Preparation method of esculentin hydrochloride intermediate

Abstract

The invention provides a preparation method of an esculentin hydrochloride intermediate, which comprises the following steps: taking 4-fluoro-3-methylaniline as an initial raw material; the key intermediate 2-methyl-3-fluoro-5-dibenzylamino-6-benzyloxybenzoic acid phenyl ester of the etencycline hydrochloride is obtained through bromination, nitrite selective aryl nucleophilic substitution, diazotization hydrolysis, catalytic hydrogenation reduction of nitryl, simultaneous protection of amino and phenolic hydroxyl by a one-pot method, and catalytic carbonyl insertion reaction in sequence, and the key intermediate 2-methyl-3-fluoro-5-dibenzylamino-6-benzyloxybenzoic acid phenyl ester of the etencycline hydrochloride is obtained. The preparation method provided by the invention has the advantages of short steps and mild reaction conditions; the intermediate obtained in the reaction process is easy to separate and purify, and the product quality is stable and reliable; the raw materials are cheap and easily available, the reaction conversion rate is greatly improved, the cost of the current synthesis method is remarkably reduced, and industrial production is facilitated.

Description

Technical Field

[0001] The invention relates to the field of drug synthesis, and in particular to a method for preparing 2-methyl-3-fluoro-5-dibenzylamino-6-benzyloxybenzoic acid phenyl ester, an intermediate of exalacycline hydrochloride. Background Art

[0002] Eravacycline hydrochloride (whose structure is shown in Formula I) is an antibacterial drug developed by Tetraphase Pharmaceuticals. It was approved by the FDA on August 27, 2018 and is marketed under the trade name Xerava. The drug is a new type of fluorotetracycline antibacterial drug used to treat complicated intra-abdominal infections (CIAI) in patients aged 18 years and above. It exhibits strong in vitro antibacterial activity against Gram-negative bacteria, Gram-positive aerobic and facultative bacteria, and multidrug-resistant bacteria to β-lactams / β-lactamase inhibitors.

[0003] 2-Methyl-3-fluoro-5-dibenzylamino-6-benzyloxybenzoic acid phenyl ester is a key intermediate for synthesizing exalacycline hydrochloride, and its structure is shown in formula II.

[0004]

[0005] Patent WO2010126607 discloses the synthesis of tetracycline and its intermediates, and the specific synthesis route is as follows:

[0006]

[0007] The synthetic route uses 5-fluoro-2-methoxybenzoic acid as the starting material, deprotonates it with lithium diisopropylamide at low temperature, methylates it with a large excess of methyl iodide to generate carboxylic acid, removes the methyl ether protecting group after phenol esterification, and then nitrates it to obtain phenyl nitrobenzoate; benzyl protects the phenolic hydroxyl group, reduces it with hydrosulfite, and then benzyl protects the amino group to obtain the intermediate.

[0008] The starting materials and auxiliary materials of this synthetic route are expensive, the reaction conversion rate is low, and the material cost is high; ultra-low temperature conditions such as -30°C and -78°C are required, which has high requirements for scale-up production equipment and high energy consumption; the intermediates in many steps are oily substances, which is not conducive to purification and control of impurities; nitration reaction is required, which poses certain safety risks; nitro reduction uses insurance powder, which produces a large amount of high-salt wastewater, and the post-processing operation is complicated, causing great pollution to the environment.

[0009] The literature "China Pharmaceutical Industry Journal", 2017, 48, 506 reported a method for synthesizing the intermediate, and the specific synthetic route is as follows:

[0010]

[0011] This route is mainly aimed at the problem of low conversion rate in the methylation step of the above patent WO2010126607, and the raw material 5-fluoro-2-methoxybenzoic acid is recovered, but there are many impurities, and the purification method and recycling after recovery are not reported. In addition, some of the above problems such as ultra-low temperature reaction and nitration reaction still exist.

