A method for synthesizing fosfomycin intermediate levofloxacin salt

Abstract

The application relates to the technical field of compound preparation, and discloses a synthesis method of fosfomycin intermediate levofosfoxacin salt, which comprises the following steps: taking propynol as raw material, performing esterification reaction, adding Pt / C, Cu (II) EDTA and hydrogen into the obtained reaction solution to prepare a cis-propenyl dichloro oxygen phosphorus solution, adjusting the pH of the reaction solution by using ammonia gas after hydrolysis, and performing salt reaction and epoxidation by using R- (+) -alpha-phenylethylamine to obtain the product after post-treatment. The propynol is not hydrolyzed after esterification, so that the impurity propadienyl phosphate is reduced; the later hydrogenation can obtain higher-purity cis-propenyl phosphate; the step of hydrolysis after esterification is reduced, a large amount of water does not need to be distilled and concentrated, and energy consumption is reduced; the reaction temperature and hydrogen pressure in the hydrogenation step are both low, and the reaction safety is high; R- (+) -alpha-phenylethylamine is used in the epoxidation stage, so that the splitting operation is not needed, and the process is simplified; the solvents can be recycled and reused, and the method is environment-friendly.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of compound preparation, in particular to a synthesis method of fosfomycin intermediate levofosmidium salt. BACKGROUND

[0002] Fosfomycin is a broad-spectrum antibiotic. Fosfomycin can penetrate the blood-brain barrier and irreversibly inhibit the early stages of cell wall synthesis. Fosfomycin has antibacterial activity against a range of bacteria, including multi-drug resistant (MDR), extensively drug-resistant (XDR) and pandrug-resistant (PDR) bacteria. It is used for respiratory tract infections, urinary tract infections, skin and soft tissue infections caused by sensitive bacteria, etc. Levofosmidium salt is an important organic intermediate for the synthesis of fosfomycin, and its chemical formula is C 11 H 18 NO4P, CAS No.: 25383-07-7.

[0003] At present, the synthesis method of levofosmidium salt mainly includes the following methods:

[0004] One route is to use propynol as a raw material, to esterify, rearrange, hydrolyze and hydrogenate to obtain cis-propenyl phosphonic acid, and then to obtain levofosmidium salt by salifying and epoxidizing cis-propenyl phosphonic acid with R-(+)-alpha-phenethylamine. This method is a classical method for preparing levofosmidium salt, but has the following disadvantages: large solvent consumption, complicated distillation and concentration steps, large energy consumption, etc.

[0005] Another route is also to use propynol as a raw material to obtain cis-propenyl phosphonic acid, and then to obtain levofosmidium salt by salifying and epoxidizing cis-propenyl phosphonic acid with (±) alpha-phenethylamine, and then by separating and recrystallizing. However, this method has a long route, many side reactions, especially complex operation of racemic salt separation, large energy consumption and low product yield.

[0006] Another route is to use activated carbon supported H2WO4 / C and PW / C as catalysts to catalyze the epoxidation reaction of cis-propenyl phosphonic acid (±)-alpha-phenethylamine salt, and the catalyst can be used for several times. However, the activity of H2WO4 / C catalyst is low, the yield of racemic salt is low, the preparation cost of PW / C catalyst is high, the process is complex, and industrialization is difficult to realize. SUMMARY

[0007] In order to solve the above technical problems, the purpose of the present application is to provide a synthesis method of fosfomycin intermediate levofosmidium salt, which has simple process, low energy consumption and high reaction yield.

[0008] To achieve the above purpose, the present application provides the following technical scheme: the synthesis method comprises the following steps:

[0009] S1. Stir phosphorus trichloride with solvent to 70~85℃, drop propargyl alcohol and solvent mixture solution under stirring, protect with nitrogen, keep temperature after drop, concentrate reaction solution to dry under reduced pressure, add dichloroethane for standby;

[0010] S2. Put S1 reaction solution, Pt / C and Cu(II)EDTA into autoclave, do nitrogen replacement and hydrogen replacement, hydrogenation reaction, filter, get cis-propenyl dichloro phosphine oxide solution;

[0011] S3. Add water to cis-propenyl dichloro phosphine oxide solution obtained in S2, adjust system pH=0.5~1.5 by passing ammonia gas, filter, drop R-(+)-α-phenethylamine to filtrate, adjust system pH=5.0~6.5, add sodium tungstate, tetrabutylammonium bromide and EDTA-2Na, drop 35% hydrogen peroxide at 10~50℃, keep temperature, then do liquid separation, add ethanol, cool and crystallize, filter, wash, refine, dry under reduced pressure to get product levomethadyl acetate hydrochloride monohydrate crude.

