Method for synthesizing high-optical-purity five-membered lactam skeleton bulk drug through rhodium catalysis

Abstract

The invention discloses a method for synthesizing a five-membered lactam skeleton bulk drug with high optical purity under the catalysis of rhodium, which is characterized in that racemic and cheap gamma-substituted alpha, beta-unsaturated gamma-lactam is used as a raw material, a dicyclooctene hydroxyl rhodium (I) dimer is used as a catalyst, a cheap chiral phosphine ligand is used as a ligand, and the raw material is synthesized by a one-step method. The high enantioselectivity arylation reaction with arylboronic acid is realized. According to the method, the optical purity limit of a traditional route is successfully broken through, the specific rotation of the obtained trans-beta, gamma-disubstituted gamma-lactams with three single configurations is remarkably higher than the highest value in the literature, and a high-enantioselectivity key synthesis building block is provided for synthesis of a protein kinase C regulator, a glutamate receptor antagonist and CGN-10100. The method provided by the invention is simple and easy to operate, mild in reaction condition, high in yield and strong in derivation ability, and provides a new method for efficient and high-enantioselectivity preparation of chiral bulk drugs.

Description

Technical Field

[0001] This invention belongs to the interdisciplinary field of organic synthetic chemistry and medicinal chemistry, specifically relating to a catalytic asymmetric synthesis method for chiral active pharmaceutical ingredients. More specifically, this invention relates to a method for efficiently and enantioselectively constructing chiral active pharmaceutical ingredients (protein kinase C regulators, glutamate receptor antagonists, and key intermediates of CNG-10100 pharmaceutical active molecules) using racemic compounds as starting materials through an asymmetric arylation reaction catalyzed by chiral rhodium metal complexes. Background Technology

[0002] Chiral five-membered ring lactam structural units are the core framework for constructing many bioactive molecules. As shown below, chiral aryl compounds 3a, 3b, and 3c are key building blocks for the preparation of protein kinase C regulators, glutamate receptor antagonists, and CNG-10100, respectively.

[0003]

[0004] In existing technologies, obtaining high-optical-purity chiral active pharmaceutical ingredients mainly relies on two synthetic routes: The first is synthesis using pre-prepared chiral raw materials. Although this method can control the stereoconfiguration to some extent, the limited availability and variety of chiral raw materials severely restricts the structural diversity of the products, and the cost of large-scale production is also high. The second route involves first synthesizing the racemic mixture and then resolving it using physical or chemical methods. This route has poor atom economy, with a theoretical yield ceiling of only 50%, and the resolving process is usually cumbersome and inefficient, requiring the use of equivalent chiral resolving agents and generating a large amount of non-target enantiomeric waste, which does not meet the requirements of green chemistry and sustainable development.

[0005] Both of the aforementioned traditional methods have significant limitations: the improvement of the enantiomeric excess value (ee value) of the obtained products has reached a bottleneck, especially for aryl compounds 3a, 3b, and 3c, where effective separation on a chiral column in high-performance liquid chromatography is difficult, thus restricting further improvement in their optical purity. Literature reports also confirm that the specific rotation values ​​of 3a, 3b, and 3c synthesized from chiral starting materials are relatively low (see...). J. Am. Chem. Soc. 1998, 120, 6629-6630; J. Med. Chem. 2015, 58 (6131–6150), whose optical purity is difficult to meet the stringent requirements of the next generation of highly selective drugs.

[0006] In recent years, although some studies have attempted to directly construct chiral centers using transition metal / chiral ligand catalytic systems (such as rhodium / chiral dienes), many problems remain, such as low reaction yields, low specific rotation of products, and cumbersome and expensive chiral ligand preparation steps (see [link to study]). ACS Catal.(2023, 13, 6603-6609). Therefore, developing a new chiral synthesis method that is efficient, highly selective, atom-economical, and suitable for large-scale production remains a key challenge that urgently needs to be overcome in this field. Summary of the Invention

[0007] The purpose of this invention is to overcome the problems of low specific rotation and limited substrate types in the synthesis methods of chiral active pharmaceutical ingredients, such as protein kinase C modulators and glutamate receptor antagonists, and to provide a method for synthesizing high optical purity pentamic lactam skeleton active pharmaceutical ingredients using inexpensive and readily available racemic compounds as raw materials and rhodium catalysis.