[0012] Patent CN202211408228 discloses a method for preparing the intermediate (II), and its specific synthesis route is as follows:

[0013]

[0014] This route uses 4-fluoro-3-methylphenol as the starting material, and obtains compound II through multiple steps of transformation such as bromination, condensation, Grignard, and esterification. However, the intermediate after bromination of 4-fluoro-3-methylphenol is unstable and prone to dimerization to produce impurities, especially after alkaline post-treatment and concentration, it is very easy to deteriorate, producing nearly 20% or more impurities (J.Org.Chem.2017,82,936-943). The dimer impurity is difficult to remove and will seriously affect the quality of the final product Compound II. In addition, the preparation of Grignard reagents or the exchange of Grignard reagents requires strict anhydrous and oxygen-free conditions, and the operation requirements are high. Moreover, according to the patented process, the conversion rate of repeated bromides is low during the Grignard reaction or the exchange with Grignard reagents and then the reaction with carbon dioxide, and a large amount of debrominated impurities are produced. Summary of the invention

[0015] In order to solve the defects of the prior art in preparing 2-methyl-3-fluoro-5-dibenzylamino-6-benzyloxybenzoic acid phenyl ester, an intermediate of eracycline hydrochloride, such as complicated process, harsh reaction conditions, low conversion rate of raw and auxiliary materials, high cost, and limited yield purity, the present invention aims to provide a preparation method of 2-methyl-3-fluoro-5-dibenzylamino-6-benzyloxybenzoic acid phenyl ester, an intermediate of eracycline hydrochloride, which uses 4-fluoro-3-methylaniline as a raw material, has low-priced and readily available raw and auxiliary materials, mild reaction conditions, high product purity and yield, lower cost, and an overall green and environmentally friendly synthetic route.

[0016] In order to achieve the above technical objectives, the technical solution adopted by the present invention is as follows:

[0017] A method for preparing an elacycline hydrochloride intermediate, the synthetic route is as follows:

[0018]

[0019] Furthermore, the preparation method of the exalacycline hydrochloride intermediate comprises the following steps:

[0020] (1) dissolving 4-fluoro-3-methylaniline (III) in solvent 1 and reacting with a brominating agent to obtain a dibrominated compound IV;

[0021] (2) dissolving compound IV in solvent 2 and reacting with a nitrite solution to obtain a nitro-substituted compound V;

[0022] (3) Compound V undergoes a diazotization reaction with nitrite under acidic conditions to generate a diazonium salt, which is then hydrolyzed to obtain a phenolic compound VI;

[0023] (4) Compound VI is dissolved in solvent 3, and then catalytically hydrogenated in the presence of a catalyst to reduce the nitro group to obtain amino compound VII;

[0024] (5) Compound VII reacts with a benzyl halide under alkaline conditions, and the amino group and the phenolic hydroxyl group are simultaneously protected by benzyl groups to obtain compound VIII;

[0025] (6-A) Compound VIII is dissolved in solvent 4, a catalyst, a phosphorus ligand and an organic base are added, and the compound is subjected to carbonyl insertion reaction with phenyl formate to obtain the target compound II; or

[0026] (6-B) Compound VIII reacts with phenol, NaCN, copper halide and ligand to obtain target compound II.

[0027] Furthermore, in step (1), the solvent 1 is selected from one or more of dichloromethane, chloroform, dichloroethane, methanol, ethanol, isopropanol, acetonitrile, acetic acid, etc., preferably dichloromethane or acetic acid; the reaction temperature is 10 to 60°C; preferably 20 to 40°C; the bromination reagent is selected from bromine, N-bromosuccinimide, dibromohydantoin, etc., preferably bromine; the molar ratio of the compound III to the bromination reagent is 1:2.0 to 5.0, preferably 1:2.1 to 3.0.

[0028] Furthermore, in step (2), the solvent 2 is selected from one or more of methanol, ethanol, isopropanol, acetic acid, dioxane, and water, preferably acetic acid or water; the nitrite is one or a combination of sodium nitrite or potassium nitrite; the molar ratio of compound IV to nitrite is 1:2.0-5.0, preferably 1:2.5-3.5; the reaction temperature is 0-10°C, and the reaction time is 12-24h. In step (2), compound IV and nitrite solution selectively undergo aromatic ring nucleophilic substitution reaction at the 6-position with less steric hindrance, i.e., selective nitration of bromine.

[0029] Furthermore, in step (3), the acid is selected from an inorganic acid or an organic acid, such as any one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, and acetic acid. The molar ratio of compound V to sodium nitrite is 1:1-2; the reaction temperature is 0-10°C, and the reaction time is 0.5-1h; after the reaction, the reaction solution is slowly added to the same acid solution heated to reflux state, and the reaction is continued for 1-3h after the addition is completed, and the temperature is lowered, extracted, and concentrated to obtain compound VI.

