A method for preparing amino-protected benzocyclone compounds

Abstract

The present invention discloses a method for preparing an amino-protected benzocyclone compound, comprising acetylation of a compound of formula I to prepare a compound of formula II; oxidation of the compound of formula II to prepare a compound of formula III; bromination and nitration of compound III to prepare a compound of formula IV; hydrogenation and reduction of compound IV to produce compound V; and diazotization and fluorination of compound V to produce compound VI. The preparation process of the amino-protected benzocyclone compound is simple, short, efficient, and improves yield, making it suitable for industrial preparation.

Description

Technical Field

[0001] The present invention relates to the technical field of benzocyclone compounds, in particular to a method for preparing an amino-protected benzocyclone compound. Background Art

[0002] The compound represented by Formula VI is Exatecan (DX-8951, an antitumor agent, see Japanese Patent Application Publication No. 87746 / 1994), a synthetic analog of the topoisomerase I inhibitor camptothecin. Compared to existing camptothecin compounds, this drug has increased water solubility and antitumor activity while reducing toxicity. It is clinically used to treat advanced soft tissue sarcomas, pancreatic cancer, esophageal cancer, gastric cancer, liver cancer, etc. The compound of Formula VII is an important intermediate in the total synthesis of Exatecan.

[0003]

[0004] Patent US005658920A discloses a nine-step process for obtaining compound VII using 2-fluorotoluene as a starting material, including Friedel-Crafts acylation, carbonyl reduction, nitration, cyclization, nitro reductive protection, carbonyl reduction, oxidation, amination, and deprotection. This route has numerous drawbacks, including significant process safety risks (requiring low-temperature borane reduction and high-temperature polyphosphoric acid reaction), low yield (the yield of the polyphosphoric acid cyclization step is only 25%), and difficulty in separation (isomer byproducts are produced in the nitration step).

[0005]

[0006] WO96 / 26181 discloses a novel synthetic route for synthesizing Compound VII using 2-fluoro-toluene as a starting material over 13 steps. This route is a leading method for preparing Compound VII due to its simple reaction types, convenient post-processing, and low raw material costs. However, the synthetic route is long, and the overall yield is only 17%. The method for producing the intermediate 2-acetamido-4-fluoro-5-methyl-phenylbutyric acid has several drawbacks: first, the reaction steps are long and the yield is low; second, multiple Friedel-Crafts acylation reactions occur during the reaction; and finally, the reduction of the carbonyl group requires multiple steps, including alcohol formation, dehydration, and double bond reduction. Therefore, the development of an industrially superior preparation method is needed.

[0007]

[0008] Recently, WO2019 / 044946 disclosed a new synthetic route developed by Daiichi Sankyo Co., Ltd. of Japan. This route uses 2-fluoro-4-nitro-toluene as the raw material and obtains compound VII through 8 steps of halogenation, reduction, amino protection, Heck coupling, reduction, cyclization, amination, and deprotection. This route introduces the side chain by Heck coupling reaction. The yield of this route is low when the benzene ring is halogenated in one step.

[0009] Summary of the Invention

[0010] The object of the present invention is to provide a method for preparing an amino-protected benzocyclone compound to solve the problem of cumbersome and complex preparation of the existing benzocyclone compound and low yield mentioned in the above background art.

[0011] To achieve the above object, the present invention provides the following technical solution: a method for preparing an amino-protected benzocyclone compound, comprising the following steps:

[0012] Step 1: subjecting the compound of formula I to acetylation reaction to prepare the compound of formula II;

[0013] Step 2: preparing the compound of formula III from the compound of formula II by oxidation reaction;

[0014] Step 3: Compound III undergoes bromination and nitration to prepare compound IV;

[0015] Step 4: Compound IV is reduced by hydrogenation to generate compound V;

[0016] Step 5: Compound V is reduced by diazotization and fluorination to generate compound VI.

[0017] As a preferred technical solution of the present invention, in step 1, compound I is reacted with acetyl chloride or acetic anhydride in a suitable solvent at -10 to 0°C to obtain compound II after 3 to 6 hours, and the molar ratio of compound I to the acylating agent is 1:1 to 1.1.

[0018] As a preferred technical solution of the present invention, in step 2, compound II is reacted with potassium permanganate or other oxidizing reagents, and the solvent used is a suitable solvent such as acetone and water. The molar ratio of compound II to the oxidizing reagent is 1:1.5 to 2.5.

