WO2005123746A1

WO2005123746A1 - Methods for preparation of levofloxacin and ofloxacin

Info

Publication number: WO2005123746A1
Application number: PCT/CN2004/000954
Authority: WO
Inventors: Weidong Ye; Weidong Zhang; Zhuhong Yang
Original assignee: Zhe Jiang Medicine Co., Ltd. Xinchang Pharmaceutical Factory
Priority date: 2004-06-22
Filing date: 2004-08-16
Publication date: 2005-12-29
Also published as: CN100412075C; CN1594320A

Abstract

The invention relates to the methods for the preparation of anti-infective agents, levofloxacin and ofloxacin. The methods use tetrafluorobenzoic acid as raw material, and are characterized in that a solvent is added to the crude ethyl-2-(2,3,4,5tetrafluoro-benzoyl)-3-(1-hydroxymethylethamino)acrylate and the freezing L-aminopropanol or DL-aminopropanol is added dropwise, then maintains the temperature of the reactants to react completely. To the resultant solution is added base and the reaction mixture reacts at 50-90°C while stirring, after the cyclization is finished, N-methylpiperazine is added into the mother solution and reacts for 1-3 h at 55-95 °C, followed by retrieve of N-methylpiperazine under reduced pressure. Then the resulting mixture is heated to 120-130 °C and maintains for 0.1-1.Oh. After suspending the reaction, the reaction solution is poured into water, stirred, cooled, and filtered; to the filtrate are added water and acid, and stirred the reaction mixture at the reflux temperature until hydrolysis completely. Next, the solution is adjusted to pH 7.0 with basic solution and extracted with extracting reagent, then concentrate the extracted layer to give the objective product. The present methods shorten the reaction process, abbreviate the procedure, and facilitates to collect and retrieve solvent and recycle.

Description

Preparation method of levofloxacin and ofloxacin Technical field

The invention belongs to the field of chemistry, and specifically relates to a method for preparing levofloxacin and ofloxacin.

Background technique

Fluoroquinolones have achieved great success in clinical anti-infective treatment due to their high-efficiency, broad-spectrum and low-toxic antibacterial properties. Ofloxacin and levofloxacin developed by Daiichi Pharmaceutical Co., Ltd. are among the outstanding varieties . Levofloxacin, English name: Leovfloxacin, molecular formula: C ₁₈ H ₂₀ FN ₃ 0 ₄ · 1 / 2H ₂ 0, the structural formula is as follows:

Ofloxacin, English name: Floxacin, molecular formula: C ₁₈ H ₂ . FN ₃ 0 ₄ , the structural formula is as follows:

There are three main methods for the synthesis of levofloxacin:

1. Resolution method: including high-pressure liquid phase resolution EP206283 (1986) and enzyme resolution (K, Sakano, Agina Biol. Chem .: 1987, 51, 1265) This method is not suitable for industrial production;

2. Levofloxacin UP4777253 (1988) was prepared from tetrafluorobenzoic acid in 7 steps.

3. Manufactured from trifluoronitrobenzene. EP36841 (1990), EP273399 (1988). Among them, the ring-forming synthesis method of Method 2 is a more common industrialized synthesis method currently used. The synthetic route of this method is shown in the following figure:

(I)

In the above synthetic route, when DL-aminopropanol is reacted with 2- (2, 3, 4, 5-tetrafluorobenzoyl)-3-ethoxy-ethyl acrylate (hereinafter referred to as compound (V)) Ofloxacin can be prepared by a similar method. The synthetic route is as follows:

(II) (III) (IV)

(XI)