[0030] Furthermore, in step (4), the solvent 3 is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran, methyltetrahydrofuran, dioxane, ethyl acetate, and isopropyl acetate, preferably tetrahydrofuran or isopropyl acetate; the catalyst is selected from one or a combination of palladium carbon, platinum carbon, ruthenium carbon, rhodium carbon, and Raney nickel; the hydrogen pressure of the reaction is 0.1 to 5.0 MPa, preferably 1 to 2.5 MPa; the reaction temperature is 25 to 100° C., preferably 50 to 70° C.; the mass ratio of the compound VI to the catalyst is 1:0.01 to 0.5, preferably 1:0.05 to 0.2.

[0031] Further, in step (5), the alkaline condition is carried out in the presence of an inorganic base or an organic base; the inorganic base is selected from alkali metal or alkaline earth metal hydroxide, carbonate, bicarbonate, phosphate, hydride or any combination thereof, such as any one or any combination of two or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride; the organic base is selected from alkoxide, organic amine or any combination thereof, such as any one or any combination of two or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, 4-dimethylaminopyridine, tetramethylethylenediamine.

[0032] Furthermore, in step (5), the reaction solvent is a non-protonic polar solvent, such as one or more of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and cyclopentane, preferably one or more of acetonitrile and N-methylpyrrolidone; the reaction temperature is 80-120° C.; the benzyl halide is one or more of benzyl chloride, benzyl bromide, benzyl iodide, benzyl methanesulfonate, benzyl p-toluenesulfonate, and benzyl trifluoromethanesulfonate, preferably benzyl chloride or benzyl bromide; the molar ratio of the compound VII, the base, and the benzyl halide is 1:3.0-15.0:3.0-10.0, preferably 1:6.0-10.0:3.5-5.5.

[0033] Further, in step (6-A), the solvent 4 is selected from one or more of tetrahydrofuran, methyltetrahydrofuran, dioxane, acetonitrile, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably acetonitrile or toluene; the organic base is selected from any one of triethylamine, N,N-diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, 4-dimethylaminopyridine, tetramethylethylenediamine, 1,4-diazabicyclo[2.2.2]octane, and 1,8-diazabicyclo[5.4.0]undec-7-ene, or a combination of any two or more thereof; the catalyst is a palladium catalyst, specifically selected from palladium acetate, tetrakistriphenylphosphine palladium, Pd(dppf)Cl 2 、Pd(PPh 3 ) 2 Cl 2 , Pd 2 (dba) 3 The phosphine ligand is selected from one or more of triphenylphosphine, tributylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, 1,1-bis(diphenylphosphino)ferrocene, tri-tert-butylphosphine tetrafluoroborate, Xantphos, Segphos, and BINAP.

[0034] Furthermore, in step (6-A), the molar ratio of compound VIII, catalyst and ligand is 1:0.01-0.1:0.1-0.5, preferably 1:0.02-0.05:0.15-0.25; the reaction temperature is 80-120°C, preferably 100-110°C; and the reaction time is 10-30h.

[0035] Further, in step (6-B), the cuprous halide is selected from at least one of cuprous bromide and cuprous iodide, and the ligand is selected from at least one of 1,10-phenanthroline, 2,2',6',2"-terpyridine, 5,5'-dimethyl-2,2'-bipyridine, 4,4'-di-tert-butyl-2,2'-bipyridine, and 4,4'-dimethyl-2,2'-bipyridine. Preferably, the ligand is 2,2',6',2"-terpyridine, which can obtain the best yield and purity.

[0036] Furthermore, in step (6-B), the molar ratio of VIII to phenol, NaCN, copper halide, and ligand is 1:1.1-1.2:0.05-0.1:0.1-0.2. The reaction solvent is a non-protonic polar solvent, such as at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and sulfolane; the reaction temperature is 100-120°C, the reaction time is 10-15h, the reaction is quenched after the reaction, and post-treatment is performed to obtain the target product compound II.

[0037] In step (6-B), expensive phosphorus ligands and precious metal palladium catalysts may not be used, but cheap and readily available cuprous halide may be used, and the yield and purity of compound II are higher, which has more industrial advantages.

