Method for asymmetrically synthesizing ubugepam chiral intermediate

Abstract

The invention provides a method for asymmetrically synthesizing an ubugepam chiral intermediate, which comprises the following steps: by taking N-Boc protected ketone ester as a raw material, forming an intermediate II through enamination of ketone and molecular lactam cyclization, obtaining an intermediate III through trifluoroethylation, removing Boc under an acidic condition to obtain an intermediate IV, and carrying out asymmetric synthesis on the intermediate IV under crystallization induction of 5-nitrosalicylaldehyde and chiral acid to obtain the ubugepam chiral intermediate. According to the present invention, the target of dynamic kinetic chiral resolution is achieved through the imine intermediate state, the selective construction of C-3 chirality is achieved, and the chirality of C-5 and C-6 sites is selectively controlled during double-bond cis-catalytic hydrogenation through the chirality of the C-3 site of the substrate so as to obtain the fragment A; the method is efficient, mild and suitable for large-scale production, high performance liquid chromatography chiral resolution is avoided, an expensive metal catalytic coupling step is avoided, application of enzyme catalytic reaction conditions with high technical barriers is avoided, and the amplification performance and the industrial production efficiency of the process are greatly improved.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound (medical advanced intermediate) synthesis, relates to an ubagepam chiral intermediate, and in particular to a method for asymmetric synthesis of an ubagepam chiral intermediate. Background Art

[0002] Migraine is a common chronic neurovascular disease, which is listed by the WHO as the third most common disease and the second most disabling neurological disease in the world. According to statistics, there are about 1.3 billion migraine patients in the world, about 47 million in the United States, and more than 132 million in China. Among them, Ubrogepant is a small molecule, potent CGRP receptor competitive antagonist with high selectivity and high affinity for human CGRP receptors, and can be used for the treatment of acute migraine. The drug molecule was approved by the FDA on December 23, 2019 (trade name: UBRELVY) for oral administration on demand for the acute treatment of migraine with or without aura, and has received widespread attention for its safety and effectiveness. Ubrogepant is formed by the condensation of two key fragments, of which fragment A has three chiral carbon atoms. From a synthetic point of view, the challenge is great, as shown below:

[0003]

[0004] Generally, the construction methods of fragment A can be roughly divided into several categories:

[0005] Strategy 1, usually using multiple routes to construct ketoester 1 as raw material, undergoes reductive amination, cyclization under alkaline conditions and racemization, and mainly obtains intermediates with cis substitution at the C-5,6 positions. The resulting racemic lactam needs to be chirally resolved by normal phase chromatography to obtain fragment A (as shown below). The disadvantage of this route is that the stereoselectivity during cyclization is not high, the yield of the desired isomer is low, and the chiral resolution can only obtain less than 50% of the product.

[0006]

[0007] Strategy 2, using 2-nitro-5-bromo-6-methyl-pyridin-2-(1H)-one 4 as the starting material, a palladium-catalyzed Suzuki coupling reaction is performed, and the product is reduced to cis-based 3-aminopiperidone by noble metal catalytic hydrogenation. The latter is chiral resolved to obtain a single enantiomer (as shown below). The disadvantage is that expensive metal reagents are required, and chiral resolution can only obtain a yield of <50%.

[0008]

[0009] Strategy three, also with ketoester 1 as raw material, but different from strategy one, uses biocatalytic method to construct chiral center. A relatively successful example under this strategy is: in 2017, Merck and Codexis cooperated to obtain kinetic resolution transaminase (DK-transaminase) ATA-426 through protein engineering mutation, and realized the chiral control of C-5 and C-6 positions, but the conversion could not control the chirality of C-3. After N-trifluoroethylation, the obtained product was salified by crystallization induced diastereoisomer conversion (CIDT) to obtain compound A with higher chiral purity (Org.Process Res.Dev.2017, 21, 1851) (as shown below). The advantage of this strategy is that the chirality can be highly controlled by enzyme catalysis, but the disadvantage is that the introduction or development of substrate-specific enzymes with intellectual property rights requires a long cycle and high R&D costs, and the scale-up of the process is also subject to certain restrictions.

[0010]

[0011] In summary, in order to produce the chiral fragment A of ubagepan efficiently and at low cost, it is very necessary to develop a new asymmetric synthesis route. Summary of the invention

[0012] In order to solve the above problems, the present invention provides a method for asymmetric synthesis of chiral intermediates of Ubujipan, which is efficient, mild, and suitable for scale-up production, avoiding high-performance liquid chromatography chiral resolution, avoiding expensive metal-catalyzed coupling steps, and avoiding the application of enzyme-catalyzed reaction conditions with high technical barriers, greatly improving the scalability of the process and industrial production efficiency. The technical scheme of the present invention is implemented as follows: using N-Boc-protected ketoester as a raw material, the intermediate II is formed by enamination of the ketone and cyclization of the molecular lactam, and then the intermediate III is obtained by trifluoroethylation, and the intermediate IV is removed under acidic conditions. Under the crystallization induction of 5-nitrosalicylic aldehyde and chiral acid, the intermediate IV achieves the purpose of dynamic kinetic chiral resolution through the imine intermediate state, and first realizes the selective construction of C-3 chirality. Then, through the chirality of the C-3 position of the substrate, the chirality of the C-5 and C-6 positions is selectively controlled during the cis-catalytic hydrogenation of the double bond, thereby obtaining an efficient and large-scale production process of fragment A.