In the two synthetic routes described above, the route for the synthesis of the final product (levofloxacin and ofloxacin) from compound (V), which first forms two rings at the same time, then hydrolyzes, and finally N at position 10 -Methylpiperazinyl, the synthetic route in this paragraph has the following disadvantages: 1) Due to the different solvents in each step of the reaction (N, N-dimethylformamide or dimethylsulfoxide and water are generally used), the same reaction cannot be performed Continuous operation in the reactor requires four-step operation, large solid transfer volume, dust, and difficult to ensure a satisfactory recovery and application rate of the solvent; 2) In order to meet the two loops at the same time, the reaction is not easy to carry out, making the The temperature is 120 ~ 150 ° C and the time is 4 ~ 5hr. The reaction time at high temperature is long and side reactions are easy to occur. Product quality and appearance will be affected; 3) A large amount of glacial acetic acid is required, the production cost is large, the hydrolysis reaction time is 5 to 6 hours, the dissolution is difficult, the hydrolysis is not easy to complete, the separation after the reaction is difficult, and the impact on the environment is large.

Summary of the invention

The technical problem to be solved by the present invention is to overcome the shortcomings of the prior art mentioned above, provide a process route for quickly synthesizing levofloxacin and ofloxacin from the compound (V), shorten the reaction time, and simplify the process.

The technical scheme of the present invention is as follows: The preparation method of levofloxacin is a synthesis method using tetrafluorobenzoic acid as a raw material, which is characterized in that: a) a solvent is added to the crude compound (V), and L is added dropwise by freezing; -Aminopropanol, then incubate until the conversion is complete, add a base, and react at 50-9CTC. After the reaction is complete, add N-methylpiperazine to the mother liquor, stir the reaction at 55 ~ 95 ° C for 1-3 hours and reduce the pressure. N-methylpiperazine was recovered, and the reaction temperature was raised to 120-130 ° C, and the temperature was maintained for 0.1 to 1.0 hours. The reaction was ended. The reaction solution was poured into water, stirred, and cooled to obtain S-(-) 9-fluoro-3. -Methyl- 10- (4-methyl-1-piperazinyl)-7- oxygen-2, 3-dihydro-7H-pyrido- [1, 2, 3, -de] [1, 4 0] benzoxazine-6-carboxylic acid ethyl ester (hereinafter referred to as compound (IX)); b) adding water, acid to compound (IX), stirring and refluxing until the hydrolysis is complete, adjusting the ra to 7.0 with alkaline solution After adding the extractant, the extractive layer was concentrated to obtain levofloxacin.

The preparation method of ofloxacin is a synthesis method using tetrafluorobenzoic acid as a raw material, which is characterized in that: a) a solvent is added to the crude compound (V), DL-aminopropanol is added dropwise by freezing, and then the temperature is maintained until the conversion is complete Then, add a base and react at 50-90 ° F. After the reaction is completed, add N-methylpiperazine to the mother liquor, stir the reaction at 70-80 ° C for 1-3 hours, and then recover the N-methylpiperazine under reduced pressure. Reaction temperature The temperature was raised to 120_130 ° C, and the temperature was maintained for 0.1 to 1.1 hours. The reaction was terminated. The reaction solution was poured into water, stirred, and cooled and filtered to obtain 9-fluoro_3-methyl-10- (4-methyl-1-piperidine). Azinyl) -7-oxy-2,3-dihydro-7H-pyrido- [1,2,3, -de] [1,4] benzoxazine-6-carboxylic acid ethyl ester (hereinafter referred to as Compound (X)) _; b) Add water and acid to compound (X), stir to reflux until hydrolysis is complete, adjust ra to 7.0 with alkaline solution, add extractant to extract, and concentrate the extract layer to obtain ofloxacin. -The process for preparing levofloxacin from compound (V) is as follows-

(V)

(X) (XI)

(IX) (I) The actual reaction is as follows:

(V) (IX)

Of course, ofloxacin can be prepared-

(XI)