[0038] The beneficial effects of the present invention are:

[0039] (1) The method of the present invention uses 4-fluoro-3-methylaniline (750 yuan / kg; the starting material 4-fluoro-3-methylphenol used in patent CN202211408228: 2600 yuan / kg; the starting material 5-fluoro-2-methoxybenzoic acid used in patent WO2010126607: 3000 yuan / kg) as the starting material, which is cheap and easy to obtain, has a high reaction conversion rate, and significantly reduces the cost of the current synthesis method;

[0040] (2) In step 2 of the method of the present invention, the intermediate compound IV is stable in nature and is not prone to further reaction either during the reaction process or during post-treatment.

[0041] (3) In step 4 of the method of the present invention, catalytic hydrogenation is used to selectively reduce the nitro group, and no chemical reducing agent is required, which greatly reduces the discharge of three wastes and makes the production process green and environmentally friendly;

[0042] (4) The intermediates obtained during the reaction process of the method of the present invention are easy to separate and purify, the quality is controllable, and the product purity can be greater than 99.0%;

[0043] (5) The preparation method provided by the present invention has short steps, mild reaction conditions, does not require ultra-low temperature or strict anhydrous and oxygen-free conditions, and the production process is easy to control, which has practical prospects for industrial application. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 The compound II prepared in Example 6 1 HNMR spectrum.

[0045] Figure 2 This is the ESI-MS spectrum of compound II prepared in Example 6. DETAILED DESCRIPTION

[0046] The present invention is further described below in conjunction with specific embodiments, but is not limited to the specific embodiments.

[0047] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0048] Example 1: Preparation of Compound IV

[0049]

[0050] Method 1:

[0051] Add 4-fluoro-3-methylaniline (20.0g, 0.16mol) and 200mL of dichloromethane to the reaction bottle. Control the temperature at 20-30℃, and add N-bromosuccinimide (79.7g, 0.45mol) in batches. After addition, control the temperature at 25℃ to react for 8 hours. TLC detection shows that the raw material reacts completely. Add 160mL of 10% sodium thiosulfate aqueous solution to the reaction system and continue stirring for 10 minutes. Let stand for stratification, extract the aqueous phase once with 80mL of dichloromethane, combine the organic phases, wash once with 80mL of 10% sodium thiosulfate aqueous solution and 80mL of saturated brine in turn, dry the organic phase with sodium sulfate and concentrate to obtain 45.0g of crude compound of formula IV, with a yield of 100.0%.

[0052] Method 2:

[0053] Add 500mL of glacial acetic acid and 4-fluoro-3-methylaniline (100.0g, 0.80mol) to the reaction bottle, stir and dissolve. Control the temperature at 20-30°C, slowly drop a solution of bromine (319.0g, 2.00mol) dissolved in 250mL of glacial acetic acid into the reaction system. After the addition, keep the temperature for 3-4 hours. TLC detection shows that the raw material has reacted completely. The reaction solution of the compound of formula IV is directly used for the next step.

[0054] 1 HNMR (600MHz, CDCl 3 )δppm 7.15(d,J=8.5Hz,1H),4.39(br,2H),2.27(d,J=2.5Hz,3H); LC-MS(EI):[M+H] + =283.97.

[0055] Example 2: Preparation of Compound V

[0056]

[0057] Add compound IV (41.0g, 0.14mol) and 410mL of glacial acetic acid to the reaction bottle and cool to 0-5°C. Control the temperature at 0-10°C, and add a solution of sodium nitrite (29.0g, 0.42mol) dissolved in 82mL of water dropwise to the reaction system. After addition, stir at room temperature for 17 hours. After TLC detection, the reaction is complete. The system is cooled to 0-10°C, and an aqueous sodium bisulfite solution is added dropwise. Stir for 1 hour, filter, and collect the filter cake. The filter cake is slurried with a mixed solvent of 132mL of acetonitrile and 410mL of water, stirred at 20-30°C for 2 hours, filtered, and the filter cake is rinsed three times with ice water and dried in a blast oven at 40-45°C to obtain 30.6g of compound V with a purity of 98.7% and a yield of 84.8%. 1HNMR (600MHz, CDCl 3 )δppm 6.61(s,1H),2.13(s,3H); LC-MS(EI):[M+H] + =248.97.

