CN112479946A - Method for preparing D-p-methylsulfonylphenylserine ethyl ester with high stereoselectivity - Google Patents
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Abstract
The invention discloses a method for preparing D-p-methylsulfonylphenylserine ethyl ester with high stereoselectivity, which has the advantages of mild reaction conditions, high stereoselectivity and low corrosivity to production equipment, and belongs to the field of small molecule catalyzed organic reactions. Compared with the existing chemical synthesis method, the method disclosed by the invention has the advantages that the total yield of the D-p-methylsulfonylphenylserine ethyl ester can reach 75% at most, the ee value of the obtained product reaches 73%, the cost is lower, and the yield and the optical purity are better.
Description
Technical Field
The invention belongs to the technical field of organic chemistry of small molecule catalysis, and particularly relates to a method for preparing D-p-methylsulfonylphenylserine ethyl ester with high optical purity by using a catalytic system with L-proline as a catalyst and dialkyl boron trifluoromethanesulfonate as an additive. The method has the advantages of mild reaction conditions, high stereoselectivity and low corrosivity to production equipment.
Background
Chiral control is an important part of modern drug synthesis and development processes, for the living body, the different stereo configurations of drugs can cause different effects, and if the stereo configurations are incorrect, the drugs originally used for treating diseases can become toxic drugs, so the chiral control is particularly important in the aspects of the effectiveness and the use safety of the drugs. Therefore, the attention of the synthetic workers is increasing on how to make the produced drugs or drug intermediates show good optical purity.
D-p-methylsulfonylphenylserine ethyl ester (D-p-MPSE) (shown as a formula (1)) is an important intermediate for synthesizing veterinary antibiotic florfenicol, and the florfenicol serving as a veterinary broad-spectrum antibiotic has wide application in clinical and agricultural aspects, and the demand of the florfenicol is increased year by year. Although florfenicol containing a D-p-methylsulfonylserine ethyl ester structure has good medicinal value, the florfenicol containing an L-p-methylsulfonylserine ethyl ester structure fragment in another configuration is very weak in antifungal activity. Therefore, the method has important significance for synthesizing the D-p-methylsulfonylphenylserine ethyl ester with the optical pure characteristic.
The structural formula of D-type p-methylsulfonylphenylserine ethyl ester in the formula (1)
The Aldol reaction is one of important reactions for constructing carbon-carbon bonds in organic synthesis, and is widely applied due to the excellent performance of the Aldol reaction. In recent years, a series of chiral small molecules represented by proline are also applied to asymmetric Aldol reactions. However, in most Aldol reactions, there are two different stereoconfiguration products (i.e., cis and trans) catalyzed by the addition of proline alone.
At present, the preparation method of D-p-methylsulfonylphenylserine ethyl ester mainly comprises two routes: the p-methylsulfonylphenylserine route (GB:1268866, 1969-07-24; GB:1268867, 1969-07-24; US:3733352, 1973-05-15) and the copper-p-methylsulfonylphenylserine route (CN:1302798, 2001-07-11; fine chemical industry, 2011, 28, 599-. However, both of these methods require a large amount of resolving agents after synthesis, and the use of strong acids such as hydrochloric acid and sulfuric acid also increases a part of the cost, so that the industrial production and application thereof are limited, and the recycling effect of the solvent is poor.
The chiral resolution of DL-threo-p-methylsulfonylphenylserine ethyl ester by using lipase is also a method for obtaining D-p-methylsulfonylphenylserine ethyl ester (Zhejiang agricultural science, 2012, 1203, 1197-1200), although the stereoselectivity of the product is improved, the yield is still low. Meanwhile, in order to obtain a good resolution effect, the enzyme needs to be screened, and simultaneously, the most suitable conditions for the enzyme need to be explored, so that the application difficulty of the enzyme resolution in the synthesis of D-p-methylsulfonylphenylserine ethyl ester is increased.
In summary, the existing synthesis and resolution methods have various disadvantages, such as: high requirements on reaction equipment, difficult recovery of chiral resolution reagent, low product yield and the like. Therefore, the invention aims to provide the method for preparing the D-p-methylsulfonylphenylserine ethyl ester with high stereoselectivity by catalyzing with the L-proline, which is simple to operate and low in production cost.
Disclosure of Invention
The invention aims to provide a method for preparing D-p-methylsulfonylphenylserine ethyl ester with high stereoselectivity by catalyzing L-proline, which is simple to operate and low in production cost, aiming at the problems in the prior art.
