Preparation method of besifloxacin hydrochloride side chain

Abstract

The invention discloses a preparation method of a besifloxacin hydrochloride side chain (formula 1). The preparation method comprises the following steps: (1) carrying out esterification reaction on L-lysine and methanol under the action of thionyl chloride to obtain L-lysine methyl ester hydrochloride; (2) carrying out intramolecular cyclization reaction on the L-lysine methyl ester hydrochloride under the action of strong base, and carrying out in-situ racemization to obtain alpha-aminocaprolactam; (3) carrying out crystallization induced dynamic resolution on the alpha-aminocaprolactam to efficiently obtain (R)-alpha-aminocaprolactam; and 4) carrying out hydroboration reduction on the (R)-alpha-aminocaprolactam to finally prepare the besifloxacin hydrochloride side chain. According to the method, a crystallization-induced dynamic resolution technology is adopted, the resolution efficiency is remarkably improved, and the resolution yield reaches 70% or above and is about two times that of a traditional resolution technology. Meanwhile, the L-lysine which is naturally sourced is used as a starting material, the use of an expensive reduction reagent lithium aluminum hydride is avoided, and the method has the advantages of low raw material cost, mild reaction conditions, high optical purity of the product and the like, and is suitable for industrial production. # imgabs0 #

Description

Technical Field:

[0001] The present invention belongs to the field of preparation of pharmaceutical compounds, and specifically relates to a method for preparing the side chain of besifloxacin hydrochloride. Background Art:

[0002] Besifloxacin Hydrochloride is a new type of quinolone antibacterial drug developed by Bausch & Lomb Inc., USA, mainly used for the treatment of bacterial conjunctivitis. Its chemical name is (R)-7-(3-aminoazepan-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride, and its chemical structural formula is as follows:

[0003]

[0004] Clinical studies have shown that besifloxacin hydrochloride has significant broad-spectrum antibacterial activity, showing excellent bactericidal effects against various ocular pathogenic bacteria (such as Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, etc.) that cause bacterial conjunctivitis. At the same time, its unique chemical structure gives it a relatively low risk of drug resistance, providing a new solution for the treatment of ophthalmic infections.

[0005] As shown above, the molecular structure of besifloxacin hydrochloride is composed of two parts: a quinolone mother nucleus and a side chain (R)-3-amino-hexahydro-1H-azepane. Among them, the structures of the quinolone drug mother nuclei are generally similar and have been mass-produced commercially and are easily obtained; the side chain (R)-3-amino-hexahydro-1H-azepane, as a key intermediate of besifloxacin hydrochloride, introduces a chiral center with drug activity in its structure, which is the core difficulty in the synthesis process. Its market price remains high, exceeding 10,000 yuan / kg, becoming the main factor restricting the production cost of besifloxacin hydrochloride.

[0006] The synthesis of the side chain (R)-3-amino-hexahydro-1H-azepane mostly starts from D-lysine hydrochloride, and its preparation process is as follows (see US20100029936):

[0007]

[0008] This synthesis route starts from D-lysine hydrochloride and obtains the target product through three steps of esterification, cyclization, and reduction with lithium aluminum hydride. Although this route has relatively few reaction steps, it still has the following significant defects: 1) The starting material D-lysine hydrochloride is expensive, and the reduction reagent lithium aluminum hydride also has a high cost, resulting in a high overall raw material cost; 2) During the cyclization reaction, R-α-aminocaprolactam is prone to partial racemization under the action of strong base sodium methoxide, resulting in a low optical purity of the final product and making it difficult to meet the production requirements of high-purity chiral drugs. Summary of the Invention:

[0009] In view of the above deficiencies and combining with the structural characteristics that compound α - aminocaprolactam is prone to racemization under the action of strong base or aldehyde, the present invention provides a new low - cost preparation method for the side chain of besifloxacin hydrochloride. Using the inexpensive natural product L - lysine as the raw material, the product is obtained through four steps of esterification, cyclization and racemization, dynamic resolution, and borohydride reduction. The specific reaction equation is shown in the appendix Figure 1 .