[0008] The method for synthesizing a high-optical-purity pentamic lactam framework active pharmaceutical ingredient provided by this invention is as follows: A bicyclic octene hydroxyrhodium(I) dimer, a chiral phosphine ligand, racemic substrate 1, and arylboronic acid 2 are added to a solvent, and an arylation reaction is carried out at 40–60 °C under anhydrous and oxygen-free conditions. After the reaction is completed, the mixture is separated and purified to obtain a chiral pentamic lactam framework active pharmaceutical ingredient 3. The reaction equation is as follows:

[0009] In the formula, Ar represents phenyl, 3-bromophenyl, or 2,2-dimethyl-4-phenylene oxide. H Any one of -1,3-benzodioxane-6-yl groups.

[0010] The structural formula of the bicyclic octene hydroxyrhodium(I) dimer is shown below:

[0011] The chiral phosphine ligand (( R The structure of )-binap is shown below:

[0012] The molar ratio of racemic substrate 1 to arylboronic acid 2 is 1:1.2 to 2.

[0013] In the above synthesis method, the amount of the bicyclooctene hydroxyrhodium(I) dimer added, based on the amount of rhodium, is preferably 2% to 4% of 1 mole of the racemic substrate.

[0014] In the above synthesis method, the amount of chiral phosphine ligand added is preferably 3% to 6% of 1 mole of racemic substrate.

[0015] In the above synthesis method, it is preferred to stir the reaction at 40–60 °C for 10–12 hours under anhydrous and oxygen-free conditions.

[0016] In the above synthesis method, the solvent is preferably a mixture of 1,4-dioxane and deionized water in a volume ratio of 8 to 12:1.

[0017] In the above synthesis method, the separation and purification method is as follows: first, using ethyl acetate as the eluent, the mixture after reaction is filtered through a short silica gel column, and the solvent is removed by rotary evaporation to obtain the crude product. Then, using a mixture of n-hexane and ethyl acetate in a volume ratio of 5:1 as the eluent, the crude product is separated by silica gel column chromatography with a mesh size of 200-300.

[0018] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. This invention does not involve the "transfer" of chiral sources or the "separation" of mixtures, but rather the "creation" of chirality during the reaction process through asymmetric catalysis. This fundamental difference enables the method of this invention to overcome the optical purity bottleneck of traditional methods. The specific rotation of the product obtained by this invention is significantly higher than the highest value in the literature, achieving high enantioselectivity and solving the industry problem that the product cannot be verified by conventional chiral chromatography.

[0019] 2. This invention avoids the theoretical yield loss (50%) of traditional splitting and can theoretically achieve 100% atomic utilization, efficiently converting all raw material molecules into target chiral molecules, thus reducing waste at the source.

[0020] 3. By simply replacing arylboronic acid 2, this invention can efficiently and selectively derive a variety of high-value chiral active pharmaceutical ingredients (3a, 3b, and 3c, etc.) with diverse structures, providing highly enantioselective key raw materials for the synthesis of protein kinase C regulators, glutamate receptor antagonists, and CNG-10100.

[0021] 4. This invention is simple to operate, avoids the use of expensive and potentially difficult-to-recycle chiral auxiliary reagents or resolving agents, and has mild reaction conditions, which are more in line with the requirements of green chemistry and industrial production. Attached Figure Description

[0022] Figure 1 This is the 1H NMR spectrum of protein kinase C regulator intermediate 3a.

[0023] Figure 2 This is the 1H NMR spectrum of glutamate receptor antagonist intermediate 3b.

[0024] Figure 3 This is the hydrogen NMR spectrum of CNG-10100 intermediate 3c. Detailed Implementation

[0025] The present invention will be further described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention is not limited to these embodiments.

[0026] In the following embodiments, racemic substrate 1 is based on the literature J. Med. Chem. The preparation method is reported in 2015, 58, 6131–6150.

[0027] As shown in Table 1, the present invention screened catalysts, boron sources, ligands, solvents and temperatures, and finally obtained the optimal conditions.

[0028]

[0029] Table 1

[0030] Note: In the table a Reaction conditions: 1 (0.20 mmol), boron source (0.30 mmol), catalyst (3.0 mol%Rh), ligand (4.0 mol%), solvent 1 mL / 0.1 mL, stirred in an oil bath at 50 °C for 10 hours; b Reaction conditions: 1 (0.20 mmol), 2a (0.40 mmol), [RhCl(coe)2]2 (5.0 mol% Rh), L1a (4.0 mol%), triethylamine (0.6 mmol), solvent 1 mL / 0.1 mL, stirred in an oil bath at 60 °C for 14 hours.