[0058] Example 3: Preparation of Compound VI

[0059] Method 1:

[0060]

[0061] Add 14 mL of water, 17.7 g of phosphoric acid, and then add compound V (5.0 g, 0.02 mol) to the reaction bottle, heat to 85 ° C and stir for 2 hours, then cool to 0-5 ° C. Add an aqueous solution of sodium nitrite (1.5 g, 0.02 mol) dissolved in 5 mL of water to the reaction system at a temperature of 0-5 ° C. After the addition, stir at 0-5 ° C for 0.5 hours, and detect by TLC. The diazotization reaction is complete, and store at 0-5 ° C for later use;

[0062] 25 mL of water and 7.9 g of phosphoric acid were added to the reaction flask and heated to reflux. The above diazo solution was slowly added dropwise to the phosphoric acid solution. After the addition was completed, the reaction was kept warm for 3 hours. TLC detected that the reaction was complete. The temperature was lowered to room temperature, and toluene was used for extraction (25 mL × 3). The toluene phase was concentrated to obtain 3.8 g of compound VI with a purity of 98.1% and a yield of 76.2%.

[0063] Method 2:

[0064] Slowly drop 15.7g of concentrated sulfuric acid into 47mL of water while stirring. Add compound V (10.0g, 0.04mol), raise the temperature to 60℃, and keep stirring for 2 hours. Cool the ice-salt bath to below 0℃, and drop a solution of sodium nitrite (4.1g, 0.06mol) dissolved in 10mL of water into the reaction system, and control the temperature not to exceed 5℃. After the dropwise addition, keep stirring and react for 0.5 hours. According to the TLC control test, the diazotization reaction is complete and stored at 0-5℃ for later use;

[0065] Prepare 100 mL of 5% sulfuric acid solution in another reaction bottle, heat to 100°C, and slowly drop the above diazonium salt solution. Continue stirring and reacting for 1 hour after the addition. Cool to room temperature, extract with toluene (50 mL × 3), and concentrate the toluene phase to obtain 8.1 g of compound VI with a purity of 97.3% and a yield of 80.9%.

[0066] 1 HNMR (600MHz, CDCl 3 )δppm 11.03 (s, 1H), 7.79 (d, J = 8.9 Hz, 1H), 2.43 (d, J = 2.4 Hz, 3H).

[0067] Example 4: Preparation of Compound VII

[0068]

[0069] Method 1:

[0070] Add compound VI (20.0 g, 0.08 mol), isopropyl acetate 200 mL, and Raney nickel 2.0 g to the hydrogenation kettle, and seal the hydrogenation kettle. Replace with nitrogen-vacuum three times, replace with hydrogen-nitrogen three times, maintain the hydrogen pressure at 2.0 MPa, heat to 50 ° C, stir and react for 16 hours, take samples for TLC detection, and the raw materials react completely. Cool the reactor to room temperature, replace with nitrogen three times, filter, and concentrate the filtrate under reduced pressure to obtain 17.4 g of brown solid, with a purity of 97.8% and a yield of 99.1%.

[0071] Method 2:

[0072] Add compound VI (20.0 g, 0.08 mol), 200 mL of tetrahydrofuran, 1.0 g of 5% platinum carbon catalyst to the hydrogenation kettle, and seal the hydrogenation kettle. Replace with nitrogen-vacuum three times, replace with hydrogen-nitrogen three times, maintain the hydrogen pressure at 1.0 MPa, heat to 60°C, stir and react for 20 hours, take samples for TLC detection, and the raw materials react completely. Cool the reactor to room temperature, replace with nitrogen three times, filter, and concentrate the filtrate under reduced pressure to obtain 17.7 g of brown solid with a purity of 97.6% and a yield of 100.0%.

[0073] 1 HNMR (600MHz, CDCl 3 )δppm 6.42(d,J=10.4Hz,1H),5.25(br,1H),3.83(br,2H),2.21(d,J=2.3Hz,3H); MS(ESI):[M+H] + =219.97.

[0074] Example 5: Preparation of Compound VIII

[0075]

[0076] Method 1:

[0077] Add compound VII (17.4 g, 0.08 mol), N-methylpyrrolidone 174 mL, benzyl bromide (68.0 g, 0.40 mol), diisopropylethylamine (85.3 g, 0.66 mol) to a 500 mL reaction bottle, heat to 110 ° C and stir for 20 hours, take a sample for TLC detection, and the raw material reaction is complete. Cool to 70 ° C, add 200 mL of water to precipitate crystals. Cool to 0-5 ° C, continue stirring for 3 hours. Filter, wash the filter cake to obtain a light brown solid crude product. Add the crude product to 40 mL of methanol and slurry at room temperature for 3 hours. Filter, collect the filter cake and dry it in a 50-60 ° C forced air oven to obtain 31.3 g of compound VIII, with a purity of 99.1% and a yield of 80.7%.

