阅读说明：本技术 吉米沙星侧链化合物的制备方法 (Preparation method of gemifloxacin side chain compound ) 是由 刘宇晶 马昂 罗桓 张文腾 张强 赵隋红 孙跃军 袁伟锋 童元峰 谌宗永 于 2021-10-12 设计创作，主要内容包括：本发明公开了一种吉米沙星侧链化合物的制备方法。所述制备方法包括如下步骤：S1、1-N-叔丁氧羰基-4-氰基-3-吡咯烷酮与甲氧基胺盐酸盐进行反应得到式(Ⅴ)所示化合物；S2、在惰性气氛中,在10～50℃的温度下、在钯碳存在的条件下,式(Ⅴ)所示化合物在0.1～0.5Mpa氢气氛围下进行加氢还原反应1～3h；再加入Boc酸酐,于10～50℃和0.1～0.5Mpa的条件下继续进行加氢还原反应4～8h,得到式(Ⅵ)所示化合物；S3、式(Ⅵ)所示化合物与酸反应脱除保护基,即得式(Ⅰ)所示吉米沙星侧链化合物。本发明制备方法,工艺简单,反应条件非常温和,很容易实现；(2)原料价格低廉,成本低；(3)开创一种新的、有效的吉米沙星侧链的合成工艺路线。(The invention discloses a preparation method of gemifloxacin side chain compound. The preparation method comprises the following steps: s1, reacting 1-N-tert-butyloxycarbonyl-4-cyano-3-pyrrolidone with methoxyamine hydrochloride to obtain a compound shown as a formula (V); s2, carrying out hydrogenation reduction reaction on the compound shown in the formula (V) in an inert atmosphere at the temperature of 10-50 ℃ in the presence of palladium carbon for 1-3 h under the hydrogen atmosphere of 0.1-0.5 Mpa; adding Boc anhydride, and continuously carrying out hydrogenation reduction reaction for 4-8 h at 10-50 ℃ and 0.1-0.5 Mpa to obtain a compound shown in a formula (VI); s3, reacting the compound shown in the formula (VI) with acid to remove a protecting group, and obtaining the gemifloxacin side chain compound shown in the formula (I). The preparation method has simple process, very mild reaction conditions and easy realization; (2) the raw materials are low in price and low in cost; (3) a new and effective synthesis process route of the gemifloxacin side chain is created.)

1. The preparation method of the gemifloxacin side chain compound shown in the formula (I) comprises the following steps:

s1, reacting 1-N-tert-butyloxycarbonyl-4-cyano-3-pyrrolidone with methoxyamine hydrochloride to obtain a compound shown as a formula (V);

in the formula (V), Boc represents tert-butoxycarbonyl;

s2, carrying out hydrogenation reduction reaction on the compound shown in the formula (V) in an inert atmosphere at the temperature of 10-50 ℃ in the presence of palladium carbon for 1-3 h under the hydrogen atmosphere of 0.1-0.5 Mpa; adding Boc anhydride, and continuously carrying out hydrogenation reduction reaction for 4-8 h at 10-50 ℃ and 0.1-0.5 Mpa to obtain a compound shown in a formula (VI);

the mass percentage of palladium in the palladium-carbon is 1-20%;

the amount of the palladium-carbon is 1-30% of the mass of the compound shown in the formula (V);

the using amount of the Boc anhydride is 1-5 times of the molar amount of the compound shown in the formula (V);

the reaction system of the hydrogenation reduction reaction is neutral;

s3, reacting the compound shown in the formula (VI) with acid to remove a protecting group, and obtaining the gemifloxacin side chain compound shown in the formula (I);

2. the method of claim 1, wherein: in step S1, the reaction is performed under the catalysis of pyridine;

the molar ratio of the N-tert-butoxycarbonyl-4-cyano-3-pyrrolidone, the methoxylamine hydrochloride and the pyridine is 1: 1-2: 1 to 2.

