A continuous flow synthesis method for 4-fluoro-2-methoxy-5-nitrophenol

Abstract

The invention discloses a continuous flow synthesis method of 4-fluoro-2-methoxy-5-nitrophenol. The method of the invention includes esterification, nitration, and hydrolysis 3-step reactions, wherein 4-fluoro-2-methoxyphenol (2) and a solution of an alkali and a solution of propyl chloroformate are synchronously mixed through a metering pump through a first continuous flow coil reactor, and an intermediate 3 is obtained by reaction at room temperature; a solution of 3 and a nitrating agent are synchronously mixed through a metering pump through a second continuous flow coil reactor, and an intermediate 4 is obtained by reaction at room temperature; a solution of 4 and an alkaline solution are synchronously mixed through a metering pump through a third continuous flow coil reactor, and a target product 4-fluoro-2-methoxy-5-nitrophenol (1) is obtained by reaction at room temperature, and the purity is 96.8%. The total residence time of the synthesis method of the invention is 234 seconds, the reaction conditions are mild, the process is continuous, safe and controllable, the production efficiency is improved, and it is easy to realize amplified production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and specifically relates to a continuous flow synthesis method of 4-fluoro-2-methoxy-5-nitrophenol. Background Art

[0002] 4-Fluoro-2-methoxy-5-nitrophenol (1) is a key intermediate for the synthesis of the GnRH receptor antagonist Linzagolix (5). Linzagolix is ​​a new oral GnRH receptor antagonist developed by Japan's Kissei and ObsEve. It was approved for marketing by the European Union in June 2022 for the treatment of leiomyoma. Currently, a Phase III clinical trial (CTR20230985) for the treatment of endometriosis, uterine fibroids and pain is being conducted in China. Compared with previous GnRH receptor antagonists, Linzagolix is ​​not easily cleaved by enzymes in the body, has strong stability, a long half-life, and has best-in-class characteristics.

[0003]

[0004] 4-Fluoro-2-methoxy-5-nitrophenol (1) is an important intermediate, and its existing synthesis is completed in a batch reactor. CN116496180 A and CN116425642 A use 4-fluoro-2-methoxyphenol (2) as the starting material, and undergo hydroxyl protection, nitration reaction, and deprotection to obtain compound 1. The batch reaction synthesis route is as follows:

[0005]

[0006] However, the above-mentioned route has disadvantages such as long reaction time and high reaction temperature. In particular, the batch intermittent nitration reaction has the disadvantages of large amount of mixed acid, intense heat release, high energy consumption due to low reaction temperature, and slow heat dissipation due to the viscosity of the system and difficulty in stirring, which brings great safety hazards to actual production.

[0007] Therefore, it is very necessary to develop a new synthesis process of 4-fluoro-2-methoxy-5-nitrophenol to improve production efficiency and reaction safety by improving process performance. Summary of the invention

[0008] Purpose of the invention: The purpose of the present invention is to provide a continuous flow synthesis method for 4-fluoro-2-methoxy-5-nitrophenol in view of the deficiencies of the prior art. The method of the present invention has mild conditions, high yield, high product quality, and achieves the technical effect of continuous, safe and controllable process, improving production efficiency, and facilitating the realization of scaled-up production.

[0009] Technical solution: The purpose of the present invention is achieved through the following technical solution:

[0010] The present invention provides a continuous flow synthesis method of 4-fluoro-2-methoxy-5-nitrophenol, comprising the following steps:

[0011] (1) dissolving 4-fluoro-2-methoxyphenol 2 in an organic solvent A under alkaline conditions to prepare component A; dissolving propyl chloroformate in an organic solvent A to prepare component B;

[0012] (2) Component A and component B are mixed at the same flow rate and then enter into a first continuous flow reactor, the temperature of which is controlled at 20 to 30° C. After staying for 0.5 to 5 min, the reaction mixture flows out of the first continuous flow reactor and is post-treated to obtain an intermediate 3;