[0078] Method 2:

[0079] Add 150mL acetonitrile and compound VII (10.0g, 0.05mol) to a 500mL reaction bottle, stir and dissolve, add potassium carbonate powder (18.8g, 0.14mol), and drop benzyl bromide (27.0g, 0.16mol). Heat to reflux, stir and react for 24 hours, take a sample for TLC detection, and the raw material reaction is complete. Cool to room temperature, filter, and rinse the filter cake with acetonitrile. The filtrate is concentrated under reduced pressure to recover acetonitrile to a paste, and 50mL of water is added to disperse the solid under vigorous stirring. Cool to 0-5℃, continue stirring for 3 hours. Filter, and rinse the filter cake to obtain a light brown solid crude product. Add the crude product to 20mL methanol and slurry at room temperature for 3 hours. Filter, collect the filter cake and dry it in a 50-60℃ forced air oven to obtain 16.4g of compound VIII, with a purity of 98.3% and a yield of 74.2%.

[0080] HNMR (600MHz, CDCl 3 )δppm 7.62~7.61(m,2H),7.45~7.42(m,2H),7.40~7.38(m,1H),7.31~7.25(m,6H),7.20~7.18(m,4H ),6.55(d,J=11.3Hz,,1H),5.14(s,2H),4.30(s,4H),2.32(d,J=2.3Hz,,3H); MS(ESI):[M+H] + =491.12.

[0081] Example 6: Preparation of Compound II

[0082]

[0083] Method 1:

[0084] Add compound VIII (10.0 g, 0.02 mol), 100 mL toluene, phenyl formate (15.0 g, 0.14 mol) to a 500 mL reaction bottle, replace the vacuum-nitrogen atmosphere three times, and then add palladium acetate (0.07 g, 0.46 mmol), tri-tert-butylphosphine tetrafluoroborate (1.24 g, 4.83 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (21.3 g, 0.14 mol) under nitrogen protection. Heat to 105 ° C and reflux for 16 hours. Take a sample for TLC detection. The raw material reacts completely. Cool to 70 ° C, filter the reaction system through diatomaceous earth, wash the filtrate with water (20 mL × 2), and concentrate the toluene phase to obtain a crude brown oil. Add 50 mL of isopropanol, raise the temperature to 60°C and stir for 1 hour, lower the temperature to 0-10°C and stir for 1 hour, filter, and dry the filter cake in a forced air oven at 45°C to obtain 8.5 g of compound II with a purity of 99.5% and a yield of 80.0%.

[0085] Method 2:

[0086] Compound VIII (10.0 g, 0.02 mol), 100 mL of acetonitrile, and phenyl formate (7.3 g, 0.06 mol) were added to a 500 mL reaction bottle. After vacuum-nitrogen replacement three times, Pd(dppf)Cl was added under nitrogen protection. 2 (0.45g, 0.61mmol), Xantphos (2.31g, 4.01mmol) and diisopropylethylamine (18.2g, 0.14mol). Heat to 80℃ and reflux for 24 hours. Take a sample for TLC detection. The raw materials react completely. Cool to 60℃, filter the reaction system through diatomaceous earth, and concentrate the filtrate under reduced pressure to recover the solvent to obtain a crude brown oil. Add 50mL of methanol, heat to 50℃ and stir for 1 hour, cool to 0-10℃ and stir for 1 hour, filter, and dry the filter cake in a blast oven at 45-50℃ to obtain 8.3g of compound II with a purity of 99.5% and a yield of 78.2%.

[0087] Method 3:

[0088] Compound VIII (10.0 g, 0.02 mol), DMF 100 mL, phenol (2.25 g, 0.024 mol) were added to a 500 mL reaction bottle. After vacuum-nitrogen replacement three times, CuI (0.19 g, 1 mmol) and 1,10-phenanthroline (0.36 g, 2 mmol) were added under nitrogen protection. The temperature was raised to 120 ° C for 10 hours, and the sample was taken for TLC detection. The raw material reaction was complete. The temperature was lowered, and the reaction was quenched with a NaCl aqueous solution. The reaction solution was then extracted with ethyl acetate, the organic phase solution was combined and washed with water several times, and the organic phase solution was finally separated. Drying over anhydrous sodium sulfate, filtering, and then distilling under reduced pressure on a rotary evaporator, the resulting liquid was separated by column chromatography (petroleum ether: ethyl acetate volume ratio = 7:3), and 8.9 g of compound II was obtained, with a purity of 99.9% and a yield of 83.8%.