[0019] As a preferred technical solution of the present invention, in the step 3, compound III is dissolved in a sulfuric acid solution with a mass fraction of 70 to 98%, and a bromination reagent such as NBS or dibromohydantoin is added in batches at -10 to 0°C. After the raw material disappears, 65% concentrated nitric acid or nitrate is added dropwise, and an ester hydrolysis reaction occurs at 20 to 30°C. After 5 to 8 hours, the reaction is quenched with an ice-water mixture to obtain compound IV. The molar ratio of compound III to the bromination reagent is 1:1.1 to 1.3; the molar ratio of compound III to the nitration reagent is 1:1.2 to 1.5.

[0020] As a preferred technical solution of the present invention, in step 4, compound IV is hydrogenated and reduced, the solvent used is methanol or glacial acetic acid, the catalyst is Raney nickel, palladium carbon or platinum carbon, and the reaction is carried out at room temperature for 8 to 10 hours; the amount of the metal catalyst used is 1 / 1000 to 5% equivalent.

[0021] As a preferred technical solution of the present invention, in step 5, compound V is dissolved in pyridine hydrofluoric acid, cooled to -5 to 10°C, sodium nitrite is added for diazotization, and the diazo liquid is heated to 30 to 40°C for thermal decomposition to obtain the target product.

[0022] Compared with the prior art, the present invention has the advantages that the preparation process of the amino-protected benzocyclone compound is simple, short, efficient, and has improved yield, and is suitable for industrial preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 It is a schematic diagram of the process of the present invention. DETAILED DESCRIPTION

[0024] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0025] See also Figure 1 The technical solution of the present invention is: a method for preparing an amino-protected benzocyclone compound, comprising the following steps:

[0026] Step 1, synthesis of compound II: 32.2g of compound I (0.2mol) was added to a round-bottom flask with a volume of 1L, dissolved in 400ml of dichloromethane, 32g (0.42mol) of pyridine was added, and after mixing and stirring at -5°C for 10min, 18.8g of acetyl chloride was added dropwise. After the addition, the temperature was slowly raised to room temperature for 4h. TLC monitored the complete reaction of the substrate. The reaction system solution was dissolved in 500mL of water and stirred for 30min. The layers were separated and the aqueous layer was extracted with dichloromethane (200mL x 3). The organic phases were combined and washed sequentially with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, and saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 39.8g of compound II with a yield of 98%. HPLC analysis showed a purity of 98%, and the mixture was directly used in the next reaction without further separation and purification.

[0027] Step 2, Synthesis of Compound III: Compound II (34 g, 1.0 eq) and acetone (800 L) were added to a 2L three-necked reaction flask. The raw materials were completely dissolved, sodium bicarbonate (16 g, 1.2 eq) was added at room temperature, and potassium permanganate solid (50 g, 4.0 eq) was added in batches over 4 hours. The addition was completed and the reaction was continued at room temperature for 2 hours. The reaction was completed by TLC detection, and 20 mL of 5% sodium bicarbonate solution was added to quench the mixture. The filter cake was washed with 200 mL of dichloromethane and concentrated under reduced pressure to remove acetone and dichloromethane. 1 L of dichloromethane was added, and the organic phase was washed with sodium bisulfate solution, sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was slurried with isopropanol and methyl tert-butyl ether to obtain 29 g of a light yellow solid with a yield of 79%;

[0028] Step 3, Synthesis of Compound VI: Concentrated sulfuric acid (200 ml) was added to a 500 ml three-necked flask, and compound III (20.0 g, 1.00 eq) was added in batches in an ice-water bath at 5 ° C. After complete dissolution, NBS (23 g, 1.15 eq) was added in batches at 5 ° C. The temperature was maintained at about 20-25 ° C. After the addition was complete, the temperature was raised to room temperature and the reaction was reacted for 2 hours. TLC detection showed that the reaction was complete, and the temperature was lowered to -15 ° C. 12 g of concentrated nitric acid (1.15 eq) was added dropwise, and the temperature was maintained at about -10 ° C. After the addition was complete, the temperature was maintained for the reaction. After TLC detection showed that the reaction of the raw materials was complete, the reaction solution was slowly added to 600 mL of ice-water mixture to precipitate a solid, filter, alkalize the solid (sodium bicarbonate solution) to neutrality, and dry to obtain the target product as a bright yellow solid 17.6 g, with a yield of 56%;