3. The production method according to claim 1 or 2, characterized in that: in the step S1, the reaction temperature is 20-25 ℃ and the reaction time is 3-15 h.

4. The production method according to any one of claims 1 to 3, characterized in that: in step S2, the solvent used in the hydrogenation reduction reaction is at least one of methanol, ethanol, isopropanol, n-propanol, tetrahydrofuran, and 1, 4-dioxane;

the dosage of the solvent is as follows: 5-20 mL/g of the compound represented by the formula (V).

5. The production method according to any one of claims 1 to 3, characterized in that: in the step S2, the pressure of the hydrogenation reduction reaction is 0.1-0.2 MPa.

6. The production method according to any one of claims 1 to 5, characterized in that: in step S3, the acid is at least one of hydrochloric acid, methanesulfonic acid, and trifluoroacetic acid.

Technical Field

The invention relates to a preparation method of gemifloxacin side chain compounds, belonging to the technical field of drug synthesis.

Background

Gemifloxacin is a fourth generation of a new fluoroquinolone antibacterial agent developed by LG chemicals, korea, as shown by compound (III): 7- (4-aminomethyl-3-methoxyiminopyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro [1,8] naphthyridine-3-carboxylic acid, trade name Factive, has the advantages of good therapeutic efficacy and low toxic side effects.

Gemifloxacin is the first antibiotic approved for community-acquired pneumonia caused by multidrug-resistant streptococcus pneumoniae strains (MDRSP). Can be used for treating acute bronchitis, chronic bronchitis, and upper respiratory infection caused by Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, Haemophilus influenzae or Moraxella catarrhalis and pneumococcus, community-acquired pneumonia caused by Chlamydia pneumoniae, and urinary system, reproductive system, digestive system, skin and soft tissue infection caused by anaerobic bacteria.

Gemifloxacin is a powerful new quinolone antibacterial drug, and the reason is that the lipophilicity of the derivative is increased by the replacement of the pyrrolidinyl group of the 7-position side chain, so that the effect on gram-attached bacteria can be enhanced, and the chemical substance has antibacterial activity and antitumor activity. Meanwhile, the 7-position side chain has unique methoxime (CH)₃O-N ═ C) structure, and the structure-activity relationship shows that the special structure has prominent influence on the antibacterial spectrum and can improve the activity against gram-positive bacteria. The new structure of gemifloxacin brings about a powerful medicineHigh effect and high safety.

The gemifloxacin is mainly obtained by condensing a mother nucleus compound (II) 1-cyclopropyl-7-chlorine-6 fluorine-4-oxo-1, 4-dihydro [1,8] naphthyridine-3-carboxylic acid and a side chain compound (I) 4-aminomethyl-3-methoxyimino pyrrolidine, and the synthetic route is as follows:

many reports exist about the mature research of parent nucleus compounds, but the synthesis of side chain compounds is rarely reported, and most of the existing synthesis methods adopt a column chromatography method for purification, so that the operation is not easy in industrial production and the cost is high.

For example, European patent EP0688771A1 discloses a synthesis method of gemifloxacin side chain compound 4-aminomethyl-3-methoxyimino pyrrole, and the synthesis route is as follows:

the route takes N-tert-butyloxycarbonyl-4-cyano-3-pyrrolidone as an initial raw material, and is subjected to reduction, protection, oxidation, oximation and deprotection steps, the route is long and low in yield, the intermediate multi-step purification needs to be completed by means of column separation, and meanwhile, reagents which are not beneficial to industrial production, such as lithium aluminum hydride, Jones reagent and the like, are used, so that the cost is high and the pollution is large.

Patent CN1149192C protects a synthetic route of gemifloxacin side chain compound 4-aminomethyl-3-methoxyimino pyrrole:

the route comprises 5 steps of chemical reaction, the initial raw material N-tert-butyloxycarbonyl-4-cyano-3-pyrrolidone needs to be reduced by two steps of raney nickel and palladium carbon, the reduction pressure is more than 4Mpa, and the industrial production is not facilitated.