[0013] In order to achieve the above object, the present invention adopts the following technical solutions:

[0014] The present invention provides a method for asymmetric synthesis of an ubagepan chiral intermediate, the synthesis method comprising the following steps:

[0015] (a) the substance represented by formula (I) is reacted with an amino reagent to form a ring to obtain a compound represented by formula (II);

[0016] (b) the compound represented by formula (II) is subjected to trifluoroethylation reaction to obtain the compound represented by formula (III);

[0017] (c) removing the Boc protecting group from the compound represented by formula (III) to obtain the compound represented by formula (IV);

[0018] (d) the compound represented by formula (IV) is subjected to an aldehyde-catalyzed kinetic resolution process, and then induced by chiral acid salt formation and precipitation to obtain the compound represented by formula (V);

[0019] (e) a compound represented by formula (V), after adding a Boc protecting group, an acetyl group or a benzoyl group to the amino group to obtain a compound represented by formula (VI);

[0020] (f) the compound represented by formula (VI) is subjected to catalytic hydrogenation to obtain the compound represented by formula (VII);

[0021] (g) removing the Boc protecting group from the compound represented by formula (VII) to obtain the compound represented by formula (A);

[0022] Among them, the compound represented by formula (I):

[0023] The compound represented by formula (II):

[0024] The compound represented by formula (III):

[0025] The compound represented by formula (IV):

[0026] The compound represented by formula (V):

[0027] The compound represented by formula (VI):

[0028] The compound represented by formula (VII):

[0029] The compound represented by formula (A):

[0030] In the formula, R is any alkyl or aryl group, and chiral acid is any chiral acid that can form a salt with the free base of compound IV.

[0031] As a preferred embodiment of the present invention, in step a), the reaction temperature is 70°C-80°C.

[0032] As a preferred embodiment of the present invention, in the step b), the trifluoroethylation reagent is trifluoroethyl trifluoromethanesulfonate, and the reaction temperature is 0°C-10°C.

[0033] As a preferred embodiment of the present invention, in step c), the reagent used for the Boc deprotection condition comprises any acid with a suitable pka; and the reaction temperature is 20°C-35°C.

[0034] As a preferred embodiment of the present invention, in the step d), the chiral acid is any chiral acid that can form a salt with the free base of compound IV, including S-mandelic acid, L-glutamic acid, L-malic acid or L-tartaric acid; the catalyst is any aromatic aldehyde compound that forms an imine intermediate with III and undergoes racemization at the imine alpha position under alkaline conditions; and the reaction temperature is 110°C-130°C.

[0035] As a preferred embodiment of the present invention, in step e), the reagent for the Boc protecting group, acetyl group or benzoyl group on the amino group is di-tert-butyl dicarbonate, acetyl chloride or benzoyl chloride, and the reaction temperature is 20°C-35°C.

[0036] As a preferred embodiment of the present invention, in step f), the catalyst for the hydrogenation reaction is at least one of a palladium catalyst and a nickel catalyst.

[0037] As a preferred embodiment of the present invention, in the step f), the temperature of the hydrogenation reaction is 40° C.-55° C., and the pressure of the hydrogenation reaction is 1 MPa-10 MPa.

[0038] As a preferred embodiment of the present invention, in step g), the reagent used for the de-Boc, deacetylation or debenzoylation protection conditions comprises any acid with a suitable pka.

[0039] In the present invention, the suitable range of pka is -10 to -3.

[0040] As a preferred embodiment of the present invention, in step g), the reaction temperature is 20°C-35°C.

[0041] Compared with the prior art, the present invention has the following beneficial effects:

[0042] 1) The present invention avoids the step of high performance liquid chromatography for chiral separation, avoids the use of a large amount of chromatography-grade solvents, and greatly reduces the generation of waste solvents.

[0043] 2) The present invention avoids the use of expensive platinum metal, also avoids the use of expensive transition metal coupling reactions, avoids the use of corresponding ligands for coupling reactions, and greatly reduces costs.

[0044] 3) The present invention avoids the application of enzyme-catalyzed reaction conditions, reduces the difficulty of technology transfer from small-scale trial processes to industrial production, and reduces the technical barriers to large-scale production.

[0045] 4) The post-treatment process adopted by the present invention also does not need to use column chromatography to purify and separate the product, and most steps do not need to purify the crude product, which saves production time, improves production efficiency, and greatly reduces costs. It is suitable for industrial mass production and also suitable for small-scale preparation in the laboratory.

