catalyzed reactions have a high technical threshold, limiting the scale-up of the process.

[0012]

[0013] Strategy 4: Using compound 7 as a starting material, compound 8 is obtained through endenamide reaction and N-trifluoroethylation reaction. Subsequently, compound A is obtained through crystallization-induced dynamic kinetic resolution and hydrogenation reduction. This strategy avoids enzyme-catalyzed reactions and does not require high-performance liquid chromatography chiral separation. However, the crystallization-induced dynamic kinetic resolution process requires four steps: deprotection, pH adjustment, dynamic crystallization resolution, and protection addition. The operation is relatively cumbersome and results in significant losses (CN 119431222 A).

[0014]

[0015] In summary, it is crucial to develop a simpler and more efficient method for the asymmetric synthesis of the key fragment of ubrogepant (compound A). Summary of the Invention

[0016] The purpose of this invention is to provide a method for synthesizing chiral δ-caprolactam compounds. Using N-Boc-L-pyroglutamate (Formula I) as a starting material, intermediate II is obtained through nucleophilic ring-opening with a Grignard reagent. This intermediate is then subjected to enamidation of a ketone and cyclization with a lactam to form intermediate III. Intermediate III is halogenated to obtain intermediate IV, which is then coupled with a metal-catalyzed reaction to obtain intermediate V. By controlling the chirality at the C-3 position of intermediate V and catalytically reducing the C5-C6 carbon-carbon double bond, chiral intermediate VI is obtained. Intermediate VI undergoes trifluoroethylation and crystal-induced diastereomeric transformation to prepare the key aminolactam intermediate A for the drug ubrogepant. This method cleverly preserves the chiral center in the starting material, avoiding high-performance liquid chromatography chiral resolution, the high-tech barriers of transaminase catalysis, and the cumbersome salt-forming resolution process, thus greatly improving the efficiency of the synthesis process and achieving the efficient preparation of the key aminolactam intermediate for the drug ubrogepant.

[0017] The technical solution of this invention is implemented as follows:

[0018] A synthetic method for chiral δ-caprolactam compounds, the synthetic route is as follows:

[0019] ;

[0020] Wherein, R is selected from C1 to C6 alkyl, and X is selected from Cl, Br, and I;

[0021] Includes the following steps:

[0022] Step (1): Using tetrahydrofuran (THF) as the reaction solvent, under the action of a methyl Grignard reagent, the N-Boc-L-pyroglutamic acid ester represented by Formula I undergoes a nucleophilic ring-opening reaction to obtain compound II;

[0023] Step (II): Using isopropanol as the reaction solvent, compound II reacts with an ammonia donor reagent to form a cyclization reaction, yielding compound III;

[0024] Step (3): Using tetrahydrofuran as the reaction solvent, compound III undergoes a halogenation reaction with a halogenating agent to obtain compound IV;

[0025] Step (IV): Using a mixed solution of 1,4-dioxane and water as the reaction solvent, under the protection of nitrogen or inert gas and in the presence of a base, compound IV and arylboronic acid derivatives undergo a coupling reaction in the presence of a metal catalyst to obtain compound V.

[0026] Step (5): Using methanol as the reaction solvent, under a hydrogen atmosphere, compound V undergoes a hydrogenation reaction in the presence of a catalyst to obtain compound VI;

[0027] Step (VI): Using tetrahydrofuran as the reaction solvent, under the catalysis of an alkaline catalyst, compound VI and the trifluoroethylating reagent undergo a trifluoroethylation reaction to obtain compound VII;

[0028] Step (7): Compound VII undergoes deprotection of the Boc protecting group and crystallization-induced diastereomeric transformation to obtain compound A.

[0029] As a preferred embodiment of the present invention, in step (i), the methyl Grignard reagent is methyl magnesium chloride or methyl magnesium bromide.

[0030] The molar ratio of the N-Boc-L-pyroglutamate ester to the methyl Grignard reagent is 1:1 to 1:1.4, preferably 1:1.2.

[0031] The nucleophilic ring-opening reaction is performed at a temperature of -55℃ to -20℃.

[0032] After the reaction was completed, saturated NH4Cl solution was added to quench the reaction, and the organic phase was removed under reduced pressure. The residue was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound II.

[0033] As a preferred embodiment of the present invention, in step (ii), the ammonia donor reagent is any reagent capable of providing ammonia molecules; specifically, the ammonia donor reagent is at least one of ammonium acetate (NH4OAc), ammonium formate, ammonium carbonate, ammonium bicarbonate, a methanol solution of ammonia, and the like.