[0010] The core advantage of this preparation method lies in the adoption of Crystallization - induced dynamic resolution (CIDR) technology during the resolution process. The CIDR technology combines in - situ racemization with selective crystallization to achieve efficient chiral resolution: the target enantiomer forms an insoluble salt with the resolution reagent and selectively crystallizes out, while the non - target enantiomer is in - situ converted into a racemate under the action of a racemization catalyst and re - enters the resolution cycle. This technology breaks through the limitation of the traditional resolution theory yield of 50%, significantly improves the resolution efficiency, and provides an innovative solution for the large - scale preparation of chiral compounds.

[0011] The preparation method of the present invention includes the following steps:

[0012] (1) The starting material L - lysine and methanol are esterified under the action of thionyl chloride to obtain L - lysine methyl ester hydrochloride;

[0013] (2) Dissolve L - lysine methyl ester hydrochloride in an alcohol solvent, reflux and react under the action of an excessive strong base, carry out intramolecular cyclization and racemization reactions to obtain α - aminocaprolactam;

[0014] (3) Dissolve α - aminocaprolactam in an alcohol solvent, carry out crystallization - induced dynamic resolution under the combined action of a resolution reagent and a racemization catalyst to obtain a chiral salt, and then obtain R - α - aminocaprolactam through alkali hydrolysis;

[0015] (4) Dissolve R - α - aminocaprolactam in an ether solvent, and obtain the side chain of besifloxacin hydrochloride through borohydride reduction reaction.

[0016] The alcohol solvent in step (2) is one of methanol, ethanol, and isopropanol, preferably ethanol. The strong base is one of sodium hydroxide, potassium hydroxide, sodium methoxide, and sodium ethoxide, preferably sodium ethoxide; the molar ratio of the base to intermediate 1 is 2.2 - 2.8:1, preferably 2.5:1.

[0017] The alcohol solvent in step (III) is one of methanol, ethanol, and isopropyl alcohol, preferably ethanol. The resolution reagent is D-pyroglutamic acid or D-tartaric acid, preferably D-pyroglutamic acid; the molar ratio of the resolution reagent to α-aminocaprolactam is 0.8:1 to 1.1:1, preferably 1:1. The racemization catalyst is one of 5-nitrosalicylaldehyde, 3-nitrosalicylaldehyde, and 5-fluorosalicylaldehyde, preferably 5-nitrosalicylaldehyde; the molar ratio of the racemization catalyst to α-aminocaprolactam is 1% to 10%, preferably 5%.

[0018] The ether solvent in step (IV) is 2-methyltetrahydrofuran, and the reducing agent is zinc borohydride.

[0019] Compared with the prior art, the method for preparing the besifloxacin hydrochloride side chain provided by the present invention has the following remarkable advantages: 1) The product has high optical purity and the total yield is significantly improved; 2) The raw material cost is greatly reduced, and the raw material cost per kilogram of the side chain is controlled below one thousand yuan; 3) The reaction conditions are mild and the operation is simple, which is suitable for industrial production.

[0020] Specifically, the technical advantages of the present invention are reflected in the following steps.

[0021] Step (I): Using naturally sourced L-lysine as the starting material, whose unit price is only one-tenth of that of D-lysine, significantly reducing the raw material cost.

[0022] Step (II): Through a one-step alkali reflux reaction, the cyclization and racemization of L-lysine methyl ester are completed simultaneously, which not only reduces the reaction steps but also simplifies the operation process and improves the process efficiency.

[0023] Step (III): Using the crystallization-induced dynamic resolution technique, the R configuration of α-aminocaprolactam is selectively precipitated by the resolution reagent, and at the same time, the remaining enantiomers in the reaction solution are in-situ racemized by the racemization catalyst, realizing the integrated operation of crystallization and racemization. The resolution yield of this step can reach more than 70%, which is more than twice that of the traditional crystallization resolution; in addition, the resolution reagent can be recycled, further reducing the production cost.