[0029] Step 4. Synthesis of Compound V: 16.4 g of compound IV (0.03 mol) was added to a 250 mL round-bottom flask and completely dissolved in a mixed solution of DCM:THF = 1:1 (1.5 L). Triethylamine (63.60 mL, 3.00 eq) and palladium carbon (1.6 g, 10 wt%) were added and reacted under a hydrogen atmosphere at room temperature. After TLC detection of the complete reaction of the raw material, the reaction solution was filtered (diatomaceous earth plus silica gel), concentrated under reduced pressure, dried by a vacuum pump, and directly used in the next reaction;

[0030] Step 5, Synthesis of Compound VI: Compound V4.6g (0.02mol) was added to 50ml of pyridine hydrofluoric acid solution, sodium nitrite was added, and the reaction was carried out at 0°C for 2 hours. The system was connected to a tail gas recovery device, and the system was heated to 40°C for reaction. When no gas was released from the system, the reaction was completed. 100mL of water was added to the reaction solution, and the aqueous phase was separated after separation. The organic phase was washed with water, saturated sodium carbonate solution, and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4.4g of a crude product, which was then slurried with ethanol to obtain 4.1g of white compound VI with a yield of 89%;

[0031] 1H NMR (400MHz, CDCl3) δ12.31(s,1H),8.40(d,J=12.9Hz,1H),2.88(t,J=6.1Hz,2H ),2.66(t,J=6.4Hz,2H),2.22(s,3H),2.14(d,J=1.4Hz,3H),2.12–2.05(m,2H).

[0032] The contents not described in detail in this specification belong to the prior art known to those skilled in the art.

[0033] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing an amino-protected benzocyclone compound, characterized in that: The following steps are involved: Step 1: subjecting the compound of formula I to acetylation reaction to prepare the compound of formula II; Step 2: preparing the compound of formula III from the compound of formula II by oxidation reaction; Step 3: Compound III undergoes bromination and nitration to prepare compound IV; Step 4: Compound IV is reduced by hydrogenation to generate compound V; Step 5: Compound V is reduced by diazotization and fluorination to generate compound VI; The compound I is 4-methyl-5,6,7,8-tetrahydronaphthalene-1-amine; The compound II is N-(4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide; The compound III is N-(4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide; The compound IV is N-(2-bromo-4-methyl-3-nitro-8-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide; The compound V is N-(3-amino-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide; The compound VI is N-(3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide.

2. The method for preparing an amino-protected benzocyclone compound according to claim 1, wherein In the step 1, compound I is reacted with acetyl chloride or acetic anhydride in a suitable solvent at -10 to 0° C. to obtain compound II after 3 to 6 hours. The molar ratio of compound I to the acylating agent is 1:1 to 1.

1.

3. The method for preparing an amino-protected benzocyclone compound according to claim 1, wherein In the step 2, compound II is reacted with potassium permanganate or other oxidizing agents, the solvent used is acetone or water, and the molar ratio of compound II to the oxidizing agent is 1:1.5-2.

5.

4. The method for preparing an amino-protected benzocyclone compound according to claim 1, wherein In the step 3, compound III is dissolved in a sulfuric acid solution having a mass fraction of 70 to 98%, and NBS or dibromohydantoin bromination reagent is added in batches at -10 to 0°C. After the raw material disappears, 65% concentrated nitric acid or nitrate is added dropwise, and an ester hydrolysis reaction occurs at 20 to 30°C. After 5 to 8 hours, the reaction is quenched with an ice-water mixture to obtain compound IV. The molar ratio of compound III to the bromination reagent is 1:1.1 to 1.3; and the molar ratio of compound III to the nitration reagent is 1:1.2 to 1.

5.

5. The method for preparing an amino-protected benzocyclone compound according to claim 1, wherein In step 4, compound IV is hydrogenated and reduced, the solvent used is methanol or glacial acetic acid, the catalyst is Raney nickel, palladium carbon or platinum carbon, and the reaction is carried out at room temperature for 8 to 10 hours; the amount of the metal catalyst used is 1 / 1000 to 5% equivalent.

6. The method for preparing an amino-protected benzocyclone compound according to claim 1, wherein In the step 5, compound V is dissolved in pyridine hydrofluoric acid, cooled to -5 to 10°C, and sodium nitrite is added for diazotization. The diazotization solution is heated to 30 to 40°C to undergo thermal decomposition to obtain the target product.

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