[0034] The molar ratio of compound II to the ammonia donor reagent is 1:1 to 1:10, preferably 1:5.

[0035] The reaction temperature is 60℃~120℃.

[0036] After the reaction was completed, the organic phase was removed under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain crude compound III. The crude compound III was dissolved in a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1 to 3:1 and subjected to rapid column chromatography. The filtrate was evaporated to dryness and then sonicated in petroleum ether to crystallize, yielding compound III.

[0037] As a preferred embodiment of the present invention, in step (iii), the halogenating agent is any halide that can monohalogenate the double bond; specifically, the halogenating agent is at least one of NCS, NBS, NIS, CuCl2, CuBr2 and the like.

[0038] The molar ratio of compound III to the halogenated reagent is 1:1 to 1:1.5, preferably 1:1.2.

[0039] The reaction temperature is 0℃~30℃.

[0040] After the reaction was completed, the reaction solution was diluted with ethyl acetate, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. A mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1 to 1:1 was added to the residue, and rapid column chromatography was performed. The filtrate was evaporated to dryness and then sonicated in petroleum ether to crystallize, yielding compound IV.

[0041] In a preferred embodiment of the present invention, in step (iv), the metal catalyst is any reagent capable of catalyzing the coupling reaction between the halide and the arylboronic acid derivative. Specifically, the metal catalyst includes at least one of palladium acetate, tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), palladium dichloride, nickel chloride, nickel bromide, and other metal analogs.

[0042] The molar ratio of compound IV to the metal catalyst is 100:1 to 10:1, preferably 40:1.

[0043] The molar ratio of compound IV to the arylboronic acid derivative is 1:1 to 1:2, preferably 1:1.2.

[0044] The arylboronic acid derivative is phenylboronic acid.

[0045] The alkali is sodium carbonate; the molar ratio of compound IV to the alkali is 1:2 to 1:2.5, preferably 1:2.4.

[0046] The coupling reaction is carried out at a temperature of 25°C to 120°C, preferably 60°C.

[0047] The volume ratio of 1,4-dioxane to water is 8:1 to 8.5:1.

[0048] Specifically, compound IVa, arylboronic acid derivatives, an aqueous solution of a base, and 1,4-dioxane are mixed, a metal catalyst is added, and a coupling reaction is carried out under a nitrogen or inert gas atmosphere.

[0049] After the reaction was completed, the reaction solution was diluted with ethyl acetate, and the organic phase was taken. The organic phase was washed successively with water and saturated brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the residue was dissolved in a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1 to 1:1. The mixture was subjected to rapid column chromatography under reduced pressure using a Buchner funnel lined with 300-mesh silica gel. The filtrate was evaporated to dryness and slurried at room temperature with a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:5 to obtain compound V.

[0050] Specifically, the rapid column chromatography can be performed twice.

[0051] When pulping, the ratio of compound IV to mixed solvent is 1g:8mL to 1g:8.5mL.

[0052] The pulping temperature is room temperature.

[0053] As a preferred embodiment of the present invention, in step (v), the catalyst for the hydrogenation reaction is any catalyst capable of catalyzing the hydrogenation reduction of double bonds; specifically, the catalyst is palladium, platinum, nickel, ruthenium or rhodium, preferably 10% Pd / C.

[0054] The hydrogenation reaction temperature is 0℃~60℃; the hydrogenation reaction pressure is 0.1 MPa~10 MPa.

[0055] After the hydrogenation reaction was completed, the catalyst was removed by diatomaceous earth filtration, the filtrate was dried by rotary evaporation, and then slurryed with a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:6 to obtain compound VI.

[0056] When pulping, the ratio of compound V to mixed solvent is 1g:5mL to 1g:8mL.

[0057] The pulping temperature is room temperature.

[0058] As a preferred embodiment of the present invention, in step (vi), the trifluoroethylating agent is 2,2,2-trifluoroethyltrifluoromethanesulfonate, trifluoroethyl p-toluenesulfonate, or trifluoroiodoethane.

[0059] The molar ratio of compound VI to the trifluoroethylated reagent is 1:1 to 1:1.5, preferably 1:1.3.

[0060] The alkaline catalyst is sodium thiosulfate and lithium tert-butoxide.