[0013] (3) dissolving the intermediate 3 in an organic solvent A to prepare component C; and using a nitrating agent as component D;

[0014] (4) Component C and component D enter the precooling module for precooling, are mixed, and enter the second continuous flow reactor, where the temperature is controlled at 0 to 40° C. After staying for 12 to 144 seconds, the reaction mixture flows out of the second continuous flow reactor and is post-treated to obtain intermediate 4;

[0015] (5) dissolving the intermediate 4 in the organic solvent B to prepare component E; dissolving the base in the organic solvent B to prepare component F;

[0016] (6) Component E and component F are mixed at the same flow rate and then enter a third continuous flow reactor, where the temperature is controlled at 0 to 40° C. After staying for 43 seconds to 2.5 minutes, the reaction mixture flows out of the third continuous flow reactor and is post-treated to obtain the product 4-fluoro-2-methoxy-5-nitrophenol (Compound 1);

[0017] The synthetic route is as follows:

[0018]

[0019] The continuous flow synthesis method of the present invention comprises three steps of esterification, nitration and hydrolysis. In the first step of esterification, 4-fluoro-2-methoxyphenol (2) and a solution of an alkali and a solution of propyl chloroformate are synchronously mixed by metering pumps and passed through a first continuous flow reactor, and reacted at room temperature to obtain an intermediate 3; in the second step of nitration, a solution of 3 and a nitrating agent are synchronously mixed by metering pumps and passed through a second continuous flow reactor, and reacted at room temperature to obtain an intermediate 4; in the third step of hydrolysis, a solution of 4 and an alkali solution are synchronously mixed by metering pumps and passed through a third continuous flow coil reactor, and reacted at room temperature to obtain a target product 4-fluoro-2-methoxy-5-nitrophenol (1).

[0020] Preferably, the organic solvent A is selected from dichloromethane or 1,2-dichloroethane; and the organic solvent B is selected from methanol or ethanol.

[0021] Preferably, in step (1), the molar ratio of 4-fluoro-2-methoxyphenol to propyl chloroformate is 1:1.5 to 1:2.

[0022] Preferably, the base is selected from triethylamine, N,N-diisopropylethylamine or pyridine.

[0023] Further preferably, the base is selected from triethylamine.

[0024] Preferably, in step (1), the concentration of component A is 0.1 M; the concentration of component B is 0.15-0.2 M; and the flow rate of component A and component B is 0.1-1.0 mL / min.

[0025] Preferably, in step (3), the concentration of component C is 0.2-1.0 M; the nitrating agent is concentrated sulfuric acid and concentrated nitric acid; and the molar ratio of the concentrated sulfuric acid to the concentrated nitric acid is 1.5-4.2.

[0026] Preferably, in step (4), the flow rate of component C is 0.166-2.00 mL / min, and the flow rate of component D is 0.10-1.20 mL / min; the flow rate ratio of component C to component D is 5:3.

[0027] Preferably, in step (5), the concentration of component E is 0.25-1.0 M; the concentration of component F is 0.375-1.5 M; and the base is a methanol solution of sodium hydroxide, an aqueous solution of sodium hydroxide, sodium bicarbonate, triethylamine or triethylenediamine.

[0028] Preferably, in step (6), the flow rate of component E and component F is 0.2-0.7 mL / min.

[0029] Preferably, the continuous flow reactor is a continuous flow coil reactor, and its material is PTFE.

[0030] Beneficial effects:

[0031] (1) The synthesis method of the present invention has mild reaction conditions, short reaction time and high efficiency;

[0032] (2) The synthesis methods of the present invention all use commercial equipment, which is cheap and readily available, and has flexible and efficient construction;

[0033] (3) The present invention uses a continuous flow reactor to replace the traditional dangerous kettle nitration reaction, avoiding the accumulation of heat in the reaction, greatly reducing the probability of danger, and having extremely high safety.