In summary, the existing synthesis techniques all have the disadvantages of long route, low yield and being not beneficial to industrial production, and a new route is urgently needed to be developed to solve the problem.

Disclosure of Invention

The invention aims to provide a preparation method of gemifloxacin side chain compound, which has mild condition and simple operation steps and is beneficial to industrial production.

The invention provides a preparation method of gemifloxacin side chain compound shown in formula (I), which comprises the following steps:

s1, reacting 1-N-tert-butyloxycarbonyl-4-cyano-3-pyrrolidone with methoxyamine hydrochloride to obtain a compound shown as a formula (V);

in the formula (V), Boc represents tert-butoxycarbonyl;

s2, carrying out hydrogenation reduction reaction on the compound shown in the formula (V) in an inert atmosphere at the temperature of 10-50 ℃ in the presence of palladium carbon for 1-3 h under the hydrogen atmosphere of 0.1-0.5 Mpa; adding Boc anhydride, and continuously carrying out hydrogenation reduction reaction for 4-8 h at 10-50 ℃ and 0.1-0.5 Mpa to obtain a compound shown in a formula (VI);

the hydrogen atmosphere is preferably 0.1-0.2 Mpa;

s3, reacting the compound shown in the formula (VI) with acid to remove a protecting group, and obtaining the gemifloxacin side chain compound shown in the formula (I);

in the above preparation method, in step S1, the structural formula of the 1-N-tert-butoxycarbonyl-4-cyano-3-pyrrolidone is shown as (IV):

in step S1, the reaction is performed under the catalysis of pyridine;

the molar ratio of the N-tert-butoxycarbonyl-4-cyano-3-pyrrolidone, the methoxylamine hydrochloride and the pyridine is 1: 1-2: 1-2, such as 1: 1.2: 1.2.

in the preparation method, in the step S1, the reaction temperature is 20-25 ℃ and the reaction time is 3-15 hours.

In the preparation method, in step S2, the mass percentage of palladium in the palladium carbon is 1 to 20%, preferably 10%.

The amount of the palladium-carbon used may be 1 to 30%, preferably 5 to 20%, most preferably 15% of the amount of the compound represented by formula (V).

In the above preparation method, in step S2, the temperature of the hydrogenation reduction reaction is preferably 20 to 25 ℃, and the pressure is preferably 1 to 2 atmospheres.

In the preparation method, in step S2, the Boc anhydride is used in an amount of 1 to 5 times, preferably 1 to 1.5 times, and most preferably 1.05 times the molar amount of the compound represented by formula (v);

the reaction system of the hydrogenation reduction reaction in the step S2 is neutral.

In the above preparation method, in step S2, the solvent used in the hydrogenation reduction reaction may be at least one of methanol, ethanol, isopropanol, n-propanol, tetrahydrofuran and 1, 4-dioxane, preferably methanol;

the dosage of the solvent is as follows: 5-20 mL/g of the compound shown in the formula (V), preferably 10mL/g of the compound shown in the formula (V).

In the above preparation method, in step S3, the acid may be at least one of hydrochloric acid, methanesulfonic acid and trifluoroacetic acid, and methanesulfonic acid is preferred.

The preparation method of the invention has the following synthetic route:

the invention has the following beneficial technical effects:

(1) the preparation method has simple process, very mild reaction conditions and easy realization;

(2) the raw materials are low in price and low in cost;

(3) a new and effective synthesis process route of the gemifloxacin side chain is created.

Drawings

FIG. 1 is a LC-Ms spectrum of Compound V, prepared according to example 1 of the present invention.

FIG. 2 is a LC-Ms spectrum of Compound VI prepared in example 1 of the present invention.

FIG. 3 is a LC-Ms spectrum of Compound I prepared in example 1 of the present invention.