[0061] The molar ratio of compound VI to sodium thiosulfate is 40:1 to 10:1, preferably 20:1.

[0062] The molar ratio of compound VI to lithium tert-butoxide is 1:1 to 1:1.5, preferably 1:1.3 to 1:1.35.

[0063] The temperature for the trifluoroethylation reaction is -10℃ to 25℃.

[0064] Specifically, compound VI and sodium thiosulfate are dissolved in tetrahydrofuran, and a tetrahydrofuran solution of lithium tert-butoxide is added dropwise. A trifluoroethylating reagent is then added to carry out the trifluoroethylation reaction.

[0065] After the trifluoroethylation reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was dried with anhydrous Na2SO4, concentrated under reduced pressure, and slurried with a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:6 to obtain compound VII.

[0066] During pulping, the ratio of compound VI to the mixed solvent is 10g:6mL to 10g:10mL.

[0067] The pulping temperature is room temperature.

[0068] As a preferred embodiment of the present invention, in step (vii), the Boc protecting group is removed by using ethyl acetate as the reaction solvent and under acidic conditions; wherein the acidic conditions are provided by trifluoroacetic acid, hydrochloric acid, formic acid or p-toluenesulfonic acid; and the reaction temperature for removing the Boc protecting group is 0℃~40℃.

[0069] The crystallization-induced diastereomeric transformation described above: under the action of a racemic catalyst, compound VI, after removing the Boc protecting group, undergoes enantiomerization transformation and enrichment with a salt-forming reagent under heating conditions.

[0070] The solvent for the crystallization-induced diastereomeric transformation is acetonitrile.

[0071] The salt-forming reagent used in the crystallization-induced diastereomeric transformation is any acid capable of forming a salt with compound A, including at least one of p-methylbenzoic acid, L-malic acid, indole-3-carboxylic acid, dibenzoic acid, Ac-L-phenylalanine, p-nitrobenzoic acid, or their analogues; the molar ratio of compound VI to the salt-forming reagent is 1:1. The racemization catalyst is any aromatic aldehyde compound capable of forming an imine intermediate with compound A and undergoing ex-α-racemization of the imine under heating conditions; the aromatic aldehyde compound is 3,5-dichlorosalicylaldehyde.

[0072] The temperature for the crystallization-induced diastereomeric transformation is 60℃~130℃.

[0073] The molar ratio of compound VI to the racemic catalyst is 1:1.

[0074] Specifically, ethyl acetate was used as the reaction solvent under acidic conditions to remove the Boc protecting group from compound VI. After the Boc protecting group was removed, Na2CO3 solution was added until all the product was transferred to the organic phase. The organic layer was separated, and the organic phase was dried with anhydrous Na2SO4 and concentrated under reduced pressure. The residue was dissolved in acetonitrile, and a salt-forming reagent and catalyst were added to carry out crystallization-induced enantiomerization. The mixture was cooled to 0°C and crystallized for half an hour. The crystals were then filtered, washed with acetonitrile until the filtrate was colorless, and dried to obtain compound A.

[0075] Compared with the prior art, the present invention has the following beneficial effects:

[0076] (1) The present invention avoids the use of high performance liquid chromatography for chiral separation, thus avoiding the use of a large amount of chromatographic solvents and greatly reducing the generation of waste solvents.

[0077] (2) This invention avoids the use of enzyme catalysis, which reduces the difficulty of technology transfer from pilot-scale process to industrial production and lowers the technical barriers to scale-up production.

[0078] (3) The present invention avoids the cumbersome crystallization-induced dynamic kinetic resolution process, reduces the synthesis steps, saves operation time, and the total yield is greater than 50%, which is a significant improvement compared with the traditional chemical method.

[0079] (4) The present invention uses rapid column chromatography, pulping or recrystallization to purify intermediates and target products, which saves production time, improves production efficiency, and greatly reduces costs. It is suitable for industrial mass production and also suitable for laboratory small-scale preparation.

[0080] (5) The process route of this invention is different from that of the prior art and is a novel synthesis strategy that can achieve industrial scale-up production. Attached Figure Description

[0081] Figure 1 This is the crystal structure diagram of compound V.

[0082] Figure 2 This is the HPLC purity spectrum of intermediate A, a key aminolactam in the drug ubrogepant.

[0083] Figure 3 This is the chiral HPLC purity spectrum of A, the key aminolactam intermediate in the drug ubrogepant.