[0024] Step (IV): Selecting zinc borohydride as the reducing reagent, compared with lithium aluminum hydride, the reaction process is milder, and the price is only one-twentieth of that of lithium aluminum hydride, greatly reducing the reagent cost. Description of the Drawings: Figure 1 This is the specific reaction equation of the present invention. Detailed Embodiments:

[0026] The following further describes the present invention in detail with reference to the embodiments, but the embodiments of the invention are not limited thereto. Example 1 Preparation of L-lysine methyl ester hydrochloride

[0027] L-lysine (321.6 g, 2.2 mol) and anhydrous methanol (2000 ml) were added into a 5 L reaction flask, and stirring was started. The temperature was lowered by cooling, and thionyl chloride (523.5 g, 4.4 mol) was added dropwise while controlling the temperature below 10 °C. After the addition was complete, the reaction was carried out at 0 - 10 °C for 2 hours, then heated to reflux and kept reacting for 8 - 9 hours. The reaction was monitored by TLC (ethyl acetate:methanol:ammonia water = 20:10:1, volume ratio, developed with 0.3% ninhydrin ethanol solution). The temperature was lowered for crystallization, and crystallization was carried out at 0 - 10 °C for 5 hours. Filtration was performed by suction, and the filter cake was washed with cold methanol and dried in a blast dryer at 60 °C to obtain 493.6 g of L-lysine methyl ester hydrochloride, a white-like solid, with a yield of 96.2%.

[0028] Example 2 Preparation of α-aminocaprolactam

[0029] Anhydrous ethanol (4 L) was added to a 10 L reaction flask and stirred. Under cooling with cold water, sodium ethoxide (360.0 g, 5.3 mol) was added and stirred until dissolved. At room temperature, L-lysine methyl ester hydrochloride (490.0 g, 2.1 mol) obtained in Example 1 was added, and the mixture was heated to reflux and kept reacting for 10 hours. The reaction was monitored by TLC (ethyl acetate:methanol:ammonia water = 20:10:1, volume ratio, developed with 0.3% ninhydrin ethanol solution). The temperature was lowered to room temperature, ammonium chloride (80.0 g, 1.5 mol) was added, and stirring was carried out for 4 - 5 hours. Filtration was performed by suction, and the filter cake was washed with anhydrous ethanol. The filtrate was evaporated to dryness under reduced pressure to obtain 253.6 g of α-aminocaprolactam, a white-like solid, with a yield of 94.2%.

[0030] Example 3 Preparation of R-α-aminocaprolactam (crystallization-induced dynamic resolution method)

[0031] α-Aminocaprolactam (27.0 g, 0.21 mol) obtained in Example 2 and 500 ml of ethanol were added into a 1 L reaction flask, and 5-nitrosalicylaldehyde (1.67 g, 0.01 mol) and D-pyroglutamic acid (27.1 g, 0.21 mol) were added. The mixture was heated to reflux for 16 h, and solids gradually precipitated during the reaction. The reaction solution was cooled to about 20 °C, filtered by suction, and the filter cake was washed with ethanol to obtain R-α-aminocaprolactam D-pyroglutamate. The salt was dissolved in water, and the pH was adjusted to 10 by dropping ammonia water. Extraction was carried out three times with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was evaporated to dryness under reduced pressure to obtain 19.6 g of R-α-aminocaprolactam, a light yellow viscous oil, with a yield of 72.6%, a chemical purity of 99.6%, and an optical purity of 99.7%.

[0032] Example 4 Preparation of R-α-aminocaprolactam (crystallization-induced dynamic resolution method)

[0033] Add α - aminocaprolactam (27.0 g, 0.21 mol) obtained in Example 2 and 500 ml of ethanol into a 1 L reaction flask, and then add 5 - nitrosalicylaldehyde (1.67 g, 0.01 mol) and D - tartaric acid (31.5 g, 0.21 mol). Heat under reflux for 20 h, and a solid gradually precipitates during the reaction. Cool the reaction solution to about 20 °C, filter by suction, and wash the filter cake with ethanol to obtain R - α - aminocaprolactam D - tartrate. Treat this salt according to the method of Example 3 to obtain 17.5 g of R - α - aminocaprolactam, a light yellow oil, with a yield of 64.8%, a chemical purity of 99.5%, and an optical purity of 98.6%.