[0046] 5) The process route of the present invention is different from the prior art and is a novel synthesis strategy that can realize industrial scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative labor.

[0048] Figure 1 It is the synthesis route diagram of the present invention.

[0049] Figure 2 It is the HPLC purity spectrum of the compound VII of Example 5 of the present invention.

[0050] Figure 3 is Example 5 Compound VII of the present invention 1 HNMR spectrum.

[0051] Figure 4 It is the HPLC purity spectrum of the compound VII of Example 5 of the present invention.

[0052] Figure 5 is Example 5 Compound VII of the present invention 1 HNMR spectrum. DETAILED DESCRIPTION

[0053] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0054] See also Figure 1 The present invention provides a method for asymmetric synthesis of Ubudepan chiral intermediates.

[0055] The specific steps are:

[0056] a) The substance represented by formula (I) is dissolved in a solvent, and an aminating agent such as aqueous ammonia, ammonium formate, ammonium acetate, etc. is added, and the reaction is heated until the reaction is completed. The reaction solution is concentrated, extracted and washed, and then cooled to room temperature, and a base and a crystallization solvent are added. After filtering and drying, the compound represented by formula (II) is obtained.

[0057] b) The substance represented by formula (II) is dissolved in a solvent, a base is added at 0-10°C and the mixture is stirred under the condition of heat preservation, and then trifluoroethyl trifluoromethanesulfonate is added to react until the reaction is completed. The reaction solution is quenched with acid, extracted, washed, dried and concentrated to obtain the compound represented by formula (III).

[0058] c) The substance represented by formula (III) is dissolved in a solvent, an acid is added dropwise to remove the protecting group, and then a base is added dropwise to neutralize it. After extraction, stratification, washing, drying and concentration, a compound represented by formula (IV) is obtained.

[0059] d) dissolving the substance represented by formula (IV) in a solvent, adding a chiral acid capable of forming a salt therewith and a catalytic amount of an aldehyde, such as 5-nitrosalicylicylaldehyde and 3,5-dichlorosalicylicylaldehyde, etc., and an appropriate amount of water in sequence, heating the mixture to a certain temperature and keeping the temperature for an appropriate time, then slowly cooling the mixture, filtering and drying the mixture to obtain a compound represented by formula (V).

[0060] e) reacting the substance represented by formula (V) with an acylation protecting agent, such as di-tert-butyl dicarbonate, acetyl chloride, benzoyl chloride, etc., adding an extraction solvent, separating the layers, washing, drying and concentrating to obtain a compound represented by formula (VI).

[0061] f) dissolving the compound represented by formula (VI) in a solvent, adding a noble metal catalyst, such as palladium-carbon, Ru-C, Pt-C, PtO2, Rh(PPh3)3Cl, etc., and reacting at room temperature or at elevated temperature under a hydrogen pressure of 1-10 MPa until completion. The compound represented by formula (VII) can be obtained by suction filtration and desolvation.

[0062] g) The compound represented by formula (VII) is dissolved in a solvent, an acid is added dropwise to remove the protecting group, a base is added dropwise to neutralize, and after extraction, stratification, washing, drying and concentration, a compound represented by formula (A) is obtained.

[0063] Some of the raw materials, reagents or equipment used in the present invention can be purchased from the market, see Table 1.

[0064] Table 1. Sources of raw materials

[0065]

[0066]

[0067] In the present invention, the starting materials used are produced by the applicant company, and the synthesis method can refer to patent WO2013 / 169348A1.

[0068] Figure 1 In the above, R1 is a C1-C3 alkyl group, R2 is an acyl protecting group, preferably -Boc, acetyl or benzoyl, R*CO2H is an optically active chiral acid, including but not limited to mandelic acid, acetylglutamic acid, malic acid, tartaric acid, diphenyl tartrate, camphoric acid, etc. in R or S configuration, and the hydrogenation catalyst is a homogeneous or heterogeneous catalyst containing a transition metal such as Ni, Pd, Pt, Ru or Rh.

[0069] Example 1

[0070] See also Figure 1 This embodiment provides a route for the asymmetric synthesis of a chiral intermediate of Ubudepan, comprising:

[0071] 1) Compound Ia: methyl 2-((tert-butyloxycarbonyl)amino)-5-oxo-4-phenylhexanoate (92.6 g, 1.0 eq), acetic acid (82.8 g, 5.0 eq), ammonium acetate (106.5 g, 5.0 eq) were added to a 500 mL reaction bottle. After nitrogen replacement three times, stirring was started, the internal temperature was raised to about 75°C and kept warm for 18 hours, and potassium bicarbonate solution (potassium bicarbonate: 163.5 g, water: 600 g) and TBME (290 g) were added after cooling to room temperature. A large amount of white solid was precipitated, and 36.2 g of compound II was obtained after filtering and drying. White solid, yield: 93.6%, HPLC purity: 99.3%.