In the above preparation method, a first ring is firstly placed at a low temperature (60 to 70 ° C), then a methylpiperazinyl group is added, then a second ring is placed at a high temperature (120-13CTC), and finally hydrolyzed. Since the above-mentioned stepwise ring formation method (which is totally different from the prior art synchronous ring formation method) is adopted, that is, two rings are formed at two different temperatures, the present invention makes the reaction time in the high temperature stage short (0. 1-1 0 hours), most of the reaction time is in the low temperature stage of 60 ~ 80 ° C, and the product quality and appearance have been significantly improved. Since the same solvent is used in the reaction for preparing the compound (D or (X)) from the compound (V), the three reaction processes can be completed in one step in the same reactor, so the compound (V) The preparation of the final product is actually a two-step reaction, which shortens the reaction time. After the reaction is completed, the solvent can be recovered and applied centrally, which reduces the production cost. In addition, because the methylpiperazinyl group is firstly hydrolyzed, the hydrolysis is in a fully dissolved state Completed, easier to hydrolyze completely, greatly shortening the reaction time.

In the method for preparing levofloxacin and ofloxacin, the solvent is isoamyl alcohol, xylene, dioxane, N, N-dimethylformamide (DMF) or dimethyl sulfoxide ( DMS0), different solvents have an effect on the yield of the reaction.

In the method for preparing levofloxacin and ofloxacin, the base in step a is potassium carbonate, sodium bicarbonate, triethylamine or pyridine.

The present invention provides a method for preparing levofloxacin and ofloxacin, which has the following beneficial effects: 1) By controlling the reaction temperature, the first ring is added first, then the methylpiperazinyl group is added, and then The second ring is finally hydrolyzed, and the reaction is easy to perform, which shortens the high temperature time and the entire reaction time; 2) The same solvent is used in the reaction process, and the compound (V) can be prepared in the same reactor as the compound (IX) or (X) The inner step is completed, the operation is convenient, the reaction steps are shortened, and the process is simplified; 3) it is convenient to perform centralized recovery of the solvent and apply it, and it has a good recovery and application rate, which reduces the production cost; 4) water The solution is fast and complete; 5) Due to the short high temperature time, the product quality and appearance have been significantly improved.

detailed description

Example 1

a) Preparation of compound (IX): Put 60. Og of compound (V), 150 ml of DMF in a 500-ml three-necked flask, freeze to 0 ° C, dropwise add 14. Og L-aminopropanol, and then incubate at 0.5 After 4 hours, 45.0 g of K2CO3 was added, and the mixture was reacted at 60-70 ° C for 3 hours. 30. Og of N-methylpiperazine was added to the mother liquor, and the reaction was stirred at 70-80 ° C for 2 hours to recover N-methylpiperazine under reduced pressure. Og Compound Raise the reaction temperature to 120-130 ° C, 0.5 hours later, the reaction is completed, the reaction solution is poured into a 1000ml beaker containing 500ml of water, and stirred, that is, a white solid precipitates, cooled, filtered, and dried to obtain 43. Og compounds (IX), with a yield of 57.9%.

b) Preparation of levofloxacin (I): In a 500ml three-necked flask, 50.5g of the compound (IX) obtained in step a, 150ml of water, and 50ml of concentrated hydrochloric acid were sequentially put in and stirred under reflux for half an hour, and the solid was completely dissolved. The reaction is over. After the solution was slightly cold, 150 ml of water and 30. OgNaOH lye were added to adjust the pH to 7.0, and then extracted with 50 ml / times x 5 times of chloroform, and the concentrated chloroform layers were combined to obtain 38.5 g of levofloxacin, Yield: 94.2%.

Example 2

3%。 The difference from Example 1 is that using isoamyl alcohol as a solvent, the base added is sodium bicarbonate, the yield obtained in step a is 45.7%, and the yield obtained in step b is 92.3%.

Example 3

a) Preparation of compound (X): In a 500ml three-necked flask, 60.0g of compound (V), 150ml of DMF were sequentially put in, frozen to 0 ° C, 14.0g of DL-aminopropanol was added dropwise, and then kept at 0.5 After 4 hours, add Λ 45.0 gK2CO3, react at 60-70 ° C for 3 hours, add 30.0 g of N-methylpiperazine to the mother liquor, and stir at 70-80 ° C for 2 hours to recover N-methylpiperazine under reduced pressure. . 0g ， Raising the reaction temperature to 120-130 ° C, 0.5 hours later, the reaction was completed, the reaction solution was poured into a 1000ml beaker filled with 500ml of water, and stirred, that is, a white solid precipitated, cooled and dried to 45.0g, Yield: 60.6%.

b) Preparation of ofloxacin (XI): Put the obtained in step a in a 500ml three-necked bottle in turn.