[0089] Method 4:

[0090] Compound VIII (10.0 g, 0.02 mol), DMF 100 mL, phenol (2.25 g, 0.024 mol) were added to a 500 mL reaction bottle. After vacuum-nitrogen replacement three times, CuI (0.19 g, 1 mmol) and 2,2',6',2"-terpyridine (0.87 g, 2 mmol) were added under nitrogen protection. The temperature was raised to 110 ° C for reaction for 10 hours, and a sample was taken for TLC detection. The raw material reaction was complete. The temperature was lowered, and the reaction was quenched with a NaCl aqueous solution. The reaction solution was then extracted with ethyl acetate, the organic phase solution was combined and washed with water several times, and the separated organic phase solution was finally dried over anhydrous sodium sulfate, filtered, and then the liquid obtained after reduced pressure distillation on a rotary evaporator was separated by column chromatography (petroleum ether: ethyl acetate volume ratio = 7:3) to obtain 9.4 g of compound II with a purity of 99.9 and a yield of 88.5%.

[0091] Figure 1 The compound II prepared in Example 6 1 HNMR spectrum. 1 HNMR (600MHz, CDCl 3 )δppm

[0092] 7.49~7.47(m,2H),7.40~7.35(m,5H),7.32~7.24(m,7H),7.21~7.19(m,4H),7.10~7 .04(m,2H),6.62(d,J=11.4Hz,1H),5.32(s,2H),4.34(s,4H),2.31(d,J=1.9Hz,3H);

[0093] MS(ESI):[M+Na] + =554.21.

[0094] Figure 2 This is the ESI-MS spectrum of compound II prepared in Example 6.

[0095] Figure 1 , Figure 2 It can be confirmed that the product obtained by the preparation method of the present invention is the target compound II.

Claims

1. A method for preparing an elacycline hydrochloride intermediate, characterized in that: The synthetic route is as follows:

2. The preparation method according to claim 1, characterized in that: The following steps are involved: (1) 4-fluoro-3-methylaniline (III) is subjected to a bromination reaction with a bromination reagent to obtain a dibromo compound IV; (2) reacting compound IV with a nitrite solution to obtain a nitro-substituted compound V; (3) Compound V undergoes a diazotization reaction with nitrite under acidic conditions to generate a diazonium salt, which is then hydrolyzed to obtain a phenolic compound VI; (4) Compound VI is subjected to catalytic hydrogenation in the presence of a catalyst to reduce the nitro group to obtain an amino compound VII; (5) Compound VII reacts with a benzyl halide under alkaline conditions, and the amino group and the phenolic hydroxyl group are simultaneously protected by benzyl groups to obtain compound VIII; (6-A) Compound VIII, in the presence of a catalyst, a phosphorus ligand and an organic base, undergoes carbonyl insertion reaction with phenyl formate to obtain the target compound II; or (6-B) Compound VIII reacts with phenol, NaCN, copper halide and ligand to obtain target compound II.

3. The preparation method according to claim 2, characterized in that In step (1), the reaction solvent is selected from one or more of dichloromethane, chloroform, dichloroethane, methanol, ethanol, isopropanol, acetonitrile, acetic acid, etc., preferably dichloromethane or acetic acid; the reaction temperature is 10 to 60°C; preferably 20 to 40°C; the bromination reagent is selected from bromine, N-bromosuccinimide, dibromohydantoin, preferably bromine; the molar ratio of the compound III to the bromination reagent is 1:2.0 to 5.0, preferably 1:2.1 to 3.

0.

4. The preparation method according to claim 2, characterized in that In step (2), the reaction solvent is selected from one or more of methanol, ethanol, isopropanol, acetic acid, dioxane, and water, preferably acetic acid or water; the nitrite is at least one of sodium nitrite or potassium nitrite; the molar ratio of compound IV to nitrite is 1:2.0-5.0, preferably 1:2.5-3.5; the reaction temperature is 0-10°C, and the reaction time is 12-24h.