FIG. 4 is an HPLC chromatogram of Compound I prepared in example 1 of the present invention.

FIG. 5 is an NMR spectrum of Compound I prepared in example 1 of the present invention.

FIG. 6 is an Ms spectrum of Compound III prepared in example 2 of the present invention.

FIG. 7 is an NMR spectrum of a compound III prepared in example 2 of the present invention.

FIG. 8 is an HPLC chromatogram of Compound III prepared in example 2 of the present invention.

FIG. 9 is an LC-Ms spectrum of intermediate state 1 of Compound IV prepared according to example 1 of the present invention.

FIG. 10 is an LC-Ms spectrum of intermediate state 2 of Compound IV prepared according to example 1 of the present invention.

FIG. 11 is a LC-Ms spectrum of Compound IV prepared according to comparative example 1 of the present invention.

Detailed Description

The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.

Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

Example 1 preparation of gemifloxacin side chain

(1) Synthesis of Compound V

Purchasing compound IV, adding 105.0g of compound IV, 50.1g (1.2eq) of methoxylamine hydrochloride and 1000ml of methanol into a 2L reaction bottle, adding 47.5g (1.2eq) of pyridine as a catalyst, reacting at 20-25 ℃ for 5h, monitoring the reaction by TLC, distilling under reduced pressure until the reaction is finished, adding water and dichloromethane for layering, washing an organic phase by saturated sodium bicarbonate solution and saturated common salt water in turn, drying anhydrous sodium sulfate, and distilling under reduced pressure until the organic phase is dried to obtain compound V (117.8g, the yield is 98.4%).

The LC-Ms pattern of compound V is shown in FIG. 1.

(2) Synthesis of Compound VI

Adding 20g of the compound V, 200ml of methanol and 3g of 10% palladium carbon into a stainless steel hydrogenation kettle, and reacting for 2 hours at 20-25 ℃ under the hydrogen atmosphere of 0.1-0.2 Mpa; and adding 21.9g (1.05eq) of Boc anhydride, stirring at room temperature for 0.5h, continuing to react for 4h under the hydrogen atmosphere of 0.1-0.2 Mpa, monitoring the reaction by TLC, filtering by suction after the reaction is finished, filtering Pd/C, and concentrating under reduced pressure to dryness to obtain a compound VI, wherein the mass of the compound VI is 27.8g, and the compound VI is directly used for the next reaction without purification.

The LC-Ms pattern of compound VI is shown in FIG. 2.

The yield of the reaction of this step was 96.8%.

Experimental studies show that the reaction sequence of the step is as follows:

the steps are explained as follows:

firstly, carrying out palladium-carbon catalytic hydrogenation on a compound V to obtain an imine compound, namely, an intermediate state 1, wherein LC-Ms shows that a mass spectrum signal of a target chromatographic peak is 242, and the mass spectrum signal is an M + H peak of the intermediate state 1, as shown in FIG. 9;

secondly, after adding Boc anhydride, LC-Ms shows that the chromatographic peak of intermediate state 1 (15.192min) is converted into the chromatographic peak of intermediate state 2 (11.560min), and the intermediate state 2 is not easy to ionize, so that the mass spectrum signal is not captured, as shown in FIG. 10;

thirdly, continuously carrying out catalytic hydrogenation, converting the intermediate state 2 into a target compound VI, wherein the LC-Ms shows that a mass spectrum signal of a target chromatographic peak is 366, namely an M + Na peak of the compound VI, as shown in figure 2;

through the step-by-step feeding mode, the reaction pressure can be reduced, the generation of side reaction impurities is avoided, the purity of the product is improved, and the subsequent improvement of the yield of the subsequent salt forming step is facilitated.