[0084] Figure 4 It is the key aminolactam intermediate A of the drug ubrogepant. 1 HNMR spectrum.

[0085] Figure 5 This is the crystal structure diagram of A, the key aminolactam intermediate in the drug ubrogepant. Detailed Implementation

[0086] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. These embodiments can enable those skilled in the art to fully understand the present invention, but should not be considered as limiting the scope of the present invention.

[0087] Chiral purity determination conditions: Agilent 1260 high performance liquid chromatograph, column: CHIRALPAK ® IE (Part No. 85325, length 250mm × inner diameter 4.6mm, particle size 5μm), mobile phase: n-hexane:isopropanol:n-butylamine volume ratio = 90:10:0.1, detection wavelength: 254nm.

[0088] Example 1

[0089] Preparation of (S)-2-((tert-Butoxycarbonyl)amino)-5-oxohexanoic acid ethyl ester (compound IIa)

[0090]

[0091] In a 2 L flask, Boc-L-pyroglutamic acid ethyl ester (compound Ia, 51.4 g, 0.2 mol) was dissolved in tetrahydrofuran (0.8 L) to obtain a tetrahydrofuran solution of Boc-L-pyroglutamic acid ethyl ester. Subsequently, while stirring, a 3.0 mol / L methylmagnesium chloride THF solution (80.0 mL, 0.24 mol) was added dropwise to the tetrahydrofuran solution of Boc-L-pyroglutamic acid ethyl ester at -55 °C, and stirring was continued at -55 °C for 0.5 hours. The reaction was then confirmed to be complete by TLC (electrolyte: ethyl acetate: petroleum ether = 1:2 V / V). The reaction solution was quenched with saturated NH4Cl solution, and the organic phase was removed under reduced pressure. The residue was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound IIa (colorless to pale yellow oil, 51.4 g, yield 94%).

[0092] 1 H NMR (400 MHz, CDCl3) δ 5.10 (d, J = 6.5 Hz, 1H), 4.22 (dt, J = 8.5,4.3 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 2.61 – 2.43 (m, 2H), 2.12 (s, 3H),2.10 – 2.05 (m, 1H), 1.89 – 1.79 (m, 1H), 1.40 (s, 9H), 1.25 (t, J = 7.1 Hz,3H); 13 C NMR (101 MHz, CDCl3) δ 207.67, 172.47, 155.56, 80.00, 61.58, 52.98,39.48, 30.13, 28.37, 26.67, 14.25.

[0093] Preparation of tert-butyl-(S)-(6-methyl-2-oxo-1,2,3,4-tetrahydropyridin-3-yl)carbamate (compound III)

[0094]

[0095] In a 1 L flask, compound IIa (54.7 g, 0.2 mol) was dissolved in isopropanol (0.6 L) to obtain an isopropanol solution of compound IIa. Then, NH4OAc (77.1 g, 1.0 mol) was added to the isopropanol solution of compound IIa, and the mixture was stirred at 100 °C for 8 hours. The reaction was monitored by TLC at this point to indicate completion (electrolyte: ethyl acetate: petroleum ether = 1:2 V / V). The reaction mixture was cooled to room temperature, and the organic phase was removed under reduced pressure. The residue was extracted three times with ethyl acetate using an aqueous solution, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a yellow oil. The oily substance was dissolved in a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1. Rapid column chromatography was performed under reduced pressure using a Buchner funnel lined with 300-mesh silica gel. The filtrate was evaporated to dryness and then dissolved again in a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1. Rapid column chromatography was performed again, and the filtrate was evaporated to dryness. The filtrate was then dissolved in petroleum ether (50 mL) and crystallized by sonication at 10 °C (ultrasonic power 240 W; sonication promotes the dissolution of impurities in the product, while the product concentration is high, resulting in crystal precipitation). Compound III (white powder solid, 39.4 g, yield 87%, ee = 99.2%) was obtained.

[0096] 1 H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 5.47 (d, J = 5.3 Hz, 1H), 4.85 (dq, J = 6.9, 1.8 Hz, 1H), 4.22 – 4.14 (m, 1H), 2.74 (dt, J = 15.2, 7.1 Hz, 1H), 2.20 – 2.03 (m, 1H), 1.79 (dd, J = 2.8, 1.3 Hz, 3H), 1.42 (s, 9H); 13 CNMR (101 MHz, CDCl3) δ 170.46, 155.72, 132.93, 100.96, 79.78, 50.08, 28.42,27.43, 18.91; HRMS calc'd for C 11 H 18 N₂O₃Na [M + Na] +249.1215, found 249.1210.