[0031] As shown in Table 1, commercially available phenylboronic acid as a boron source yields better results than potassium phenyltrifluoroborate; the in-situ generated alkaline catalyst [Rh(OH)(coe)2]2 yields better results than [RhCl(coe)2]2 / NEt3; and the inexpensive and readily available ( R The 1,4-binap reaction yielded better results than the cumbersome and expensive preparation of chiral diene ligands; the reaction with 1,4-dioxane as a solvent yielded better results than toluene; and the product obtained at 50 °C had higher specific rotation when the yield did not fluctuate significantly.

[0032] Example 1 Synthesize the protein kinase C regulator intermediate 3a with the following structural formula.

[0033] Add bicyclooctene hydroxyrhodium(I) dimer (2.0 mg, 3.0 mmol, 3.0 mol% Rh) to a 10 mL dry, sealed tube equipped with a stirring magnet. R)-binap (4.9 mg, 8 mmol, 4.0 mol%) was purged with nitrogen three times, and then anhydrous 1,4-dioxane (1.0 mL) was added under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 min to allow complete coordination of the catalyst with the chiral ligand, resulting in a bright red color. Then, racemic substrate 1 (65.5 mg, 0.20 mmol), phenylboronic acid (36.6 mg, 0.30 mmol), and deionized water (0.1 mL) were added sequentially, and the mixture was stirred at 50 °C for 10 h. After the reaction was complete and cooled to room temperature, the mixture was filtered through a short silica gel column using ethyl acetate as the eluent. The solvent was removed using a rotary evaporator to obtain a dark red crude product. The crude product was then separated by silica gel column chromatography (200–300 mesh) using a 5:1 (v / v) mixture of n-hexane and ethyl acetate as the eluent, and the product was collected. R f A solution with a concentration of 0.3 was subjected to vacuum distillation to recover the solvent, yielding a white solid compound 3a, i.e., (4 S 5 R )-3a (73.1 mg, 0.18 mmol), yield 90%.

[0034] The NMR spectrum of compound 3a was measured using a Bruker AVANCE NEO NMR spectrometer, and the results are shown below. Figure 1 The specific data is as follows: 1 H NMR (600 MHz, CDCl3) δ 7.33 (t, J = 7.3 Hz, 2H), 7.25‒7.28 (m,1H), 7.19 (d, J = 7.1 Hz, 2H), 4.08 (dt, J = 3.8 Hz, 2.1 Hz, 1H), 4.00 (dd, J = 10.5 Hz, 3.3 Hz, 1H), 3.80 (dd, J = 10.6 Hz, 2.2 Hz, 1H), 3.45 (dt, J = 9.5Hz, 2.3 Hz, 1H), 3.16 (dd, J = 17.9 Hz, 9.6 Hz, 1H), 2.53 (dd, J = 17.9 Hz, 2.6 Hz, 1H), 1.53 (s, 9H), 0.91 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).

[0035] The specific rotation of compound 3a, [α], was tested using an Anton Paar MCP-4100. 25 D 57.0 (c 1.07, CHCl3), higher than the value reported in the literature [α] 25 D -41.4 (c 1.14, CHCl3) indicates that compound 3a prepared by this method has higher optical purity.

[0036] Example 2 Synthesize the intermediate 3b of the glutamate receptor antagonist with the following structural formula.

[0037] In this embodiment, 3-bromophenylboronic acid was used to replace phenylboronic acid in Example 1, and the other steps were the same as in Example 1, yielding a white solid compound 3b, i.e. (4 S 5 R )-3b (88.2 mg, 0.18 mmol) yield 91%.

[0038] The NMR spectrum of compound 3b was measured using a Bruker AVANCE NEO NMR spectrometer, and the results are shown below. Figure 2 The specific data is as follows: 1 H NMR (500 MHz, CDCl3) δ 7.40 (d, J = 7.9 Hz, 1H), 7.34 (s, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 4.06 (dt, J = 3.9 Hz, 2.1Hz, 1H), 3.99 (dd, J = 10.6 Hz, 3.9 Hz, 1H), 3.80 (dd, J = 10.6 Hz, 2.2 Hz,1H), 3.42 (dt, J = 9.6 Hz, 2.4 Hz, 1H), 3.14 (dd, J = 17.9 Hz, 9.6 Hz, 1H),2.49 (dd, J = 17.9 Hz, 2.6 Hz, 1H), 1.53 (s, 9H), 0.91 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).