The invention is realized by the following technical scheme in order to achieve the aim:
a method for preparing D-p-methylsulfonylphenylserine ethyl ester with high stereoselectivity comprises the following steps:
under the catalysis of L-proline loaded by polystyrene spheres, carrying out asymmetric Aldol reaction on p-methylsulfonylbenzaldehyde and N-Boc-glycine ethyl ester, and carrying out post-treatment after the reaction is finished to obtain D-p-methylsulfonylphenylserine ethyl ester;
expressed by the reaction formula:
in the invention, the content of L-proline in the L-proline loaded by the polystyrene spheres is 0.5-1 mmol/g;
the catalyst is used in an amount of 5 to 30 mol% based on the amount of the p-methylsulfonylbenzaldehyde substance, based on L-proline. The L-proline is combined with the polystyrene spheres and can be separated from the reaction liquid in a filtering mode after the reaction is finished, so that the problem that the catalyst is difficult to treat in the reaction is avoided, and meanwhile, the recovered catalyst can be applied to a new system again.
In the invention, an additive is also added in the reaction, and the additive is bis (n-butyl) boron trifluoromethanesulfonate (L for short)2BOTf, CAS: 60669-69-4). Preferably, the amount of the di-N-butyl boron trifluoromethanesulfonate is 1-2 times of the amount of the N-Boc glycine ethyl ester substance. Experiments prove that: if the di-N-butyl boron trifluoromethanesulfonate is added in the process, the stereoselectivity of the product can be effectively controlled, the yield of the target product D-p-methylsulfonylphenylserine ethyl ester can reach 75% with high stereoselectivity and enantioselectivity, and the optical purity can reach 73%, because the reason is presumed that the added di-N-butyl boron trifluoromethanesulfonate can control the stereoselectivity of the product N-Boc-glycine ethyl ester in the process of forming an enol structure, and the chiral assistance of L-proline enables the final product to have better stereoselectivity.
In the present invention, the kind of the solvent greatly affects the reaction yield and selectivity, and the solvent for the asymmetric Aldol reaction is preferably dichloromethane, tetrahydrofuran, ethyl acetate or toluene, and more preferably dichloromethane.
In the invention, the temperature of the asymmetric Aldol reaction is 20-30 ℃.
In the invention, the time of the asymmetric Aldol reaction is 30-120 hours.
In the invention, the post-treatment comprises removal of Boc group;
the reagent used to remove Boc groups was trifluoroacetic acid. Compared with the prior art, the invention has the following beneficial effects:
(1) the synthesis method of the invention does not need to add strong acid (such as hydrochloric acid, sulfuric acid and the like) in the synthesis of the previous step, has mild reaction conditions and low corrosivity to a production device.
(2) According to the synthesis method, the L-proline is loaded by the polystyrene spheres, so that the catalyst can be recycled, the catalyst can be separated from a reaction system by using a simple filtering mode, and the difficulty of aftertreatment is reduced to a certain extent. The amount of catalyst used may also be reduced by a suitable amount.
(3) According to the synthesis method, the chiral micromolecule catalyst L-proline and the additive di-n-butylboron trifluoromethanesulfonate are introduced simultaneously, so that the stereoselectivity of the product can be controlled better.
(4) According to the synthesis method, trifluoroacetic acid is used in the last Boc protecting group removing process, so that the yield and the optical activity of the product are not greatly influenced.
Drawings
FIG. 1 is a high performance liquid chromatography spectrum of the product obtained in example 1;
FIG. 2 is a high performance liquid chromatography spectrum of the product obtained in example 2;
FIG. 3 is a high performance liquid chromatography spectrum of the product obtained in example 3;
FIG. 4 is a high performance liquid chromatography spectrum of the product obtained in example 4.
Detailed Description
The technical solution of the present invention is further described in detail with reference to the following specific examples, but is not limited thereto.
The polystyrene beads supported L-proline of the present invention can be synthesized according to known methods, such as "Synthesis and catalytic research of chiral catalyst of proline supported on polymeric microspheres" (2013, Hubei university Master paper, Teng Ching et al).