[0097] Preparation of tert-butyl-(S)-(5-bromo-6-methyl-2-oxo-1,2,3,4-tetrahydropyridin-3-yl)carbamate (compound IVa)

[0098]

[0099] In a 1 L flask, compound III (39.7 g, 0.174 mol) was dissolved in tetrahydrofuran (0.5 L) to obtain a tetrahydrofuran solution of compound III. To reduce over-bromination, CuBr2 (46.6 g, 0.21 mol) was added to the tetrahydrofuran solution of compound III in three equal portions. After all CuBr2 was added, the mixture was stirred at room temperature for 15 minutes. TLC analysis showed that the reaction was complete at this point (electrolyte: ethyl acetate: petroleum ether = 1:1 V / V or dichloromethane: methanol = 20:1 V / V). The reaction solution was diluted with ethyl acetate to precipitate the copper-containing inorganic compound dissolved in tetrahydrofuran as a solid, reducing metal residue. The mixture was filtered through a Buchner funnel lined with a thin layer of diatomaceous earth. The filtrate was concentrated under reduced pressure. A mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1 was added to the residue. Rapid column chromatography was performed under reduced pressure using a Buchner funnel lined with 300-mesh silica gel. The filtrate was evaporated to dryness and then dissolved again in a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1 for rapid column chromatography. The filtrate was evaporated to dryness and dissolved in petroleum ether (40 ml). The mixture was then sonicated at 10 °C (ultrasonic power 240 W) to obtain compound IVa (white powder solid, 49.4 g, yield 93%, ee = 99.3%).

[0100] 1 H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 5.43 (d, J = 5.2 Hz, 1H), 4.38 (dd, J = 13.9, 6.9 Hz, 1H), 3.15 (dd, J = 16.4, 7.7 Hz, 1H), 2.74 – 2.59 (m,1H), 1.95 (dd, J = 2.7, 0.9 Hz, 3H), 1.43 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ169.47, 155.49, 130.81, 97.15, 80.23, 50.24, 37.26, 28.41, 18.81; HRMS calc'dfor C 11 H 18 BrN2O3 [M + H]+ 327.0320, found 327.0315.

[0101] Preparation of tert-butyl-(S)-(6-methyl-2-oxo-5-phenyl-1,2,3,4-tetrahydropyridin-3-yl)carbamate (compound V)

[0102]

[0103] In a 500 mL flask, compound IVa (6.1 g, 20.0 mmol), phenylboronic acid (2.94 g, 24.0 mmol), and 2 mol / L Na₂CO₃ aqueous solution (24 mL) were dissolved in 200 mL of 1,4-dioxane. Pd(PPh₃)₄ (580 mg, 0.5 mmol) was added, and the mixture was reacted at 60 °C for 2 hours under a N₂ atmosphere. TLC analysis showed the reaction was complete at this point (electrolyte: ethyl acetate:petroleum ether = 1:1 V / V or dichloromethane:methanol = 20:1). The reaction solution was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed successively with water and saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was dissolved in a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1 and subjected to rapid column chromatography under reduced pressure using a Buchner funnel lined with 300-mesh silica gel. The filtrate was evaporated to dryness and then dissolved again in a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1 for rapid column chromatography. The filtrate was evaporated to dryness and then slurried at room temperature with a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:5 (50 mL) to give compound V (white powder solid, 5.68 g, yield 94%, ee = 97.4%).

[0104] 1 H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.31 (t, J = 7.5 Hz, 2H), 7.21(t, J = 7.2 Hz, 1H), 7.19 – 7.15 (m, 2H), 5.54 (d, J = 5.3 Hz, 1H), 4.45 –4.33 (m, 1H), 3.04 (dd, J = 15.7, 7.0 Hz, 1H), 2.63 (tq, J = 15.3, 2.5 Hz, 1H), 1.88 (d, J = 2.4 Hz, 3H), 1.43 (s, 9H); 13C NMR (101 MHz, CDCl3) δ170.12, 155.72, 139.44, 128.60, 128.41, 128.32, 126.75, 114.67, 79.92, 50.36,34.06, 28.44, 16.97. HRMS calc'd for C 17 H 21 N₂O₃ [M - H] - 301.1558, found 301.1554.