[0072] 2) Add compound II (25.0 g, 1.0 eq), K2CO3 (1.2 eq), N,N-dimethylformamide to a 500 mL reaction bottle, replace the atmosphere with nitrogen three times, start stirring, add trifluoroethyl trifluoromethanesulfonate (8.7 g, 1.2 eq), heat to 100°C, and keep warm for 16 hours. After the reaction is complete, add 1.5% HCl aqueous solution (170 g) to the reaction solution, and extract twice with n-heptane (162.8 g). Combine the organic phases, wash once with 5% brine (120 g), dry over anhydrous sodium sulfate, and remove the solvent to obtain a light yellow oily compound III, which is directly used for the next step.

[0073] 3) Add isopropyl acetate (111.5 g) to the reaction bottle containing compound III to dissolve, add 20% HCl isopropyl acetate (30.2 g, 2 eq) dropwise, stir at 25-35°C for 2 hours after addition, add 30% liquid alkali (22.0 g, 2.0 eq) dropwise. After separation, the organic phase is washed once with 5% brine (120 g), dried over anhydrous sodium sulfate, and the solvent is removed to obtain a yellow oil compound IV, which is directly used for the next step reaction.

[0074] 4) Add isopropanol (100 mL) to the reaction bottle containing compound IV to dissolve, add (S)-mandelic acid (15.1 g, 1.2 eq), 5-nitrosalicylic aldehyde (0.14 g, 0.01 eq), and 1 mL of water in sequence, heat to about 110-115°C and keep warm for 48 hours, slowly reduce to 0-10°C and keep warm for 3 hours, filter and dry to obtain 29.3 g of compound Va. White solid, yield: 81.2%, HPLC purity: 99.5%.

[0075] 5) Add compound Va (18.0 g, 1.0 eq) and isopropyl acetate to a 500 mL reaction bottle, stir until dissolved, then wash with 5% potassium phosphate, dry with anhydrous sodium sulfate, remove the solvent, and add tetrahydrofuran to dissolve. Add dropwise to aqueous sodium bicarbonate and di-tert-butyl dicarbonate (1.1 eq), stir at 20-25°C for 1 hour. Add methyl tert-butyl ether, separate the layers, wash the organic phase once with 5% brine, dry with anhydrous sodium sulfate, remove the solvent, and obtain 15.2 g of compound VI. Pale yellow solid, yield: 95.9%, HPLC purity: 99.6%.

[0076] 6) Add compound VI (10.0 g, 1.0 eq), methanol, 5% palladium carbon (1.0 g) to a 500 mL high pressure reaction bottle, pressurize with hydrogen to about 3-5 MPa, heat to about 40-50 ° C and react for 24 hours. Filter and remove the solvent to obtain 9.28 g of compound VII (R2 = Boc). Light yellow solid, yield: 92.3%, isomer (3S, 5S, 6R): (3S, 5R, 6S) ratio is 95:5.

[0077] 7) Add compound VII (8.0 g, 1.0 eq) to a 100 mL reaction bottle, dissolve in isopropyl acetate, add 20% HCl isopropyl acetate (2 eq) dropwise, stir at room temperature of 20-35°C for 2 hours, and add 30% liquid caustic soda (2.0 eq) dropwise. After separation, the organic phase is washed once with 5% brine, dried over anhydrous sodium sulfate, and the solvent is removed to obtain 5.81 g of the free base form of fragment A. Pale yellow liquid, yield: 98.0%, HPLC purity: 99.9%.

[0078] Example 2

[0079] See also Figure 1 This embodiment provides a route for the asymmetric synthesis of a chiral intermediate of Ubudepan, comprising:

[0080] 1) Add compound Ib: ethyl 2-((tert-butyloxycarbonyl)amino)-5-oxo-4-phenylhexanoate (48.3 g, 1.0 eq), ammonia (3.0 eq), acetic acid (5.0 eq) to a 500 mL reaction bottle, replace the atmosphere with nitrogen three times, start stirring, raise the internal temperature to about 80°C and keep it for 14 hours, then add potassium bicarbonate solution and TBME after cooling to room temperature, and a large amount of white solid precipitates. After filtering and drying, 18.3 g of compound II is obtained. White solid, yield: 94.0%, HPLC purity: 99.0%.

[0081] 2) Add compound II (20.0 g, 1.0 eq), DMPU (1.2 eq), and tetrahydrofuran to a 500 mL reaction bottle. After nitrogen replacement three times, start stirring, cool to about 2-8 ° C, add lithium tert-butoxide (1.2 eq) and keep warm for 1 hour, add trifluoroethyl trifluoromethanesulfonate (1.2 eq), and continue to keep warm for 12 hours. Add the reaction solution to 1.5% HCl aqueous solution and extract twice with n-heptane. Combine the organic phases, wash once with 5% brine, dry over anhydrous sodium sulfate, and remove the solvent to obtain a light yellow oil compound III, which is directly used for the next step reaction.