[0039] The specific rotation of compound 3b, [α], was measured using an Anton Paar MCP-4100. 25 D -41.0 (c 1.03, CH2Cl2), higher than the reported value [α] in the literature. 25 D -26.6 (c 0.51, CH2Cl2) indicates that compound 3b prepared by this method has higher optical purity.

[0040] Example 3 The CNG-10100 intermediate 3c has the following synthetic structural formula.

[0041] In this embodiment, equimolar amounts of 2,2-dimethyl-4- H -1,3-benzodioxaneboronic acid replaced phenylboronic acid in Example 1, and the other steps were the same as in Example 1, yielding a white solid compound 3c, i.e. (4 S 5 R )-3c (88.5 mg, 0.18 mmol), yield 90%.

[0042] The NMR spectrum of compound 3c was measured using a Bruker AVANCE NEO NMR spectrometer, and the results are shown below. Figure 3 The specific data is as follows: 1 H NMR (500 MHz, CDCl3) δ 6.97 (dd, J = 8.5 Hz, 2.3 Hz, 1H), 6.77(s+d, J = 8.2 Hz, 2H), 4.81 (s, 2H), 4.01 (dt, J = 3.9 Hz, 1.9 Hz, 1H), 3.98(dd, J = 10.4 Hz, 3.9 Hz, 1H), 3.78 (dd, J = 10.4 Hz, 5.4 Hz, 1H), 3.36 (dt, J = 9.4 Hz, 2.3 Hz, 1H), 3.12 (dd, J = 17.8 Hz, 9.6 Hz, 1H), 2.48 (dd, J=17.8 Hz, 2.4 Hz, 1H), 1.53 (s, 6H), 1.52 (s, 9H), 0.9 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H). Specific rotation of compound 3c was determined using an Anton Paar MCP-4100, [α] 25 D -38.2 (c1.00, EtOH), higher than the value reported in the literature [α]. 25 D -20.7 (c 0.28, EtOH) indicates that the 3c prepared by this method has higher optical purity.

Claims

1. A method for rhodium catalyzed synthesis of high optical purity of five-membered lactam back-bone drug substance, characterized by: The bicyclooctene hydroxy rhodium (I) dimer, chiral phosphine ligand, racemic substrate 1 and aryl boronic acid 2 are added into a solvent to carry out arylization under the condition of no water and no oxygen at 40-60 DEG C, after the reaction is completed, separation and purification are carried out, and the chiral five-membered lactam skeleton raw material 3 is obtained; In the formula, Ar represents any one of phenyl, 3-bromophenyl and 2,2-dimethyl-4H-1,3-benzodioxane; The bicyclooctene hydroxy rhodium (I) dimer has the following structural formula: The chiral phosphine ligand has the following structural formula: 。 2. The rhodium catalyzed synthesis of high optical purity of five-membered lactam backbone drug substance according to claim 1, characterized in that: The molar ratio of the racemic substrate 1 to the aryl boronic acid 2 is 1:1.2-2.

3. The rhodium catalyzed synthesis of high optical purity of five-membered lactam backbone drug substance according to claim 1, characterized in that: The bicyclooctene hydroxy rhodium (I) dimer is added in an amount of 2%-4% of the molar amount of the racemic substrate 1 in terms of rhodium element.

4. The rhodium catalyzed synthesis of high optical purity of five-membered lactam backbone drug substance according to claim 1, characterized in that: The chiral phosphine ligand is added in an amount of 3%-6% of the molar amount of the racemic substrate 1.

5. The rhodium catalyzed synthesis of high optical purity of five-membered lactam backbone drug substance according to claim 1, characterized by: The stirring reaction is carried out under the condition of no water and no oxygen at 40-60 DEG C for 10-12 hours.

6. The rhodium catalyzed synthesis of high optical purity of five-membered lactam backbone drug substance according to claim 1, characterized by: The solvent is a mixed solution of 1,4-dioxane and deionized water in a volume ratio of 8-12:

1.

7. The rhodium catalyzed method of synthesis of high optical purity of five- membered lactam back bone drug substance according to claim 1, wherein: The separation and purification method is as follows: firstly, the mixture after the reaction is filtered through a short silica gel column with ethyl acetate as an eluent, and the solvent is removed by rotary evaporation to obtain a crude product, and then the crude product is separated by silica gel column chromatography with a mixed solution of n-hexane and ethyl acetate in a volume ratio of 5:1 as an eluent.

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