[0105] Compound V was dissolved in a mixed solvent of toluene and methanol in a volume ratio of 4:1, and a single crystal was prepared by slow evaporation at 25°C. Its absolute configuration was confirmed by single-crystal X-ray diffraction analysis. Figure 1 ).

[0106] Preparation of tert-butyl ((3S,5S,6R)-6-methyl-2-oxo-5-phenylpiperidin-3-yl)carbamate (compound VI)

[0107]

[0108] In a 100 mL flask, compound V (1 g, 3.30 mmol) was dissolved in methanol (30 mL), and 10% Pd / C (100 mg) was added. The mixture was stirred overnight at room temperature and atmospheric pressure under a hydrogen atmosphere. TLC analysis showed that the reaction was complete at this point (eluent: ethyl acetate: petroleum ether volume ratio = 2:1). Pd / C was removed by diatomaceous earth filtration, and the filtrate was evaporated to dryness. At room temperature, the filtrate was slurried with 7 mL of a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:6 to give compound VI (white powder solid, 0.98 g, yield 98%, ee = 97.6%).

[0109] 1 H NMR (400 MHz, CDCl3) δ 7.31 – 7.19 (m, 3H), 7.12 (d, J = 7.5 Hz, 2H), 6.47 (s, 1H), 5.55 (s, 1H), 4.20 (dd, J = 12.1, 6.4 Hz, 1H), 3.77 (d, J= 7.2 Hz, 1H), 3.38 (dt, J = 10.5, 4.9 Hz, 1H), 2.69 (t, J = 9.0 Hz, 1H), 2.04 (q, J = 12.0 Hz, 1H), 1.43 (s, 9H), 0.85 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.44, 155.93, 140.72, 128.58, 127.95, 127.05, 79.79, 51.69, 51.55, 41.95, 29.91, 28.46, 18.13.

[0110] Preparation of tert-butyl ((5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)carbamate (compound VII)

[0111]

[0112] In a 500 mL flask, compound VI (10 g, 32.85 mmol) and sodium thiosulfate (0.26 g, 1.64 mmol) were dissolved in tetrahydrofuran (100 mL); then, a solution of lithium tert-butoxide in tetrahydrofuran (2.2 mol / L, 20 mL, 44.00 mmol) was added dropwise, and the mixture was stirred at 16–22 °C for 15 minutes; 2,2,2-trifluoroethyltrifluoromethanesulfonate (10 g, 43.08 mmol) was added, and the mixture was stirred overnight at 20 °C. TLC analysis showed the reaction was complete at this point (eluent: ethyl acetate: petroleum ether = 3:1 V / V). Water (100 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and slurried at room temperature with 7 mL of a 1:6 mixture of ethyl acetate and petroleum ether to give compound VII (white powder, 11 g, yield 87%, dr = ). 10:1, ee = 97.3%.

[0113] 1H NMR (400 MHz, CDCl3) δ 7.33 (dd, J = 8.1, 6.6 Hz, 2H), 7.28 – 7.25(m, 1H), 7.17 (d, J = 7.2 Hz, 2H), 5.39 (s, 1H), 4.95 – 4.84 (m, 1H), 4.16(dt, J = 11.9, 6.1 Hz, 1H), 3.87 – 3.78 (m, 1H), 3.52 (ddd, J = 13.2, 4.9,2.8 Hz, 1H), 3.29 – 3.09 (m, 1H), 2.62 – 2.57 (m, 1H), 2.40 (q, J = 12.6 Hz,1H), 1.44 (s, 9H), 0.94 (d, J = 6.6 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ170.32, 155.99, 139.94, 128.75, 127.68, 127.30, 124.61 (d, J = 282 Hz), 79.97, 58.82, 52.50, 45.44 (q, J = 34.0 Hz), 41.91, 28.45, 27.64, 13.70; 19 FNMR (376 MHz, CDCl3) δ -69.75 (t, J = 8.9 Hz).