[0082] 3) Add isopropyl acetate to the reaction bottle containing compound III to dissolve, add 20% HCl isopropyl acetate dropwise, stir at 20-35°C for 2 hours after addition, and add 30% liquid alkali (2.0 eq) dropwise. After separation, the organic phase is washed once with 5% brine, dried over anhydrous sodium sulfate, and the solvent is removed to obtain a yellow oil compound IV, which is directly used for the next step reaction.

[0083] 4) Add isopropanol to the reaction bottle containing compound IV to dissolve, add L-tartaric acid (1.2 eq), 5-nitrosalicylic aldehyde (0.28 g), water (6.7 g) in sequence, raise the temperature to about 110-120°C and keep it for 52 hours, slowly reduce the temperature to 2-8°C and keep it for 2 hours, filter and dry to obtain 22.3 g of compound Va. White solid, yield: 77.2%, HPLC purity: 99.3%.

[0084] 5) Add compound Va (16.0 g, 1.0 eq) and isopropyl acetate to a 500 mL reaction bottle, stir until dissolved, then wash with 5% potassium phosphate, dry with anhydrous sodium sulfate, remove the solvent, and add tetrahydrofuran to dissolve. Add dropwise to aqueous sodium bicarbonate solution and di-tert-butyl dicarbonate (8.8 g, 1.1 eq), stir at 30-35°C for 1 hour. Add methyl tert-butyl ether, separate the layers, wash the organic phase once with 5% brine, dry with anhydrous sodium sulfate, remove the solvent, and obtain 13.8 g of compound VI. Pale yellow solid, yield: 98.0%, HPLC purity: 99.4%.

[0085] 6) Add compound VI (10.0 g, 1.0 eq), methanol, 10% ruthenium on carbon (1.0 g) to a 500 mL high pressure reaction bottle, pressurize the hydrogen to about 1-3 MPa, and heat to about 55°C for 36 hours. Filter and remove the solvent to obtain 9.1 g of compound VII. Pale yellow solid, yield: 90.5%, isomer (3S, 5S, 6R): (3S, 5R, 6S) ratio is 90:10.

[0086] 7) Add compound VII (7.0 g, 1.0 eq) to a 100 mL reaction bottle, dissolve in isopropyl acetate, add 20% HCl isopropyl acetate (2 eq) dropwise, stir at 20-25°C for 2 hours, and add 30% liquid caustic soda (2.0 eq) dropwise. After separation, the organic phase is washed once with 5% brine, dried over anhydrous sodium sulfate, and the solvent is removed to obtain 5.1 g of the free base form of fragment A. Pale yellow liquid, yield: 98.3%, HPLC purity: 99.9%.

[0087] Example 3

[0088] See also Figure 1 This embodiment provides a route for the asymmetric synthesis of a chiral intermediate of Ubudepan, comprising:

[0089] 1) Add compound Ic: 2-((tert-butyloxycarbonyl)amino)-5-oxo-4-phenylhexanoic acid isopropyl ester (50.2 g, 1.0 eq), formic acid (5.0 eq), ammonium formate (5.0 eq) to a 500 mL reaction bottle, replace with nitrogen three times, start stirring, raise the internal temperature to about 70-80°C and keep warm for 18 hours, cool to room temperature and add potassium bicarbonate solution (potassium bicarbonate: 82 g, water: 300 g), TBME (3V), a large amount of white solid precipitates, filter and dry to obtain 17.3 g of compound II. White solid, yield: 91.6%, HPLC purity: 99.1%.

[0090] 2) Add compound II (21.0 g, 1.0 eq) to a 500 mL reaction flask, replace the atmosphere with nitrogen three times, start stirring, cool to about 5°C, add potassium tert-butoxide (1.2 eq) and keep warm for 1 hour, add trifluoroethyl trifluoromethanesulfonate (1.2 eq), and continue to keep warm for 14 hours. Add 1.5% HCl aqueous solution (7V) to the reaction solution, extract twice with n-heptane (7V). Combine the organic phases, wash once with 5% brine (5V), dry over anhydrous sodium sulfate, remove the solvent, and obtain a light yellow oily compound III, which is directly used for the next step.

[0091] 3) Add isopropyl acetate (5V) to the reaction bottle containing compound III to dissolve, add 20% HCl isopropyl acetate (2eq) dropwise, stir at 20-35°C for 2 hours after addition, and add 30% liquid alkali (2.0eq) dropwise. After separation, the organic phase is washed once with 5% brine (5V), dried over anhydrous sodium sulfate, and the solvent is removed to obtain a yellow oil compound IV, which is directly used for the next step reaction.