[0012] Preferably, the solvent in S1 is toluene, chlorobenzene or dichloroethane.

[0013] Preferably, the temperature of keeping temperature in S1 is 70~95℃, and the reaction time is 2~8 hours.

[0014] Preferably, the temperature of hydrogenation reaction in S2 is 20~65℃, and the reaction time is 6~18 hours.

[0015] Preferably, the Pt content of Pt / C in S2 is 3~5%.

[0016] Preferably, the dosage of Pt / C in S2 is according to the weight ratio of Pt / C:propargyl alcohol= (0.0035~0.012):1.

[0017] Preferably, the dosage of Pt / C and Cu(II)EDTA in S2 is according to the molar ratio of Pt:Cu=1:(1.05~1.15).

[0018] Preferably, the temperature of dropping water and passing ammonia gas in S3 is -10~30℃.

[0019] Preferably, the molar ratio of R-(+)-α-phenethylamine:hydrogen peroxide in S3 is 1:(1.15~1.25).

[0020] Preferably, the temperature of keeping temperature in S3 is 20~60℃, and the reaction time is 2~8 hours.

[0021] Compared with the prior art, the present application has the following beneficial effects:

[0022] 1. The propynyl alcohol esterification of this invention does not hydrolyze, thus reducing the generation of impurity propadiene phosphate. Subsequent hydrogenation can yield cis-propenyl phosphate with higher purity.

[0023] 2. This invention reduces the hydrolysis step after esterification, eliminates the need for distillation and concentration of large amounts of water, and reduces energy consumption;

[0024] 3. The hydrogenation step of this invention has a low reaction temperature and hydrogen pressure, resulting in high reaction safety;

[0025] 4. In the epoxidation stage of this invention, R-(+)-α-phenylethylamine is used, which eliminates the need for a separation operation and simplifies the process;

[0026] 5. The average molar yield of this invention is not less than 45%, and all solvents used can be recycled and reused, which is environmentally friendly. Attached Figure Description

[0027] Figure 1 This is a synthetic route diagram for the present invention.

[0028] Figure 2 The product of this invention is a monohydrate of levophosphoric acid and dextrin. 1 HNMR image. Detailed Implementation

[0029] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0030] Example 1: Under nitrogen protection, 620g of phosphorus trichloride and 1100g of toluene were added to a 2000ml dry flask. The mixture was stirred and heated to 70-85℃. A mixed solution of 90g of propynyl alcohol and 90g of toluene was added dropwise over 3 hours. After the addition was complete, the mixture was kept at 85-90℃ for 4 hours. The reaction solution was concentrated to dryness under reduced pressure, and 400g of dichloroethane was added for later use.

[0031] The above reaction solution, 0.75 g of 4.2% Pt / C, and 0.79 g of Cu(II)EDTA were added to a high-pressure reactor for nitrogen and hydrogen purging. The reactor was heated at 35-40°C and under a hydrogen pressure of 0.2 MPa to absorb 7.4 g of hydrogen. The reaction was carried out for a total of 8 hours. The mixture was then filtered to obtain a propylene phosphorus oxychloride solution.

[0032] To the cis-propenyl dichloro phosphine oxide solution, slowly drop 80g of water, pass ammonia gas, control temperature 0~5℃, adjust the system pH=1.1. Filter, the filtrate is heated to 30℃, drop 153g of R- (+) -a-phenylethylamine, adjust the system pH=5.9. Add 7g of sodium tungstate, 1.5g of tetrabutylammonium bromide and 2.5g of EDTA-2Na, drop 152g of 35% hydrogen peroxide at 30~35℃, keep the reaction at 30~35℃ for 7 hours. The reaction solution is left to stand and separate, add 1200g of anhydrous ethanol to the water phase, cool to 0℃ for 1 hour to precipitate crystals, filter, the filter cake is washed once with 50g of anhydrous ethanol (0℃), the wet product is refined with 90% ethanol, and dried under reduced pressure to obtain 201.6g of levomilnacipran salt monohydrate, with a molar yield of 45.3%.