Example 1
Adding 1000g of p-methylsulfonylbenzaldehyde into a reaction kettle containing 10L of dichloromethane, adding PS-L-proline (the L-proline loading is 0.9mmol/g and 5 mol% in terms of proline), 1100g N-Boc-glycine ethyl ester and di-n-butylboron trifluoromethanesulfonate (2978g), reacting at 25 ℃ for 30 hours, separating the catalyst from the reaction system in a suction filtration mode, adding 1L of trifluoroacetic acid into the reaction system, reacting for 1.5 hours, removing the reaction solvent in vacuum, and purifying the obtained crude product in a recrystallization mode, wherein the recrystallization solvent is a mixed solvent of dichloromethane and n-hexane (the volume ratio is 1:1), and the recrystallization temperature is room temperature, so that D (-) -p-MPSE can be obtained with the yield of 45%.
And (3) purity detection: the optical purity of the product of the present invention was measured by high performance liquid chromatography, and the results are shown in fig. 1, which shows that the ee value of the obtained product is 42.58%, and the retention time and peak area of the chromatogram are as follows:
example 2
Adding 1000g of p-methylsulfonylbenzaldehyde into a reaction kettle containing 10L of dichloromethane, adding PS-L-proline (the L-proline loading is 0.9mmol/g and 10 mol% is calculated by proline), 1100g N-Boc-glycine ethyl ester and di-n-butylboron trifluoromethanesulfonate (2978g), reacting at 25 ℃ for 30 hours, separating the catalyst from the reaction system in a suction filtration mode, adding 1L of trifluoroacetic acid into the reaction system, reacting for 1.5 hours, then removing the reaction solvent in vacuum, purifying the obtained crude product in a recrystallization mode, wherein the recrystallization solvent is a mixed solvent of dichloromethane and n-hexane (the volume ratio is 1:1), and obtaining D (-) -p-MPSE with the yield of 56%.
And (3) purity detection: the optical purity of the product of the present invention was measured by high performance liquid chromatography, and the results are shown in fig. 2, which shows that the ee value of the obtained product is 59.94%, and the retention time and peak area of the chromatogram are as follows:
example 3
Adding 1000g of p-methylsulfonylbenzaldehyde into a reaction kettle containing 10L of dichloromethane, adding PS-L-proline (the L-proline loading is 0.9mmol/g and 20 mol% is calculated by proline), 1100g N-Boc-glycine ethyl ester and di-n-butylboron trifluoromethanesulfonate (2978g), reacting at 25 ℃ for 30 hours, separating the catalyst from the reaction system in a suction filtration mode, adding 1L of trifluoroacetic acid into the reaction system, reacting for 1.5 hours, then removing the reaction solvent in vacuum, purifying the obtained crude product in a recrystallization mode, wherein the recrystallization solvent is a mixed solvent of dichloromethane and n-hexane (the volume ratio is 1:1), and obtaining D (-) -p-MPSE with the yield of 73%.
And (3) purity detection: the optical purity of the product of the present invention was measured by high performance liquid chromatography, and the results are shown in fig. 3, which shows that the ee value of the obtained product is 71.24%, and the retention time and peak area of the chromatogram are as follows:
example 4
Adding 1000g of p-methylsulfonylbenzaldehyde into a reaction kettle containing 10L of dichloromethane, adding PS-L-proline (the L-proline loading is 0.9mmol/g and 30 mol% is calculated by proline), 1100g N-Boc-glycine ethyl ester and di-n-butylboron trifluoromethanesulfonate (2978g), reacting at 25 ℃ for 30 hours, separating the catalyst from the reaction system in a suction filtration mode, adding 1L of trifluoroacetic acid into the reaction system, reacting for 1.5 hours, then removing the reaction solvent in vacuum, purifying the obtained crude product in a recrystallization mode, wherein the recrystallization solvent is a mixed solvent of dichloromethane and n-hexane (the volume ratio is 1:1), and obtaining D (-) -p-MPSE with the yield of 75%.
And (3) purity detection: the optical purity of the product of the present invention was measured by high performance liquid chromatography, and the results are shown in fig. 4, which shows that the ee value of the obtained product is 73.32%, and the retention time and peak area of the chromatogram are as follows:
example 5
The procedure is as in example 4, except that the catalyst used is the catalyst recovered in example 4, giving D (-) -p-MPSE in 69% yield and an ee of 70.03%.
It can be seen that the catalyst still has high yield and purity when repeatedly used in sets.
