A process for the preparation of chiral beta-lactams

Abstract

This invention discloses a method for preparing chiral β-lactams. An organic solvent and substrate I, a proton sponge, are added to a dry reaction flask. Then, catalyst III and substrate II are added, and the reaction is maintained at a controlled temperature. Post-treatment yields product IV. This invention obtains the target product using a suitable chiral catalyst. The method is mild and exhibits high chiral selectivity.

Description

Technical Field

[0001] This invention relates to a method for preparing chiral β-lactams, and more specifically to a method for asymmetric catalytic synthesis of chiral β-lactam derivatives using a chiral catalyst. Background Technology

[0002] β-lactams are a class of organic compounds with a special structure, containing a β-lactam group in their molecule. Their general structure is shown in the following formula.

[0003] β-lactams themselves have a relatively simple structure; they were first synthesized by Staudinger in 1907, but did not attract much attention at the time. However, shortly thereafter, penicillin was discovered, and it was quickly confirmed that penicillin contained β-lactams. With the development of antibiotics, more and more antibiotics containing β-lactam structures have been discovered and applied, and these substances have received increasing attention.

[0004]

[0005]

[0006] With the increasing use of β-lactam antibiotics, many bacteria have developed resistance to them. Research has found that this resistance is primarily due to the production of β-lactamases within the bacteria. These enzymes catalyze the hydrolysis of β-lactams, thus rendering β-lactam drugs ineffective. This necessitates the development of new β-lactam antibiotics or the research and development of β-lactam inhibitors (compounds containing a β-lactam structure that can inactivate β-lactamases).

[0007] Besides their application in antibiotics, β-lactam compounds have also found use in some non-antibiotic fields, such as as protease inhibitors. Based on these combined factors, the organic synthesis of β-lactam compounds is attracting increasing attention.

[0008] The main methods for synthesizing β-lactam structures are as follows:

[0009] 1. Staudinger reaction. This reaction occurs via a [2+2] cycloaddition between an enone and an imine to generate a β-lactam.

[0010] Amines are the most common method for synthesizing β-lactam structures, and the reaction equation is as follows:

[0011]

[0012] 2. Gilman-Speeter reaction. This reaction typically involves the reaction of an imine with an α-bromoester in the presence of zinc powder. Essentially, the reaction proceeds via the condensation of an enol with an imine, followed by cyclization to yield the product. The reaction equation is as follows:

[0013]

[0014] 3. Kinugasa reaction. This reaction involves a cycloaddition reaction between a terminal alkyne and a nitroketone to yield the product. The reaction equation is as follows:

[0015]

[0016] 4. Other reactions. These mainly involve constructing suitable unimolecular structures to obtain the product through intramolecular amide condensation into a ring. While the ring-forming part of this type of reaction is simple, the construction of the preceding molecular structure is more complex, limiting its applicability.

[0017] The synthesis of chiral β-lactam structures using the Staudinger reaction mainly relies on two methods: one is to install a chiral cofactor on an imine or ketene starting material and use stereochemical induction, which is effective but cumbersome; the other is to control the stereoselectivity of the reaction through a chiral catalyst.

[0018] In 2000, Lecka's group reported the first asymmetric catalytic Staudinger reaction using cinchona bark derivatives as chiral catalysts. Normally, the Staudinger reaction can proceed at room temperature without a catalyst due to the strong nucleophilicity of imines. Lecka's group cleverly altered the reaction pathway by reversing polarity and utilized the steric hindrance of the catalyst to achieve asymmetric catalysis. Furthermore, the cinchona bark derivative, combined with a proton sponge, can react with acyl chlorides in situ to generate the corresponding enones, further broadening the selection of starting materials.

[0019]

[0020]

[0021] Lectka's research group studied a series of cinchona alkaloid derivatives, mainly the benzoate esters of cinchona alkaloid and the benzamide structure of cinchona amine. They found that although the benzamide structure of cinchona amine has a slightly higher reaction conversion rate, its ee selectivity and dr selectivity are both lower than those of the benzoate esters of cinchona alkaloid. An explanation based on the spatial structure was provided.