[0092] 4) Add isopropanol (5Vg) to the reaction bottle containing compound IV to dissolve, add (S)-mandelic acid (1.2eq), 3,5-dichlorosalicylaldehyde (0.3g), water (7g) in sequence, raise the temperature to about 115-130°C and keep it for 56 hours, slowly reduce the temperature to 5°C and keep it for 2 hours, filter and dry to obtain 22.1g of compound Va. White solid, yield: 72.8%, HPLC purity: 99.5%.

[0093] 5) Add compound V (15.0 g, 1.0 eq) and isopropyl acetate (10 V) to a 500 mL reaction bottle, stir until dissolved, then wash with 5% potassium phosphate, dry with anhydrous sodium sulfate, remove the solvent, and add tetrahydrofuran to dissolve. Add dropwise to a mixture of sodium bicarbonate aqueous solution and di-tert-butyl dicarbonate (1.1 eq), and stir at 25-30 ° C for 1 hour. Add methyl tert-butyl ether, separate the layers, wash the organic phase once with brine, dry with anhydrous sodium sulfate, and remove the solvent to obtain 13.0 g of compound VI. Pale yellow solid, yield: 98.4%, HPLC purity: 99.4%.

[0094] 6) Add compound VI (10.0 g, 1.0 eq), methanol, 5% palladium carbon (1.0 g) to a 500 mL high pressure reaction bottle, pressurize with hydrogen to 8-10 MPa, heat to about 40-45 ° C and react for 18 hours. Filter and remove the solvent to obtain 9.2 g of compound VII. Light yellow solid, yield: 91.5%, isomer (3S, 5S, 6R): (3S, 5R, 6S) ratio is 95:5.

[0095] 7) Add compound VII (7.0 g, 1.0 eq) to a 100 mL reaction bottle, dissolve in isopropyl acetate, add 20% HCl isopropyl acetate (2 eq) dropwise, stir at 20-30°C for 2 hours, and add 30% liquid caustic soda (2.0 eq) dropwise. After separation, the organic phase is washed once with 5% brine, dried over anhydrous sodium sulfate, and the solvent is removed to obtain 5.0 g of the free base of fragment A. Pale yellow liquid, yield: 96.4%, HPLC purity: 99.9%.

[0096] Example 4

[0097] Referring to Figure 7, this embodiment provides a route for asymmetric synthesis of Ubudepan chiral intermediates, comprising:

[0098] 1) Add compound II (20.0 g, 1.0 eq), NaH (1.2 eq), DMF (7 V) to a 500 mL reaction bottle, replace the atmosphere with nitrogen three times, start stirring, cool to 5 ° C, add trifluoroethyl trifluoromethanesulfonate (1.2 eq), and continue to keep warm for 12 hours. Add the reaction solution to citric acid aqueous solution and extract twice with n-heptane. Combine the organic phases, wash once with 5% brine, dry over anhydrous sodium sulfate, and remove the solvent to obtain a light yellow oil compound III, which is directly used for the next step reaction.

[0099] 2) Add isopropyl acetate to the reaction bottle containing compound III to dissolve, add 20% HCl isopropyl acetate (2.1 eq) dropwise, stir at 20-35°C for 2 hours, and add 30% liquid alkali (2.0 eq) dropwise. After separation, the organic phase is washed once with 5% brine, dried over anhydrous sodium sulfate, and the solvent is removed to obtain a yellow oil compound IV, which is directly used for the next step reaction.

[0100] 3) Add 100 mL of isopropanol to the reaction bottle containing compound IV to dissolve, add L-DBTA (1.2 eq), 5-nitrosalicylicylaldehyde (0.28 g, 0.02 eq) and 1 mL of water in sequence, heat to about 110-120°C and keep warm for 60 hours, slowly reduce to 2-8°C and keep warm for 2 hours, filter and dry to obtain 18.9 g of compound Vb. White solid, yield: 68.3%, HPLC purity: 99.4%.

[0101] 4) Add compound Vb (15.0 g, 1.0 eq) and isopropyl acetate to a 500 mL reaction bottle, stir to dissolve, then wash with 5% potassium phosphate, dry with anhydrous sodium sulfate and remove the solvent, add tetrahydrofuran to dissolve. Add dropwise to a mixture of sodium bicarbonate (aqueous solution) and di-tert-butyl dicarbonate (1.1 eq), stir at 20-30°C for 1 hour. Add methyl tert-butyl ether, separate the layers, wash the organic phase once with 5% brine, dry with anhydrous sodium sulfate, remove the solvent, and obtain 13.5 g of compound VI. Pale yellow solid, yield: 97.9%, HPLC purity: 99.5%.

[0102] 5) Add compound VI (10.0 g, 1.0 eq), methanol, tris(triphenylphosphine)rhodium chloride (1.0 g) to a 500 mL high pressure reaction bottle, pressurize the hydrogen to about 5-7 MPa, heat to 45-55 ° C and react for 24 hours. Filter and remove the solvent to obtain 9.25 g of compound VII. Light yellow solid, yield: 92.0%, isomer (3S, 5S, 6R): (3S, 5R, 6S) ratio is 97:3.