Example 6
1000g of p-methylsulfonylbenzaldehyde was charged into a reaction vessel containing 10L of methylene chloride, and after adding L-proline (L-proline loading: 0.9mmol/g, 30 mol% in terms of proline) and 1100g N-Boc-glycine ethyl ester and reacting at 25 ℃ for 30 hours, 1L of trifluoroacetic acid was added to react for 1.5 hours, followed by vacuum removal of the reaction solvent, the crude product was purified by recrystallization from a mixed solvent of methylene chloride and n-hexane (volume ratio: 1), to obtain D (-) -p-MPSE in a yield of 46% and an ee value of 51%.
The results of example 6 show that the reaction yield and purity are lower with free L-proline than with supported catalyst.
Example 7
Adding 1000g of p-methylsulfonylbenzaldehyde into a reaction kettle containing 10L of dichloromethane, adding PS-L-proline (the L-proline loading is 0.9mmol/g and 30mol percent is calculated by proline) and 1100g N-Boc-glycine ethyl ester, reacting at 25 ℃ for 30 hours, separating the catalyst from the reaction system in a suction filtration mode, adding 1L of trifluoroacetic acid into the reaction system for reacting for 1.5 hours, then removing the reaction solvent in vacuum, and purifying the obtained crude product in a recrystallization mode to obtain D (-) -p-MPSE, wherein the yield is 74 percent, and the ee value is 40.58 percent.
The results of example 6 show that the ee value decreases significantly without the addition of additives.
Example 8
Adding 1000g of p-methylsulfonylbenzaldehyde into a reaction kettle containing 10L of tetrahydrofuran, adding PS-L-proline (the L-proline loading is 0.9mmol/g and 30 mol% in terms of proline), 1100g N-Boc-glycine ethyl ester and di-n-butylboron trifluoromethanesulfonate (2978g), reacting at 25 ℃ for 30 hours, separating the catalyst from the reaction system in a suction filtration mode, adding 1L of trifluoroacetic acid into the reaction system, reacting for 1.5 hours, then removing the reaction solvent in vacuum, and purifying the obtained crude product in a recrystallization mode to obtain D (-) -p-MPSE, wherein the yield is 58% and the ee value is 71.05%.
The results of example 8 show that the reaction solvent also has an influence on the reaction yield, which is decreased when the solvent is replaced with tetrahydrofuran.
Claims (8)
1. A method for preparing D-p-methylsulfonylphenylserine ethyl ester with high stereoselectivity is characterized by comprising the following steps:
under the catalysis of L-proline loaded by polystyrene spheres, carrying out asymmetric Aldol reaction on p-methylsulfonylbenzaldehyde and N-Boc-glycine ethyl ester, and carrying out post-treatment after the reaction is finished to obtain D-p-methylsulfonylphenylserine ethyl ester;
the reaction formula is as follows:
2. the method for preparing D-p-methylsulfonylphenylserine ethyl ester with high stereoselectivity according to claim 1, wherein the content of L-proline in the L-proline loaded on the polystyrene spheres is 0.5-1 mmol/g;
the catalyst is used in an amount of 5 to 30 mol% based on the amount of the p-methylsulfonylbenzaldehyde substance, based on L-proline.
3. The method for preparing D-p-methylsulfonylphenylserine ethyl ester with high stereoselectivity according to claim 1, wherein an additive is further added in the reaction, wherein the additive is bis-n-butylboron trifluoromethanesulfonate.
4. The method for preparing D-p-methylsulfonylphenylserine ethyl ester with high stereoselectivity according to claim 3, wherein the amount of di-N-butylboron triflate is 1-2 times of the amount of N-Boc-glycine ethyl ester.
5. The method for preparing D-p-methylsulfonylphenylserine ethyl ester with high stereoselectivity according to claim 1, wherein the asymmetric Aldol reaction solvent is dichloromethane, tetrahydrofuran, ethyl acetate or toluene.
6. The method for preparing D-p-methylsulfonylphenylserine ethyl ester with high stereoselectivity according to claim 1, wherein the asymmetric Aldol reaction is carried out at a temperature of 20-30 ℃.
7. The method for preparing D-p-methylsulfonylphenylserine ethyl ester with high stereoselectivity according to claim 1, wherein the asymmetric Aldol reaction time is 30-120 hours.
8. The method for preparing D-p-methylsulfonylphenylserine ethyl ester with high stereoselectivity according to claim 1, wherein the post-treatment comprises removal of Boc group;
the reagent used to remove Boc groups was trifluoroacetic acid.
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| CN116693432A (en) * | 2023-08-09 | 2023-09-05 | 山东国邦药业有限公司 | Preparation method of florfenicol intermediate D-ethyl ester |
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Cited By (2)
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