[0114] Preparation of (3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one (compound A)

[0115]

[0116] In a 100 mL round-bottom flask, compound VII (10 g, 25.95 mmol) was dissolved in 40 mL of ethyl acetate solution containing 2 mol / L hydrochloric acid. The mixture was stirred at 40 °C for 0.5 h. 2 mol / L Na₂CO₃ solution was added until no UV absorption at 254 nm was observed in the aqueous layer, indicating that the product had been completely transferred to the organic phase. The organic layer was separated, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was dissolved in acetonitrile, and an equivalent amount of p-methylbenzoic acid and 5% mol of 3,5-dichlorosalicylaldehyde of compound VII were added. The mixture was stirred vigorously at 80 °C for 4 h, cooled to 0 °C for half an hour to allow crystallization, filtered, washed with acetonitrile until the filtrate was colorless, and dried to obtain compound A (white solid, 10.2 g, yield 93%, HPLC purity 99.8%, ee value 97.7%).

[0117] 1 H NMR (400 MHz, CD3OD) δ 7.37 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 5.6Hz, 3H), 4.80 – 4.69 (m, 1H), 4.22 (dd, J = 12.1, 6.8 Hz, 1H), 3.91 (p, J =6.4 Hz, 1H), 3.75 – 3.63 (m, 2H), 2.60 (q, J = 12.6 Hz, 1H), 2.43 (dt, J =11.5, 4.1 Hz, 1H), 0.98 (d, J = 6.5 Hz, 3H); 13 C NMR (101 MHz, CD3OD) δ166.87, 139.32, 128.58, 127.35, 127.23, 126.19, 124.80 (d, J = 282 Hz), 59.33, 50.09, 44.93 (q, J = 34.0 Hz), 41.14, 24.69, 12.40; 19 F NMR (376 MHz, CD3OD) δ -71.20 (t, J = 9.1 Hz).

[0118] Compound A was dissolved in ethyl acetate and slowly evaporated at 25°C to obtain a single crystal of compound A. Its absolute configuration was confirmed by single-crystal X-ray diffraction analysis. Figure 5 ).

[0119] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any form or substance. It should be noted that those skilled in the art can make various improvements and additions without departing from the method of the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention. Any modifications, alterations, and equivalent changes made by those skilled in the art based on the above-disclosed technical content without departing from the spirit and scope of the present invention are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, and evolutions made to the above embodiments based on the essential technology of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing chiral δ-caprolactam compounds, characterized in that: The synthesis route is as follows: ； Wherein, R is selected from C1 to C6 alkyl groups, and X is selected from Cl, Br, and I; Includes the following steps: Step (1): Using tetrahydrofuran (THF) as the reaction solvent, under the action of a methyl Grignard reagent, the N-Boc-L-pyroglutamic acid ester represented by Formula I undergoes a nucleophilic ring-opening reaction to obtain compound II; Step (II): Using isopropanol as the reaction solvent, compound II reacts with an ammonia donor reagent to form a cyclization reaction, yielding compound III; Step (3): Using tetrahydrofuran as the reaction solvent, compound III undergoes a halogenation reaction with a halogenating agent to obtain compound IV; Step (IV): Using a mixed solution of 1,4-dioxane and water as the reaction solvent, under the protection of nitrogen or inert gas and in the presence of a base, compound IV and arylboronic acid derivatives undergo a coupling reaction in the presence of a metal catalyst to obtain compound V. Step (5): Using methanol as the reaction solvent, under a hydrogen atmosphere, compound V undergoes a hydrogenation reaction in the presence of a catalyst to obtain compound VI; Step (VI): Using tetrahydrofuran as the reaction solvent, under the catalysis of an alkaline catalyst, compound VI and the trifluoroethylating reagent undergo a trifluoroethylation reaction to obtain compound VII; Step (7): Compound VII undergoes deprotection of the Boc protecting group and crystallization-induced diastereomeric transformation to obtain compound A.

2. The method for synthesizing chiral δ-caprolactam compounds according to claim 1, characterized in that: In step (i), the methyl Grignard reagent is methyl magnesium chloride or methyl magnesium bromide; the molar ratio of N-Boc-L-pyroglutamate to the methyl Grignard reagent is 1:1 to 1:1.4, preferably 1:1.2; and the temperature of the nucleophilic ring-opening reaction is -55℃ to -20℃.

3. The method for synthesizing chiral δ-caprolactam compounds according to claim 1, characterized in that: In step (ii), the ammonia donor reagent is any reagent capable of providing ammonia molecules; preferably, the ammonia donor reagent is at least one of ammonium acetate, ammonium formate, ammonium carbonate, ammonium bicarbonate, a methanol solution of ammonia, and the like; the molar ratio of compound II to the ammonia donor reagent is 1:1 to 1:10, preferably 1:5; the reaction temperature is 60℃ to 120℃.