[0022]

[0023] As shown in the above formula, when an enone combines with the benzoic acid ester of cinchona bark, the oxygen anion is bound by the hydrogen on the nitrogen-dominant carbon, compressing the entire enone into a smaller space, resulting in excellent chiral selectivity for further reactions. However, when an enone combines with the benzamide of cinchona bark, the oxygen anion is bound by the hydrogen on the amide nitrogen, resulting in a more open structure with more space for further reactions, thus exhibiting poorer chiral selectivity. Therefore, although the benzamide structure of cinchona bark shows better homology with the achiral bifunctional catalyst N-(2-(diethylamino)ethyl)benzamide, the Lecka group did not focus on it as a primary research subject.

[0024] Although cinchona bark esters exhibit better chiral selectivity, their binding stability with enone substrates is lower, and their steric tightness is higher, resulting in a lower overall reaction yield. Furthermore, the larger the R group of the enone substrate, the better its chiral selectivity, but also the lower the yield; neither can be achieved simultaneously.

[0025] To improve the conversion rate, Lecka's group introduced Lewis acid catalysts to enhance the reactivity of imines, and even combined this with sterically hindered Lewis acid catalysis to increase the yield while maintaining chiral selectivity. While this resulted in excellent yield and selectivity, the reaction system became more complex. Furthermore, the amount of both catalysts used was relatively large (10 mol%), which is not conducive to industrialization. Summary of the Invention

[0026] The purpose of this invention is to overcome the problems of harsh conditions, low selectivity of chiral reagents, large dosage, and high production costs in the synthesis of chiral β-lactam derivatives. This invention provides a method for the asymmetric catalytic synthesis of chiral β-lactam derivatives using a chiral catalyst, which requires less catalyst and significantly reduces costs. The method achieves a molar yield of over 70%, with a chiral purity reaching over 99% ee and a cis-trans selectivity of over 90% dr. Furthermore, the reaction conditions are mild, with a reaction temperature between -40 and 40°C, making it highly suitable for industrial production.

[0027] The technical solution of the present invention is as follows:

[0028] A method for preparing chiral β-lactams includes the following steps:

[0029] 1) Add organic solvent and substrate I, proton sponge to a dry reaction flask, and control the reaction system at a certain temperature (-40℃~40℃);

[0030] 2) Under nitrogen protection, add catalyst III and substrate II to the reaction flask, adjust the temperature (-40℃~40℃), and keep it warm while stirring for 2~12 hours;

[0031] 3) After the reaction is complete, the solvent is removed by vacuum distillation, and the residue is obtained by column chromatography.

[0032] In step 2), substrate II is ethyl N-Ts imine;

[0033] In step 2), the reaction temperature is preferably controlled between -20℃ and 20℃.

[0034] The structure of catalyst III in step 2) is shown below:

[0035]

[0036] Where R1 = 3,5-(CF3)2C6H3; 4-CF3C6H4; 4-FC6H4;

[0037] The molar ratio of catalyst III to substrate I is between 0.02:1 and 0.10:1;

[0038] The organic solvent mentioned in step 1) is selected from one or a mixture of the following: dichloromethane, trichloromethane, and toluene.

[0039] The molar ratio of compound II to substrate I is between 1:1 and 2:1.

[0040] The chemical reaction equation for this invention is shown below:

[0041]

[0042] Where R represents aryl; heteroaryl; Ar(CH2) n -Group, Ar represents aryl or heteroaryl, n = 1-6;

[0043] The structure of catalyst III is shown below:

[0044]

[0045] Where R1 = 3,5-(CF3)2C6H3; 4-CF3C6H4; 4-FC6H4.

[0046] General preparation method of catalyst III:

[0047]

[0048] Where R1 = 3,5-(CF3)2C6H3; 4-CF3C6H4; 4-FC6H4.

[0049] Methanol was added to a flask, followed by substituted phenol and squaric acid. The mixture was heated to reflux at 80°C for 8–10 h. After cooling, the solvent was evaporated by rotary evaporation to obtain a crude solid product. After column chromatography, the product was filtered and dried to obtain an intermediate.