[0034] (4) The product quality obtained by repeated experiments of the present invention is stable and very suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 The present invention is a general flow chart of the synthesis process of 4-fluoro-2-methoxy-5-nitrophenol.

[0036] Figure 2 The synthetic process flow chart of compound 3.

[0037] Figure 3 The synthetic process flow chart of compound 4.

[0038] Figure 4 The synthetic process flow chart of 4-fluoro-2-methoxy-5-nitrophenol (Compound 1) is shown in FIG.

[0039] Figure 5 The H NMR spectrum of intermediate 3.

[0040] Figure 6 The H NMR spectrum of intermediate 4.

[0041] Figure 7 This is the hydrogen nuclear magnetic resonance spectrum of impurity 4-IM-1.

[0042] Figure 8 This is the hydrogen nuclear magnetic resonance spectrum of impurity 4-IM-2.

[0043] Fig. 9 The hydrogen nuclear magnetic resonance spectrum of 4-fluoro-2-methoxy-5-nitrophenol 1 prepared in the present invention is shown in FIG.

[0044] Fig.10 The high performance liquid chromatogram of 4-fluoro-2-methoxy-5-nitrophenol 1 prepared in the present invention. DETAILED DESCRIPTION

[0045] The technical solution of the present invention is described in detail below through specific embodiments, but the protection scope of the present invention is not limited to the embodiments.

[0046] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0047] The continuous flow reactor used in the present invention is a continuous flow coil reactor, which is made of PTFE, 0.8mm ID, the coil volume V of the first and third continuous flow coil reactors is 1mL, and the coil volume V of the second continuous flow coil reactor is 0.65mL.

[0048] The HPLC purity of the compounds in the examples of the present invention was determined by Agilent LC2010 high performance liquid chromatograph.

[0049] Chromatographic column: Agilent Phecda C18 (250×4.6mm,×5μm).

[0050] Mobile phase: A: water; B: methanol; A:B=35:65.

[0051] Flow rate: 0.8mL / min.

[0052] Column temperature: 25℃.

[0053] Detection wavelength: 254nm.

[0054] The synthetic route adopted in the embodiment of the present invention is as follows:

[0055]

[0056] The overall process flow diagram of the synthesis of 4-fluoro-2-methoxy-5-nitrophenol of the present invention is shown in Figure 1 .

[0057] Example 1 Synthesis of 4-fluoro-2-methoxy-5-nitrophenol

[0058] (1) Compound 4-fluoro-2-methoxyphenol (2) (1.0 equiv) and triethylamine (1.2 equiv) were dissolved in 1,2-dichloroethane to prepare component A (0.1 M). Propyl chloroformate (2.0 equiv) was dissolved in 1,2-dichloroethane to prepare component B (0.2 M).

[0059] (2) Component A and component B were mixed in a T-type mixer at the same flow rate of 0.20 mL / min and then entered the first continuous flow coil reactor kept at 25°C. After a residence time of 2.5 min, the reaction mixture was quenched with 0.5 M HCl solution, dried over anhydrous Na2SO4, filtered, and distilled under reduced pressure to obtain intermediate 3. The reaction mixture was collected for 100 min to obtain 448 mg of intermediate 3 with a yield of 98.1%. The synthesis process of compound 3 is shown in Figure 2 .

[0060] Its H NMR spectrum is shown in Figure 5 . 1 H NMR (400MHz, CDCl3) δ (ppm) 7.07 (dd, J = 8.8, 5.7Hz, 1H), 6.70 (dd, J = 10.1, 2.8Hz, 1H), 6.63 (t d,J=8.3,2.8Hz,1H),4.21(t,J=6.7Hz,2H),3.83(s,3H),1.77(m,2H),1.00(t,J=7.4Hz,3H).

[0061] (3) The intermediate 3 was dissolved in 1,2-dichloroethane to prepare component C (0.5 M). The nitrating agent (the molar ratio of concentrated sulfuric acid to concentrated nitric acid was 2.1) was used as component D.