4. The method for synthesizing chiral δ-caprolactam compounds according to claim 1, characterized in that: In step (iii), the halogenating agent is any halide capable of monohalogenating double bonds; preferably, the halogenating agent is at least one of NCS, NBS, NIS, CuCl2, CuBr2 and their analogues; the molar ratio of compound III to the halogenating agent is 1:1 to 1:1.5, preferably 1:1.2; the reaction temperature is 0℃ to 30℃.

5. The method for synthesizing chiral δ-caprolactam compounds according to claim 1, characterized in that: In step (iv), the metal catalyst is any reagent capable of catalyzing the coupling reaction between the halide and the arylboronic acid derivative; preferably, the metal catalyst includes at least one of palladium acetate, tetrakis(triphenylphosphine)palladium, palladium dichloride, nickel chloride, nickel bromide, and other metal analogs; the molar ratio of compound IV to the metal catalyst is 100:1 to 10:1, preferably 40:1; the arylboronic acid derivative is phenylboronic acid; the molar ratio of compound IV to the arylboronic acid derivative is 1:1 to 1:2, preferably 1:1.2; the base is sodium carbonate; the molar ratio of compound IV to the base is 1:2 to 1:2.5, preferably 1:2.4; the temperature of the coupling reaction is 25℃ to 120℃, preferably 60℃.

6. The method for synthesizing chiral δ-caprolactam compounds according to claim 1, characterized in that: In step (v), the catalyst for the hydrogenation reaction is any catalyst capable of catalyzing the hydrogenation reduction of double bonds; preferably, the catalyst is palladium, platinum, nickel, ruthenium, or rhodium, more preferably 10% Pd / C; the temperature of the hydrogenation reaction is 0℃~60℃; and the pressure of the hydrogenation reaction is 0.1 MPa~10 MPa.

7. The method for synthesizing chiral δ-caprolactam compounds according to claim 1, characterized in that: In step (vi), the trifluoroethylating reagent is 2,2,2-trifluoroethyltrifluoromethanesulfonate, trifluoroethyl p-toluenesulfonate, or trifluoroiodoethane; the molar ratio of compound VI to the trifluoroethylating reagent is 1:1 to 1:1.5, preferably 1:1.3; the alkaline catalyst is sodium thiosulfate and lithium tert-butoxide; the molar ratio of compound VI to sodium thiosulfate is 40:1 to 10:1, preferably 20:1; the molar ratio of compound VI to lithium tert-butoxide is 1:1 to 1:1.5, preferably 1:1.3 to 1:1.35; and the temperature of the trifluoroethylation reaction is -10℃ to 25℃.

8. The method for synthesizing chiral δ-caprolactam compounds according to claim 1, characterized in that: In step (vii), the Boc protecting group is removed: compound VI is deprotected under acidic conditions using ethyl acetate as the reaction solvent; wherein the acidic conditions are provided by trifluoroacetic acid, hydrochloric acid, formic acid or p-toluenesulfonic acid; the reaction temperature for deprotection of the Boc protecting group is 0℃~40℃.

9. The method for synthesizing chiral δ-caprolactam compounds according to claim 1, characterized in that: In step (vii), the crystallization-induced diastereomeric transformation involves the following: under the action of a racemic catalyst, compound VI, after losing its Boc protecting group, undergoes an enantiomerization transformation with a salt-forming reagent under heating conditions to obtain compound A. The solvent for the crystallization-induced diastereomeric transformation is acetonitrile; the salt-forming reagent used in the crystallization-induced diastereomeric transformation is any acid capable of forming a salt with compound A; the molar ratio of compound VI to the salt-forming reagent is 1:1; the racemic catalyst is any aromatic aldehyde compound capable of forming an imine intermediate with compound A and undergoing exoracemization of the imine at the alpha position under heating conditions; the molar ratio of compound VI to the catalyst is 1:1; and the temperature for the crystallization-induced diastereomeric transformation is 60℃~130℃.

10. The method for synthesizing chiral δ-caprolactam compounds according to claim 9, characterized in that: In step (vii), the salt-forming reagent used for the crystallization-induced diastereomeric transformation is at least one of p-methylbenzoic acid, L-malic acid, indole-3-carboxylic acid, dibenzoic acid, Ac-L-phenylalanine, p-nitrobenzoic acid, or their analogues; and the racemic catalyst is 3,5-dichlorosalicylic acid.

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