[0033] Example 2: Under nitrogen protection, add 620g of phosphorus trichloride, 1100g of chlorobenzene to a 2000ml dry flask, stir and heat to 70~85℃, drop a mixed solution of 90g of propargyl alcohol and 90g of chlorobenzene, drop for 3 hours, after dropping, keep the reaction at 85~90℃ for 4 hours, concentrate the reaction solution to dryness under reduced pressure, and add 400g of dichloroethane for standby.

[0034] Add the above reaction solution, 0.75g of 4.2% Pt / C and 0.83g of Cu (II) EDTA to an autoclave, perform nitrogen replacement and hydrogen replacement, absorb 7.7g of hydrogen at 0.2Mpa hydrogen pressure at 35~40℃ for 8 hours, filter to obtain a cis-propenyl dichloro phosphine oxide solution.

[0035] To the cis-propenyl dichloro phosphine oxide solution, slowly drop 80g of water, pass ammonia gas, control temperature 0~5℃, adjust the system pH=1.1. Filter, the filtrate is heated to 30℃, drop 153g of R- (+) -a-phenylethylamine, adjust the system pH=5.9. Add 7g of sodium tungstate, 1.5g of tetrabutylammonium bromide and 2.5g of EDTA-2Na, drop 152g of 35% hydrogen peroxide at 30~35℃, keep the reaction at 30~35℃ for 7 hours. The reaction solution is left to stand and separate, add 1200g of anhydrous ethanol to the water phase, cool to 0℃ for 1 hour to precipitate crystals, filter, the filter cake is washed once with 50g of anhydrous ethanol (0℃), the wet product is refined with 90% ethanol, and dried under reduced pressure to obtain 201.6g of levomilnacipran salt monohydrate, with a molar yield of 45.3%.

[0036] Example 3: Under nitrogen protection, add 620g of phosphorus trichloride, 1100g of dichloroethane to a 2000ml dry flask, stir and heat to 70~85℃, drop a mixed solution of 90g of propargyl alcohol and 90g of dichloroethane, drop for 3 hours, after dropping, keep the reaction at 85~90℃ for 4 hours, concentrate the reaction solution to dryness under reduced pressure, and add 400g of dichloroethane for standby.

[0037] The above reaction solution, 4.2% Pt / C 0.75g, Cu (II) EDTA 0.81g was added into an autoclave, nitrogen replacement and hydrogen replacement were carried out, 7.5g of hydrogen was absorbed under the conditions of 35-40℃ and 0.2Mpa hydrogen pressure, and the total reaction time was 8 hours. Filtration was carried out to obtain a cis-propenyl dichlorophosphine oxide solution.

[0038] Slowly, 80g of water was added into the cis-propenyl dichlorophosphine oxide solution, ammonia was added, the temperature was controlled at 0-5℃, and the pH of the system was adjusted to 1.2. Filtration was carried out, the filtrate was heated to 30℃, 150g of R- (+) -α-phenethylamine was added dropwise, and the pH of the system was adjusted to 5.6. 7g of sodium tungstate, 1.5g of tetrabutylammonium bromide and 2.5g of EDTA-2Na were added, 35% hydrogen peroxide 146g was added dropwise at 30-35℃, and the reaction was carried out at 30-35℃ for 7 hours. The reaction solution was allowed to stand and separate, 1200g of anhydrous ethanol was added into the water phase, and the solution was cooled to 0℃ for crystallization for 1 hour. Filtration was carried out, the filter cake was washed once with 50g of anhydrous ethanol (0℃), the wet product was refined with 90% ethanol, and drying under reduced pressure was carried out to obtain 200.3g of levomilnacipran salt monohydrate, with a molar yield of 45.0%.

[0039] Example 4: Under nitrogen protection, 620g of phosphorus trichloride, 1100g of toluene were added into a 2000ml dry flask, stirring was carried out, the temperature was heated to 70-85℃, a mixed solution of 90g of propargyl alcohol and 90g of toluene was added dropwise, the dropping was completed in 3 hours, and the reaction was carried out at 85-90℃ for 4 hours after the addition. The reaction solution was concentrated to dryness under reduced pressure, and 400g of dichloroethane was added for standby.

[0040] The above reaction solution, 4.2% Pt / C 0.75g, Cu (II) EDTA 0.84g was added into an autoclave, nitrogen replacement and hydrogen replacement were carried out, 7.6g of hydrogen was absorbed under the conditions of 35-40℃ and 0.2Mpa hydrogen pressure, and the total reaction time was 8 hours. Filtration was carried out to obtain a cis-propenyl dichlorophosphine oxide solution.