[0034] Example 5 Preparation of R - α - aminocaprolactam (Crystallization - induced dynamic resolution method)

[0035] Add α - aminocaprolactam (27.0 g, 0.21 mol) of Example 2 and 500 ml of ethanol into a 1 L reaction flask, and then add 5 - fluorosalicylaldehyde (1.40 g, 0.01 mol) and D - pyroglutamic acid (27.1 g, 0.21 mol). Heat under reflux for 22 h, and a solid gradually precipitates during the reaction. Cool the reaction solution to about 20 °C, filter by suction, and wash the filter cake with ethanol to obtain R - α - aminocaprolactam D - pyroglutamate. Treat this salt according to the method of Example 3 to obtain 18.7 g of R - α - aminocaprolactam, a light yellow oil, with a yield of 69.3%, a chemical purity of 99.5%, and an optical purity of 98.8%.

[0036] Example 6 Preparation of R - α - aminocaprolactam (Crystallization - induced dynamic resolution method)

[0037] Add α - aminocaprolactam (27.0 g, 0.21 mol) of Example 2 and 500 ml of isopropanol into a 1 L reaction flask, and then add 5 - nitrosalicylaldehyde (0.70 g, 4.2 mmol) and D - pyroglutamic acid (27.1 g, 0.21 mol). Heat under reflux for 24 h, and a solid gradually precipitates during the reaction. Cool the reaction solution to about 20 °C, filter by suction, and wash the filter cake with isopropanol to obtain R - α - aminocaprolactam D - pyroglutamate. Treat this salt according to the method of Example 3 to obtain 16.0 g of R - α - aminocaprolactam, a light yellow oil, with a yield of 59.2%, a chemical purity of 99.6%, and an optical purity of 99.0%.

[0038] Example 7 Preparation of the side chain of Besifloxacin Hydrochloride

[0039] Add anhydrous zinc chloride (75.2 g, 0.55 mol) and 2-methyltetrahydrofuran (500 ml) into a 2 L four-necked reaction flask, and stir at room temperature for 30 minutes. Add potassium borohydride (25.0 g, 0.46 mol) at room temperature, and stir for 3 hours. Add the R-α-aminocaprolactam (19.2 g, 0.15 mol) obtained in Example 3 at room temperature, heat up to reflux and react for 8 hours, and monitor the reaction by TLC (ethyl acetate: methanol: ammonia water = 20:10:1, volume ratio, developed with 0.3% ninhydrin ethanol solution). Cool with ice water, control the temperature below 20 °C, and add 15% hydrochloric acid solution dropwise to quench the reaction. After the addition is complete, add 15% sodium hydroxide solution dropwise to adjust the pH of the reaction solution to above 10 while controlling the temperature below 20 °C. Filter the reaction solution through diatomaceous earth, let the filtrate stand and separate into layers, separate the organic layer, extract the aqueous layer three times with 2-methyltetrahydrofuran, combine the organic layers, and dry over anhydrous sodium sulfate. Filter by suction, and evaporate the obtained filtrate under reduced pressure to dryness to obtain 15.7 g of the side chain, a pale yellow oil, with a yield of 91.5%, a chemical purity of 98.6%, and an optical purity of 99.2%.

[0040] Comparative Example 1 Preparation of R-α-aminocaprolactam (traditional crystallization resolution method)

[0041] Add α-aminocaprolactam (76.8 g, 0.6 mol) of Example 2, D-pyroglutamic acid (77.4 g, 0.6 mol) and ethanol (1500 ml) into a 2 L reaction flask, and heat to dissolve. Slowly cool to about 20 °C, stir for crystallization for 3 hours, filter by suction, and recrystallize the obtained filter cake twice with absolute ethanol to obtain optically pure R-α-aminocaprolactam D-pyroglutamate. Treat this salt according to the method of Example 3 to obtain 25.8 g of R-α-aminocaprolactam, a pale yellow oily substance, with a yield of 33.6%, a chemical purity of 99.7%, and an optical purity of 99.3%.