[0050] The dried intermediate was weighed and added to a reaction flask, and dichloromethane was added and stirred to dissolve it. Quinineamine was added while maintaining the temperature at 25°C, and the reaction mixture was stirred at room temperature for 48 hours. After the reaction was completed, the mixture was washed twice with purified water. The organic phase was evaporated to dryness, slurried with methanol for 0.5 hours, filtered, and dried under reduced pressure to obtain the catalyst.

[0051] The principle of catalysis and chiral selectivity of the catalyst is as follows: The catalyst, in conjunction with the proton sponge, first reacts substrate I in situ to generate the corresponding ketene. Then, the catalyst combines with the ketene. The spatial structure of the catalyst itself ensures that substrate II can only react with substrate I in one direction, thereby obtaining the chiral substituted product we need.

[0052] Beneficial effects:

[0053] This invention utilizes an effective catalyst, requiring a small amount and significantly reducing costs. The method achieves a molar yield exceeding 70%, with a chiral purity reaching over 99% ee and a cis-trans selectivity exceeding 90% dr. Furthermore, the reaction conditions are mild, with a reaction temperature between -40 and 40°C, making it highly suitable for industrial production. Detailed Implementation

[0054] To better understand this invention, specific examples will be used to illustrate it in detail below. It should be noted that the following examples are not intended to limit the scope of this invention. Obviously, those skilled in the art can make various modifications and changes to this invention within the scope of this invention based on the description herein, and these modifications and changes are also included in the scope of this invention.

[0055] General methods for preparing catalysts:

[0056]

[0057] Where R1 = 3,5-(CF3)2C6H3; 4-CF3C6H4; 4-FC6H4

[0058] Add methanol (40 mL) to a 100 mL flask, then add substituted phenol (R1-OH, 20.5 mmol) and squaric acid (2.32 g, 20.5 mmol). Heat under reflux at 80 °C for 8–10 h. After cooling, evaporate the solvent by rotary evaporation to obtain a crude solid product. After column chromatography, filter and dry to obtain an intermediate.

[0059] The dried intermediate (1.0 mmol) was weighed and added to a reaction flask. 10 mL of dichloromethane was added and stirred to dissolve. Quinineamine was added while maintaining the temperature at 25 °C. The reaction mixture was stirred at room temperature for 48 hours. After the reaction was complete, the mixture was washed twice with 10 mL of purified water. The organic phase was evaporated to dryness, slurried with 5 mL of methanol for 0.5 hours, filtered, and dried under reduced pressure to obtain the catalyst.

[0060] Example 1

[0061]

[0062] Prepare the reaction flasks by drying them beforehand. Add toluene (30 mL), phenylacetyl chloride (2.00 g, 12.9 mmol), and a proton sponge (3.10 g, 14.2 mmol) separately to the reaction flasks and cool to -30°C. Once the temperature is reached, add dropwise a toluene (20 mL) solution of catalyst (0.81 g, 1.29 mmol) and substrate II (3.30 g, 12.9 mmol). Stir for 1 hour while maintaining the temperature, then slowly raise the temperature to 0°C and stir for 5 hours until the reaction is complete. Remove the solvent under reduced pressure, separate the crude product by column chromatography, and evaporate to dryness to obtain product IV (4.43 g, yield 92%, 96% ee, 95:5 dr).

[0063] 1H-NMR (400MHz, CDCl3): δ7.81-7.71(m,2H),7.44-7.25(m,7H),5.02(d,J=8.0 Hz, 1H), 4.89 (d, J = 8.0Hz, 1H), 4.00 (m, 2H), 2.34 (s, 3H), 1.30 (t, J = 8.0Hz, 3H).