[0103] 6) Add compound VII (5.0 g, 1.0 eq) to a 100 mL reaction bottle, dissolve in isopropyl acetate, add 20% HCl isopropyl acetate (2 eq) dropwise, stir at 25-35° C. for 2 hours, and add 30% liquid caustic soda (2.0 eq) dropwise. After separation, the organic phase is washed once with 5% brine, dried over anhydrous sodium sulfate, and the solvent is removed to obtain 3.5 g of the free base form of fragment A. Pale yellow liquid, yield: 94.5%, HPLC purity: 99.8%.

[0104] Example 5

[0105] See also Figure 1 This embodiment provides a route for asymmetric synthesis of a chiral intermediate of Ubudepam at the 100-gram level, comprising:

[0106] 1) Add compound Ic: 2-((tert-butyloxycarbonyl)amino)-5-oxo-4-phenylhexanoic acid isopropyl ester (1.03kg, 1.0eq), acetic acid (5.0eq), ammonium acetate (5.0eq) to a 10L reactor, replace with nitrogen three times, start stirring, raise the internal temperature to about 70-80°C and keep warm for 18 hours, cool to room temperature, add potassium bicarbonate solution and TBME, a large amount of white solid precipitates, filter and dry to obtain 524.3g of compound II. White solid, yield: 61.5%, HPLC purity: 99.1%.

[0107] 2) Add compound II (500 g, 1.0 eq), DMPU (1.2 eq), and tetrahydrofuran to a 10 L reaction flask. After nitrogen replacement three times, start stirring, cool to about 5 ° C, add lithium tert-butoxide (1.2 eq) and keep warm for 1 hour, add trifluoroethyl iodide (1.2 eq), and continue to keep warm for 14 hours. Add the reaction solution to 1.5% HCl aqueous solution and extract twice with n-heptane. Combine the organic phases, wash once with 5% brine, dry over anhydrous sodium sulfate, and remove the solvent to obtain a light yellow oil compound III, which is directly used for the next step reaction.

[0108] 3) Add isopropyl acetate to the reaction bottle containing compound III to dissolve, add 20% HCl isopropyl acetate (2 eq) dropwise, stir at 20-35°C for 2 hours, and add 30% liquid alkali (2.0 eq) dropwise. After separation, the organic phase is washed once with 5% brine, dried over anhydrous sodium sulfate, and the solvent is removed to obtain a yellow oil compound IV, which is directly used for the next step reaction.

[0109] 4) Add isopropanol (5V) to the reaction bottle containing compound IV to dissolve, add acetyl-L-glutamic acid (1.2eq), 5-nitrosalicylic aldehyde (0.01eq), water (0.05V) in sequence, raise the temperature to about 115-125°C and keep it for 60 hours, slowly reduce the temperature to 2-8°C and keep it for 2 hours, filter and dry to obtain 564.1g of compound Va. White solid, yield: 78.1%, HPLC purity: 99.6%.

[0110] 5) Add compound V (500 g, 1.0 eq) and isopropyl acetate to a 10 L reaction flask, stir to dissolve, then wash with 5% potassium phosphate, dry with anhydrous sodium sulfate and remove the solvent, add tetrahydrofuran to dissolve. Add dropwise to aqueous sodium bicarbonate and di-tert-butyl dicarbonate (1.1 eq), stir at 25-30 ° C for 1 hour. Add methyl tert-butyl ether, separate the layers, wash the organic phase once with 5% brine, dry with anhydrous sodium sulfate, remove the solvent, and obtain 426.5 g of compound VI. Pale yellow solid, yield: 96.8%, HPLC purity: 99.5%.

[0111] 6) Add compound VI (200.0 g, 1.0 eq), methanol, 5% PtO2 (20.0 g) to a 5 L high pressure reaction bottle, pressurize with hydrogen to 4-5 MPa, raise the temperature to about 45-55°C and react for 36 hours. Filter and remove the solvent to obtain 182.2 g of compound VII. 1 H NMR (CDCl3) δ7.34 (t, 2H), 7.25 (d, 1H), 7.19 (d, 2H), 5.41 (s, 1H),

[0112] 4.91(m,1H), 4.18(m,1H), 3.85(m,1H), 3.54(m,1H), 3.22(dt,1H), 2.62(m,1H),

[0113] 2.42 (dd, 1H), 1.46 (s, 9H), 0.96 (d, 3H). Pale yellow solid, yield: 90.6%, isomer (3S, 5S, 6R): (3S, 5R, 6S) ratio: 99%: 0.1%, HPLC purity see Figure 2 , 1 HNMR spectra see Figure 3 .