(3) Synthesis of Compound I

Taking 27.8g of compound VI, dissolving with 110ml of methanol, adding 16.3g (2.1eq) of methanesulfonic acid, stirring and reacting at 20-25 ℃ for 12h under the protection of nitrogen, cooling to 0 ℃ for crystallization for 2h, carrying out suction filtration under reduced pressure, and washing a filter cake with a small amount of methanol to obtain a solid compound I (17.5g), wherein the yield is 66.5%.

The LC-Ms, chromatogram and NMR spectrum of compound I are shown in FIG. 3, FIG. 4 and FIG. 5, respectively.

The purity of compound I prepared in this example was checked by HPLC:

a chromatographic column: CAPCELL PAK C18150 × 4.6mm × 3 um;

sample introduction volume: 10 ul;

temperature: 30 ℃;

wavelength: 210 nm;

flow rate: 1.0 ml/min;

mobile phase A: 0.005mol/L sodium octane sulfonate and 0.5mol/L potassium dihydrogen phosphate, and adjusting the pH value to 7 by using potassium hydroxide;

mobile phase B: acetonitrile;

and (3) an elution mode: a: and B is 90: 10 isocratic elution.

The HPLC profile is shown in fig. 5, and the analysis result shows that the purity of the purified gemifloxacin side chain prepared in this example is 97.017%.

According to the invention, the catalytic system in the step (2) is considered, each catalytic system, reaction conditions and results are shown in table 1, and the data in table 1 show that the catalytic system of palladium carbon/Boc anhydride has higher raw material conversion rate in shorter reaction time, lower reaction pressure, greatly reduced production cost and higher safety and operability compared with other traditional catalytic conditions.

TABLE 1 different catalytic systems and catalytic Effect

Example 2 preparation of gemifloxacin

14.1mg (5mmol) of 1-cyclopropyl-7-chloro-6-fluoro-4-oxo-1, 4-dihydro [1,8] naphthyridine-3-carboxylic acid and 15ml of water were charged into a reaction flask, triethylamine was added, 10.8g (5mmol) of 4-aminomethyl-3-methoxyiminopyrrole prepared in example 1 was further added dropwise, reacted at 20 to 25 ℃ for 15 hours, filtered, and the precipitated solid was separated and dried to obtain 16.7g (yield: 85%) of gemifloxacin (compound (III)).

The Ms, NMR and HPLC profiles of the compound (III) prepared in this example are shown in FIGS. 6 to 8, respectively.

Wherein, the detection conditions of HPLC are as follows:

a chromatographic column: CAPCELL PAK C18150 × 4.6mm × 5 um;

sample introduction volume: 20 ul;

temperature: 45 ℃;

wavelength: 270 nm;

flow rate: 1.2 ml/min;

mobile phase A: 2.0g of ammonium acetate and 3.5g of sodium perchlorate are dissolved in 650ml of water and the pH is adjusted to 2.2 with phosphoric acid;

mobile phase B: acetonitrile;

and (3) an elution mode: the elution procedure is shown in table 2:

TABLE 2 gradient elution procedure

Time (min)	Mobile phase A (%)	Mobile phase B (%)
			0	81	19
25	81	19
			35	47	53
40	47	53
			45	81	19
50	81	19

As can be seen from FIG. 8, in the compound III, the isomer is less than 0.5%, and the other unknown simple impurities are less than 0.1%, so that the requirement of the current drug declaration is met.

Comparative example 1 Synthesis of Compound VI

Adding 20g of the compound V, 200ml of methanol, 3g of 10% wet palladium carbon and 21.9g (1.05eq) of BOC anhydride into a 500ml stainless steel hydrogenation kettle, reacting for 20h at 20-25 ℃ in a hydrogen atmosphere of 1Mpa, monitoring the reaction by TLC, filtering Pd/C, and concentrating under reduced pressure to dryness to obtain a compound VI;

the experimental results show that the one-shot feeding mode can also obtain the target product, but the LC-Ms shows that the product purity is only 76.8%, the product contains 11.2% of unknown impurities (as shown in FIG. 11), and the reaction pressure is large.