[0062] (4) The flow rate of component C is 1.00 mL / min, and the flow rate of component D is 0.60 mL / min. After entering the precooling coil and being precooled at 20°C, the two are mixed in a Y-type mixer and enter the second continuous flow coil reactor insulated at 20°C. After a residence time of 24 seconds, the reaction mixture is quenched with ice water, and the organic layer is washed with saturated NaHCO3 solution, dried with anhydrous Na2SO4, filtered, and distilled under reduced pressure to obtain intermediate 4. The collection was continued for 40 minutes to obtain 2.63 g of intermediate 4, with a yield of 96.3% and a purity of 91.4%. The synthesis process of compound 4 is shown in Figure 3 .

[0063] Its H NMR spectrum is shown in Figure 6 . 1 H NMR (400MHz, CDCl3) δ (ppm) 7.98 (d, J = 7.5Hz, 1H), 6.83 (d, J = 12.2Hz, 1H), 4.24 (t, J = 6.7Hz, 2H), 3.95 (s, 3H), 1.78 (m, 2H), 1.01 (t, J = 7.4Hz, 3H).

[0064] The H NMR spectrum of impurity 4-IM-1 is shown in Figure 7 . 1 H NMR (400MHz, CDCl3) δ (ppm) 7.31 (dd, J = 9.3, 5.2Hz, 1H), 7.03–6.97 (m, 1H), 4.25 (t, J = 6.7Hz, 2H), 3.99 (s, 3H), 1.78 (m, 2H), 1.01 (t, J = 7.4Hz, 3H).

[0065] The H NMR spectrum of impurity 4-IM-2 is shown in Figure 8 . 1 H NMR (400MHz, CDCl3) δ (ppm) 8.18 (d, J = 7.4Hz, 1H), 4.30 (t, J = 6.7Hz, 2H), 4.13 (s, 3H), 1.81 (m, 2H), 1.03 (t, J = 7.4Hz, 3H).

[0066] (5) Intermediate 4 was dissolved in methanol to prepare component E (0.25 M). NaOH was dissolved in methanol to prepare component F (0.375 M).

[0067] (6) Component E and component F were mixed in a T-type mixer at the same flow rate of 0.50 mL / min and then entered the third continuous flow coil reactor kept at 25°C. After a residence time of 60 s, the reaction mixture was quenched with 0.5 M HCl, and methanol was removed by vacuum distillation. The mixture was then extracted with 1,2-dichloroethane. The organic phase was dried over anhydrous Na2SO4, filtered, and vacuum distilled to obtain product 1. The mixture was collected for 30 min to obtain 480 mg of product 1, with a yield of 93.4% and a purity of 96.8%. The synthesis process of compound 1 is shown in Figure 4 .

[0068] Its H NMR spectrum is shown in Fig. 9 . 1 H NMR (400MHz, CD3OD) δ (ppm) 7.48 (d, J = 7.4Hz, 1H), 6.96 (d, J = 12.8Hz, 1H), 3.95 (s, 3H).

[0069] Its high performance liquid chromatography Fig.10 The purity of 4-fluoro-2-methoxy-5-nitrophenol was measured to be 96.8%.

[0070] Example 2 Optimization of Synthesis Reaction Conditions of 4-Fluoro-2-Methoxyphenylpropyl Carbonate (Intermediate 3)

[0071] According to the synthesis method of intermediate 3 in Example 1, referring to the parameter settings in Table 1 and Table 2, the optimized reaction conditions of intermediate 3 were investigated.

[0072] Table 1 studies the effects of different bases on the esterification reaction.

[0073] The results showed that when the concentration of compound 2, the equivalent of propyl chloroformate, the temperature and the residence time were kept constant, the conversion of the reaction was better when triethylamine was used as the base than when pyridine and DIEA were used.