[0041] Slowly, 80g of water was added into the cis-propenyl dichlorophosphine oxide solution, ammonia was added, the temperature was controlled at 0-5℃, and the pH of the system was adjusted to 1.0. Filtration was carried out, the filtrate was heated to 30℃, 155g of R- (+) -α-phenethylamine was added dropwise, and the pH of the system was adjusted to 5.9. 7g of sodium tungstate, 1.5g of tetrabutylammonium bromide and 2.5g of EDTA-2Na were added, 35% hydrogen peroxide 152g was added dropwise at 30-35℃, and the reaction was carried out at 30-35℃ for 7 hours. The reaction solution was allowed to stand and separate, 1200g of anhydrous ethanol was added into the water phase, and the solution was cooled to 0℃ for crystallization for 1 hour. Filtration was carried out, the filter cake was washed once with 50g of anhydrous ethanol (0℃), the wet product was refined with 90% ethanol, and drying under reduced pressure was carried out to obtain 201.2g of levomilnacipran salt monohydrate, with a molar yield of 45.2%.

[0042] While embodiments of the application have been shown and described, it is to be understood that the embodiments described are merely exemplary of the principles and application of the present application. Numerous modifications and adaptions can be effected without departing from the spirit and scope of the present application, which is not limited to the exact construction and arrangement described. It is intended, therefore, to cover all modifications and adaptions that fall within the scope of the claims and their equivalents.

Claims

1. A method for the synthesis of fosfomycin intermediate levofosmidomycin salt, characterized by: The synthesis method comprises the following steps: S1. Stir phosphorus trichloride with a solvent to 70-85℃, drop a mixed solution of propargyl alcohol and solvent under stirring, protect with nitrogen gas throughout, keep warm after dropping, concentrate the reaction solution to dryness under reduced pressure, and add dichloroethane for standby; S2. Put the reaction solution of S1, Pt / C, and Cu(II) EDTA into an autoclave, perform nitrogen replacement and hydrogen replacement, hydrogenate, filter, and obtain a cis-propenyl dichloro phosphine oxide solution; S3. Add water to the cis-propenyl dichloro phosphine oxide solution obtained in S2, pass ammonia gas, and adjust the system pH to 0.5-1.5; filter, drop R-(+)-α-phenethylamine into the filtrate, adjust the system pH to 5.0-6.5; add sodium tungstate, tetrabutylammonium bromide, and EDTA-2Na, drop 35% hydrogen peroxide at 10-50℃, keep warm, and then perform liquid separation, add ethanol, cool and crystallize, filter, wash, refine, and dry under reduced pressure to obtain the product levomilnacipran salt monohydrate crude product.

2. The method for synthesizing fosfomycin intermediate levofosamil salt according to claim 1, characterized in that: The solvent in S1 is toluene, chlorobenzene, or dichloroethane.

3. The method for synthesizing fosfomycin intermediate levofosmid salt according to claim 1, characterized by the fact that: The warm reaction temperature in S1 is 70-95℃, and the reaction time is 2-8 hours.

4. The method for synthesizing fosfomycin intermediate levofosmid salt according to claim 1, characterized by the fact that: The hydrogenation reaction temperature in S2 is 20-65℃, and the reaction time is 6-18 hours.

5. The method for synthesizing the fosfomycin intermediate levop-dexamine salt according to claim 1, characterized in that: The Pt content of Pt / C in S2 is 3-5%.

6. The method for synthesizing the fosfomycin intermediate levop-dexamine salt according to claim 1, characterized in that: The amount of Pt / C in S2 is according to the weight ratio of Pt / C:propargyl alcohol= (0.0035-0.012):

1.

7. The method for synthesizing the fosfomycin intermediate levop-dexamine salt according to claim 1, characterized in that: The amount of Pt / C and Cu(II) EDTA in S2 is according to the molar ratio of Pt:Cu=1:(1.05-1.15).

8. The method for synthesizing the fosfomycin intermediate levop-dexamine salt according to claim 1, characterized in that: The water dropping and ammonia gas passing temperature in S3 is -10-30℃.

9. The method for synthesizing the fosfomycin intermediate levop-dexamine salt according to claim 1, characterized in that: The molar ratio of R-(+)-α-phenethylamine:hydrogen peroxide in S3 is 1:(1.15-1.25).

10. The method for synthesizing the fosfomycin intermediate levop-dexamine salt according to claim 1, characterized in that: The warm reaction temperature in S3 is 20-60℃, and the reaction time is 2-8 hours.

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