[0042] Comparative Example 2 Preparation of the side chain of besifloxacin hydrochloride (reduction with lithium aluminum hydride)

[0043] Referring to Patent US20100029936, 250 ml of THF was added into a 500-ml reaction flask, stirring was started, and it was cooled at low temperature. The temperature was controlled at 0-10 °C, and lithium aluminum hydride (15.2 g, 0.40 mol) was added in portions. After addition, it was stirred for 30 minutes. The solution of R-α-amino-caprolactam (21.8 g, 0.17 mol) obtained in Comparative Example 1 in tetrahydrofuran (100 ml) was added dropwise at 0-10 °C. After addition, it was naturally warmed to room temperature and reacted for 1 hour, then heated to reflux and reacted for 8 hours. The reaction was monitored by TLC (ethyl acetate: methanol: ammonia water = 20:10:1, volume ratio, developed with 0.3% ninhydrin ethanol solution). It was cooled with ice water to below 10 °C, 15 ml of water and 15 ml of 15% sodium hydroxide solution were added dropwise successively and carefully. Anhydrous sodium sulfate was added for drying, and it was stirred at 20-30 °C for 30 minutes. It was filtered by suction, and the filtrate obtained was evaporated to dryness under reduced pressure to obtain 18.3 g of a pale yellow oil, with a yield of 92.8%, a chemical purity of 98.5%, and an optical purity of 99.0%.

Claims

1. A method for preparing a side chain of besifloxacin hydrochloride, characterized in that: The following steps are involved: (i) the starting material L-lysine and methanol undergo an esterification reaction under the action of thionyl chloride to obtain L-lysine methyl ester hydrochloride; (ii) dissolving L-lysine methyl ester hydrochloride in an alcohol solvent, subjecting it to a reflux reaction under the action of an excess of a strong base, and performing an intramolecular cyclization and racemization reaction to obtain α-aminocaprolactam; (iii) dissolving α-aminocaprolactam in an alcohol solvent, performing crystallization-induced dynamic resolution under the combined action of a resolution agent and a racemization catalyst to obtain a chiral salt, and removing the resolution agent from the chiral salt to obtain R-α-aminocaprolactam; (iv) dissolving R-α-aminocaprolactam in an ether solvent and subjecting it to a borohydride reduction reaction to obtain the side chain of besifloxacin hydrochloride.

2. The preparation method according to claim 1, characterized in that: The alcohol solvent in step (ii) is one of methanol, ethanol and isopropanol, preferably ethanol.

3. The preparation method according to claim 1, characterized in that: The strong base in step (ii) is one of sodium hydroxide, potassium hydroxide, sodium methoxide and sodium ethoxide, preferably sodium ethoxide; the molar ratio of the strong base to L-lysine methyl ester hydrochloride is 2.2:1 to 2.8:1, preferably 2.5:

1.

4. The preparation method according to claim 1, characterized in that: The alcohol solvent in step (iii) is one of methanol, ethanol and isopropanol, preferably ethanol.

5. The preparation method according to claim 1, characterized in that: In step (iii), the resolving agent is one of D-pyroglutamic acid and D-tartaric acid, preferably D-pyroglutamic acid; the molar ratio of the resolving agent to α-aminocaprolactam is 0.8:1 to 1.1:1, preferably 1:

1.

6. The preparation method according to claim 1, characterized in that: In step (iii), the racemization catalyst is one of 5-nitrosalicylicylaldehyde, 3-nitrosalicylicylaldehyde and 5-fluorosalicylaldehyde, preferably 5-nitrosalicylicylaldehyde; the molar ratio of the racemization catalyst to α-aminocaprolactam is 1% to 10%, preferably 5%.

7. The preparation method according to claim 1, characterized in that: The ether solvent in step (iv) is 2-methyltetrahydrofuran.

8. The preparation method according to claim 1, characterized in that: The reducing agent in step (iv) is zinc borohydride.

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