[0074] Table 1 Screening of alkali

[0075]

[0076] Table 2 studies the effects of propyl chloroformate equivalent and residence time on the reaction.

[0077] The results showed that when the concentration and temperature of compound 2 were kept constant, when the concentration of propyl chloroformate was 1.5 equiv, the residence time was extended from 0.5 min to 5 min, and compound 2 failed to react completely. When the concentration of propyl chloroformate was 2.0 equiv, the residence time was extended from 0.17 min to 2.5 min, and the conversion of compound 2 increased from 88.2% to 100%. Further extension of the retention time had little effect on the yield.

[0078] Table 2 Effect of the equivalent and residence time of propyl chloroformate on the reaction

[0079]

[0080] Example 3 Optimization of Synthesis Reaction Conditions of 4-Fluoro-2-Methoxy-5-Nitrophenyl Propyl Carbonate (Intermediate 4)

[0081] The reaction formula is as follows:

[0082]

[0083] According to the synthesis method of intermediate 4 in Example 1, referring to the parameter settings in Table 3, Table 4 and Table 5, the optimized reaction conditions of intermediate 4 were investigated.

[0084] Table 3 studies the effect of the molar ratio of concentrated sulfuric acid to concentrated nitric acid on the reaction. The flow rate of component A was maintained at 0.500 mL / min, the flow rate of component B was maintained at 0.300 mL / min, the residence time was 48 s, and the reaction temperature was 20 ° C. When the molar ratio increased from 1.5 to 2.1, the conversion and yield reached their maximum values, 100% and 91.3%, respectively, the impurity 4-IM-1 decreased slightly, and the impurity 4-IM-2 was not detected. The molar ratio continued to increase, the conversion rate remained unchanged, but the increase of impurities 4-IM-1 and 4-IM-2 resulted in a decrease in yield, and the increase rate of 4-IM-2 was faster. Therefore, the optimal molar ratio was selected as 2.1.

[0085] Table 3 Effect of the molar ratio of concentrated sulfuric acid to concentrated nitric acid on the reaction

[0086]

[0087] Table 4 studies the effect of temperature on the reaction. Keeping the flow rate and residence time unchanged and changing the reaction temperature, the results show that temperature has little effect on the reaction conversion and yield.

[0088] Table 4 Effect of temperature on reaction

[0089]

[0090] Table 5 studies the effect of residence time on the reaction. Keeping the reaction temperature constant and changing the flow rate, the results show that a residence time of 12s results in incomplete conversion of compound 3. Extending the residence time results in complete conversion of compound 3, but has little effect on the yield.

[0091] Table 5 Effect of residence time on reaction

[0092]

[0093] Example 4 Optimization of Synthesis Reaction Conditions of 4-Fluoro-2-Methoxy-5-Nitrophenol (Compound 1)

[0094] According to the synthesis method of 4-fluoro-2-methoxy-5-nitrophenol (Compound 1) in Example 1, referring to the parameter settings in Tables 6, 7, 8 and 9, the optimized reaction conditions of the target compound 1 were investigated.

[0095] Table 6 studies the effect of different bases on the reaction in batch reaction. The concentration of 4 was kept at 0.5 mol / L, the base was 1.5 equiv, and the type of base was changed. The results showed that 1 M NaOH (in MeOH) was used as the base, and the hydrolysis efficiency was the highest.

[0096] Table 6 Screening of alkali

[0097]

[0098] Table 7 studies the effect of the concentration of intermediate 4 on the reaction. The reaction temperature, flow rate and equivalent of the base are kept constant, and the concentration of intermediate 4 and the concentration of the base are changed. The results show that as the concentration increases, the impurities increase and the purity of product 1 decreases.

[0099] Table 7 Effect of the concentration of 4 on the reaction

[0100]

[0101] Table 8 studies the effect of temperature on the reaction. The concentration, flow rate and residence time are kept constant, and the reaction temperature is changed. The results show that temperature has little effect on the reaction.