[0114] 7) Add compound VII (150.0 g, 1.0 eq) to a 100 mL reaction bottle, dissolve in isopropyl acetate, dropwise add 20% HCl isopropyl acetate (2 eq), stir at 20-30°C for 2 hours, dropwise add 30% liquid caustic soda (2.0 eq). After separation, the organic phase is washed once with 5% brine, dried over anhydrous sodium sulfate, and the solvent is removed to obtain 107.9 g of the free base of fragment A.1 H NMR (CDCl3) δ7.36 (t, 2H), 7.29 (d, 1H), 7.21 (d, 2H), 4.90 (s, 1H), 3.84 (m, 1H), 3.63 (dd, 1H), 3.22 (m, 1H), 2.39 (m, 1H), 2.26 (dd, 1H), 0.94 (d, 3H). Pale yellow liquid, yield: 97.1%, HPLC purity: 99.9% Figure 3 , 1 HNMR spectra see Figure 4 .

[0115] The above is only a preferred embodiment of the present invention, and is not any formal or substantial limitation of the present invention. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention, and these improvements and supplements should also be regarded as the protection scope of the present invention. Any technician familiar with this profession, without departing from the spirit and scope of the present invention, can make some changes, modifications and evolutions of the technical content disclosed above, which are equivalent embodiments of the present invention; at the same time, any changes, modifications and evolutions of any equivalent changes made to the above embodiments based on the essential technology of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A method for asymmetric synthesis of chiral intermediates of ubagepan, characterized in that: The synthesis method comprises the following steps: (a) the substance represented by formula (I) is reacted with an amino reagent to form a ring to obtain a compound represented by formula (II); (b) the compound represented by formula (II) is subjected to trifluoroethylation reaction to obtain the compound represented by formula (III); (c) removing the Boc protecting group from the compound represented by formula (III) to obtain the compound represented by formula (IV); (d) the compound represented by formula (IV) is subjected to an aldehyde-catalyzed kinetic resolution process, and then induced by chiral acid salt formation and precipitation to obtain the compound represented by formula (V); (e) a compound represented by formula (V), after adding a Boc protecting group, an acetyl group or a benzoyl group to the amino group to obtain a compound represented by formula (VI); (f) the compound represented by formula (VI) is subjected to catalytic hydrogenation to obtain the compound represented by formula (VII); (g) The compound represented by formula (VII) is subjected to the removal of the Boc protecting group, acetyl group or benzoyl group to obtain the compound represented by formula (A) Among them, the compound represented by formula (I): The compound represented by formula (II): The compound represented by formula (III): The compound represented by formula (IV): The compound represented by formula (V): The compound represented by formula (VI): The compound represented by formula (VII): The compound represented by formula (A): In the formula, R is any alkyl or aryl group, and Chiralacid is any chiral acid that can form a salt with the free base of compound IV.

2. The method for asymmetric synthesis of a chiral intermediate of Ubudepa according to claim 1, characterized in that: In the step a), the reaction temperature is 70°C-80°C.

3. The method for asymmetric synthesis of a chiral intermediate of Ubudepa according to claim 1, characterized in that: In the step b), the trifluoroethylation reagent is trifluoroethyl trifluoromethanesulfonate, and the reaction temperature is 0°C-10°C.

4. The method for asymmetric synthesis of a chiral intermediate of Ubudepa according to claim 1, characterized in that: In the step c), the reagent used for the Boc deprotection condition includes any acid with a suitable pka; and the reaction temperature is 20°C-35°C.

5. The method for asymmetric synthesis of chiral intermediates of Ubudepa according to claim 1, characterized in that: In the step d), the chiral acid is any chiral acid that can form a salt with the free base of compound IV, including S-mandelic acid, L-glutamic acid, L-malic acid or L-tartaric acid; the catalyst is any aromatic aldehyde compound that forms an imine intermediate with III and undergoes racemization at the imine alpha position under alkaline conditions; and the reaction temperature is 110°C-130°C.

6. The method for asymmetric synthesis of Ubudepan chiral intermediate according to claim 1, characterized in that: In the step e), the reagent for the Boc protecting group, acetyl group or benzoyl group on the amino group is di-tert-butyl dicarbonate, acetyl chloride or benzoyl chloride, and the reaction temperature is 20°C-35°C.

7. The method for asymmetric synthesis of Ubudepan chiral intermediate according to claim 1, characterized in that: In the step f), the catalyst for the hydrogenation reaction is at least one of a palladium catalyst and a nickel catalyst.

8. The method for asymmetric synthesis of Ubudepan chiral intermediate according to claim 1, characterized in that: In the step f), the temperature of the hydrogenation reaction is 40° C.-55° C., and the pressure of the hydrogenation reaction is 1 MPa-10 MPa.

9. The method for asymmetric synthesis of Ubudepan chiral intermediate according to claim 1, characterized in that: In the step g), the reagents used for the deprotection of the Boc group, acetyl group or benzoyl group include any acid with a suitable pka.

10. The method for asymmetric synthesis of Ubudepan chiral intermediate according to claim 1, characterized in that: In the step g), the reaction temperature is 20°C-35°C.

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