[0064] Example 2

[0065]

[0066] Prepare the reaction flasks by drying them beforehand. Add toluene (30 mL), p-methoxyphenylacetyl chloride (2.38 g, 12.9 mmol), and a proton sponge (3.10 g, 14.2 mmol) separately to the reaction flasks and cool to -30°C. Once the temperature is reached, add dropwise a toluene (20 mL) solution of catalyst (0.81 g, 1.29 mmol) and substrate II (3.30 g, 12.9 mmol). Stir for 1 hour while maintaining the temperature, then slowly raise the temperature to 10°C and stir for 5 hours until the reaction is complete. Remove the solvent under reduced pressure, separate the crude product by column chromatography, and evaporate to dryness to obtain product IV (4.47 g, yield 86%, 99% ee, 99:1 dr).

[0067] 1H-NMR (400MHz, CDCl3): δ7.81-7.71(m,2H),7.44-7.30(m,4H),7.05-6.95(m,2H),5.02(d,J=8 .0Hz,1H),4.89(d,J=8.0Hz,1H),4.00(m,2H),3.85(s,3H),2.34(s,3H),1.30(t,J=8.0Hz,3H).

[0068] Example 3

[0069]

[0070] Prepare the reaction flasks by drying them beforehand. Add toluene (30 mL), phenylacetyl chloride (2.00 g, 12.9 mmol), and a proton sponge (3.10 g, 14.2 mmol) separately to the reaction flasks and cool to -30°C. Once the temperature is reached, add dropwise a toluene (20 mL) solution of catalyst (0.81 g, 1.29 mmol) and substrate II (3.30 g, 12.9 mmol). Stir for 1 hour while maintaining the temperature, then slowly raise the temperature to 0°C and stir for 5 hours until the reaction is complete. Remove the solvent under reduced pressure, separate the crude product by column chromatography, and evaporate to dryness to obtain product IV (4.33 g, yield 90%, 96% ee(ent), 95:5 dr).

[0071] Example 4

[0072]

[0073] Prepare the reaction flasks by drying them beforehand. Add toluene (30 mL), phenylacetyl chloride (2.00 g, 12.9 mmol), and a proton sponge (3.10 g, 14.2 mmol) separately to the reaction flasks and cool to -30°C. Once the temperature is reached, add a 20 mL solution of catalyst (0.73 g, 1.29 mmol) and substrate II (3.30 g, 12.9 mmol) in toluene to the reaction flasks. Stir for 1 hour while maintaining the temperature, then slowly raise the temperature to 0°C and stir for 5 hours until the reaction is complete. Remove the solvent under reduced pressure, separate the crude product by column chromatography, and evaporate to dryness to obtain product IV (4.72 g, yield 98%, 90% ee, 90:10 dr).

Claims

1. A process for the preparation of chiral β-lactams, characterized in that, Substrate I and substrate II react to yield the product under the catalysis of catalyst III and a proton sponge. The chemical reaction equation is shown below: ； wherein R is aryl; heteroaryl; Ar(CH2) n - group, Ar represents aryl or heteroaryl, n = 1-6; The structure of catalyst III is shown below: ； Where R1 = 3,5-(CF3)2C6H3; 4-CF3C6H4; 4-FC6H4.

2. The process for the preparation of chiral β-lactams according to claim 1, characterized in that, Includes the following steps: 1) Add organic solvent, substrate I, and proton sponge to the reaction flask, and control the reaction system at -40℃ to 40℃; 2) Under nitrogen protection, add catalyst III and substrate II to the reaction flask, adjust the temperature to -40℃~40℃, and stir for 2~12 hours. 3) After the reaction is complete, the solvent is removed by vacuum distillation, and the residue is obtained by column chromatography.

3. The process for the preparation of chiral β-lactams according to claim 1, characterized in that, The molar ratio of catalyst III to substrate I is between 0.02:1 and 0.10:

1.

4. The method for preparing chiral β-lactams according to claim 2, characterized in that, The organic solvent is selected from one or a mixture of the following: dichloromethane, trichloromethane, and toluene.

5. The process for the preparation of chiral β-lactams according to claim 2, characterized in that, In step 1), the reaction temperature is controlled between -20℃ and 20℃.

6. The method for preparing chiral β-lactams according to claim 2, characterized in that, The molar ratio of substrate II to substrate I is between 1:1 and 2:1.

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