[0102] Table 8 Effect of temperature on reaction

[0103]

[0104] Table 9 studies the effect of residence time on the reaction. Keeping the concentration and reaction temperature constant, changing the flow rate, and then changing the residence time. The results show that when the residence time is less than 60s, the reaction conversion is incomplete; further extending the residence time has little effect on the reaction.

[0105] Table 9 Effect of residence time on reaction

[0106]

[0107] As described above, although the present invention has been shown and described with reference to specific preferred embodiments, it should not be construed as limiting the present invention itself. Various changes in form and details may be made without departing from the spirit and scope of the present invention as defined in the appended claims.

Claims

1. A continuous flow synthesis method for 4-fluoro-2-methoxy-5-nitrophenol, characterized in that: The following steps are involved: (1) Dissolve 4-fluoro-2-methoxyphenol 2 in an organic solvent A under alkaline conditions to prepare component A; dissolve propyl chloroformate in an organic solvent A to prepare component B; (2) Component A and component B are mixed at the same flow rate and then enter into a first continuous flow reactor, the temperature of which is controlled at 20-30°C. After staying for 0.5-5 minutes, the reaction mixture flows out of the first continuous flow reactor and is post-treated to obtain intermediate 3; (3) Dissolving the intermediate 3 in an organic solvent A to prepare component C; and using a nitrating agent as component D; (4) Component C and component D enter the precooling module for precooling, are mixed, and enter the second continuous flow reactor. The temperature is controlled at 0-40°C. After staying for 12-144 seconds, the reaction mixture flows out of the second continuous flow reactor and is post-treated to obtain intermediate 4. (5) Dissolving intermediate 4 in organic solvent B to prepare component E; dissolving alkali in organic solvent B to prepare component F; (6) Component E and component F are mixed at the same flow rate and then enter a third continuous flow reactor, where the temperature is controlled at 0-40°C. After staying for 43s-2.5min, the reaction mixture flows out of the third continuous flow reactor and is post-treated to obtain the product 4-fluoro-2-methoxy-5-nitrophenol, i.e., compound 1; In step (2), the flow rate of component A and component B is 0.1-1.0 mL / min; In step (4), the flow rate of component C is 0.166-2.00 mL / min, and the flow rate of component D is 0.10-1.20 mL / min; the flow rate ratio of component C to component D is 5:3; In step (6), the flow rate of component E and component F is 0.2-0.7 mL / min; The synthetic route is as follows: 。 2. The preparation method according to claim 1, characterized in that: The organic solvent A is selected from dichloromethane or 1,2-dichloroethane; the organic solvent B is selected from methanol or ethanol.

3. The preparation method according to claim 1, characterized in that: In step (1), the molar ratio of 4-fluoro-2-methoxyphenol to propyl chloroformate is 1:1.5 to 1:

2.

4. The preparation method according to claim 1, characterized in that: In step (1), the base is selected from triethylamine, N,N-diisopropylethylamine or pyridine.

5. The preparation method according to claim 1, characterized in that: In step (1), the concentration of component A is 0.1 M; the concentration of component B is 0.15-0.2 M.

6. The preparation method according to claim 1, characterized in that: In step (3), the concentration of component C is 0.2-1.0 M; the nitrating agent is concentrated sulfuric acid and concentrated nitric acid; and the molar ratio of the concentrated sulfuric acid to the concentrated nitric acid is 1.5-4.

2.

7. The preparation method according to claim 1, characterized in that: In step (5), the concentration of component E is 0.25-1.0 M; the concentration of component F is 0.375-1.5 M; and the base is a methanol solution of sodium hydroxide, an aqueous solution of sodium hydroxide, sodium bicarbonate, triethylamine or triethylenediamine.

8. The preparation method according to claim 1, characterized in that: The continuous flow reactor is a continuous flow coil reactor, and its material is PTFE.

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