5. The preparation method according to claim 2, characterized in that In step (3), the acid is selected from an inorganic acid or an organic acid, such as any one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, and acetic acid; the molar ratio of compound V to sodium nitrite is 1:1-2; the reaction temperature is 0-10°C, and the reaction time is 0.5-1h; after the reaction, the reaction solution is slowly added to the same acid solution heated to reflux state, and after the addition is completed, the reaction is continued for 1-3h, the temperature is lowered, extraction is carried out, and concentration is performed to obtain compound VI.

6. The preparation method according to claim 2, characterized in that In step (4), the reaction solvent is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran, methyltetrahydrofuran, dioxane, ethyl acetate, and isopropyl acetate, preferably tetrahydrofuran or isopropyl acetate; the catalyst is selected from at least one of palladium carbon, platinum carbon, ruthenium carbon, rhodium carbon, and Raney nickel; the hydrogen pressure of the reaction is 0.1 to 5.0 MPa, preferably 1 to 2.5 MPa; the reaction temperature is 25 to 100° C., preferably 50 to 70° C.; the mass ratio of the compound VI to the catalyst is 1:0.01 to 0.5, preferably 1:0.05 to 0.

2.

7. The preparation method according to claim 2, characterized in that In step (5), the alkaline condition is carried out in the presence of an inorganic base or an organic base; the inorganic base is selected from alkali metal or alkaline earth metal hydroxide, carbonate, bicarbonate, phosphate, hydride or any combination thereof, such as at least one of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride and potassium hydride; the organic base is selected from alkoxide, organic amine or any combination thereof, such as at least one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, 4-dimethylaminopyridine and tetramethylethylenediamine.

8. The preparation method according to claim 2, characterized in that In step (5), the reaction solvent is a non-protonic polar solvent, such as one or more of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and cyclopentane, preferably one or more of acetonitrile and N-methylpyrrolidone; the reaction temperature is 80-120° C.; the benzyl halide is one or more of benzyl chloride, benzyl bromide, benzyl iodide, benzyl methanesulfonate, benzyl p-toluenesulfonate, and benzyl trifluoromethanesulfonate, preferably benzyl chloride or benzyl bromide; the molar ratio of the compound VII, the base, and the benzyl halide is 1:3.0-15.0:3.0-10.0, preferably 1:6.0-10.0:3.5-5.

5.

9. The preparation method according to claim 2, characterized in that In step (6-A), the reaction solvent is selected from tetrahydrofuran, methyltetrahydrofuran, dioxane, acetonitrile, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, preferably acetonitrile or toluene; the organic base is selected from triethylamine, N,N-diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, 4-dimethylaminopyridine, tetramethylethylenediamine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4 .0] at least one of undec-7-ene; the catalyst is a palladium catalyst, specifically selected from one or more of palladium acetate, tetrakistriphenylphosphine palladium, Pd(dppf)Cl2, Pd(PPh3)2Cl2, Pd2(dba)3; the phosphine ligand is selected from one or more of triphenylphosphine, tributylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, 1,1-bis(diphenylphosphino)ferrocene, tri-tert-butylphosphine tetrafluoroborate, Xantphos, Segphos, and BINAP; Furthermore, in step (6-A), the molar ratio of compound VIII, catalyst and ligand is 1:0.01-0.1:0.1-0.5, preferably 1:0.02-0.05:0.15-0.25; the reaction temperature is 80-120°C, preferably 100-110°C; and the reaction time is 10-30h.

10. The preparation method according to claim 2, characterized in that In step (6-B), the cuprous halide is selected from at least one of cuprous bromide and cuprous iodide, and the ligand is selected from at least one of 1,10-phenanthroline, 2,2',6',2"-terpyridine, 5,5'-dimethyl-2,2'-bipyridine, 4,4'-di-tert-butyl-2,2'-bipyridine, and 4,4'-dimethyl-2,2'-bipyridine; Furthermore, in step (6-B), the molar ratio of VIII to phenol, NaCN, copper halide, and ligand is 1:1.1-1.2:0.05-0.1:0.1-0.2; the reaction solvent is a non-protonic polar solvent, such as at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and cyclopentane sulfone; the reaction temperature is 100-120°C, the reaction time is 10-15h, the reaction is quenched after the reaction, and post-treatment is performed to obtain the target product compound II.

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