52.0 g of a solid compound, 150 ml of water, and 50 ml of concentrated hydrochloric acid were stirred under reflux for half an hour, and the reaction was completed. After the solution was slightly cold, 400 ml of ethanol was added to precipitate a large amount of white solid. After stirring and freezing, it was filtered and dried to obtain 41.5 g of ofloxacin with a yield of 97.1%.

Example 4

The difference from Example 3 is that xylene was used as the solvent, the base added was pyridine, the yield obtained in step a was 23.7%, and the yield obtained in step b was 94.6%.

Claims

Rights request

1. The preparation method of levofloxacin is a synthesis method using tetrafluorobenzoic acid as a raw material, which is characterized by: a) in 2- (2, 3, 4, 5-tetrafluorobenzoyl) -3- A solvent was added to the crude ethoxy-ethyl acrylate, and L-aminopropanol was added dropwise by freezing. After the temperature was kept constant, the base was added and reacted at 50-9CTC. After the reaction was completed, N-methyl piperazine was added to the mother liquor. Azine, 55 ~ 95 ° C, stirred for 1-3 hours to recover N-methylpiperazine under reduced pressure, and the reaction temperature was raised to 120-130 ° C, and the temperature was maintained for 0.1 to 1.1 hours, the reaction was terminated, and the reaction solution was poured. Pour into water, stir, cool and filter to obtain S- (-) 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl)-7_oxy-2,3-dihydro-7H -Pyrido- [1,2,3, -de] [l, 4] benzoxazine-6-carboxylic acid ethyl ester; b) water and acid are added to the product obtained in step a, and the mixture is stirred and refluxed until the hydrolysis is completed , Ra was adjusted to 7.0 with alkaline solution, chloroform extraction was added, and the extracted layer was concentrated to obtain levofloxacin.

2. The method for preparing levofloxacin according to claim 1, wherein the solvent is isoamyl alcohol, xylene, dioxane, N, N-dimethylformamide or dimethyl Sulfoxide.

3. The method for preparing levofloxacin according to claim 1, wherein the base in step a is potassium carbonate, sodium bicarbonate, triethylamine or pyridine.

4. The preparation method of ofloxacin is a synthesis method using tetrafluorobenzoic acid as a raw material, which is characterized by: a) at 2- (2, 3, 4, 5-tetrafluorobenzoyl) -3-ethyl A solvent was added to the crude oxy-ethyl acrylate, and DL-aminopropanol was added dropwise by freezing. After the temperature was kept constant, the base was added and reacted at 50-90 ° F. After the reaction was completed, N-methylpiperazine was added to the mother liquor. , 55 ~ 95 ° C, stirring the reaction for 1-3 hours, and then recovering N-methylpiperazine under reduced pressure, the reaction temperature was raised to 120-130 ° C, and the temperature was maintained for 0. 1-1. 0 hours, the reaction was terminated, and the reaction solution was poured into Stir in water and filter with cooling to obtain 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido- [1, 2, 3, _de] [1,4] benzoxazine-6-carboxylic acid ethyl ester; b) add water and acid to the product obtained in step a, stir and reflux until the hydrolysis is complete, adjust the pH to 7 with alkaline solution 0, add chloroform for extraction, and concentrate the extraction layer to obtain ofloxacin.

5. The method for preparing ofloxacin according to claim 4, characterized in that the solvent is isoamyl alcohol, xylene, dioxane, N, N-dimethylformamide or dimethyl Sulfoxide.

6. The method for preparing ofloxacin according to claim 4, wherein the base in step a is potassium carbonate, sodium bicarbonate, triethylamine or pyridine.