Preparation method of Linzaagolix intermediate

Abstract

The invention discloses a preparation method of a Linzagolix intermediate, which comprises the following steps: under an alkaline condition and the action of an organic phosphorus ligand, 2, 3-difluoro-6-methoxybenzyl alcohol and 2-methoxy-4-fluorophenol are subjected to a Mitsunobu reaction to obtain 1, 2-difluoro-3-(4-fluoro-2-methoxyphenoxy methyl)-4-methoxybenzene, and the 1, 2-difluoro-3-(4-fluoro-2-methoxyphenoxy methyl)-4-methoxybenzene is subjected to the Mitsunobu reaction to obtain 1, 2-difluoro-3-(4-fluoro-2-methoxyphenoxy methyl)-4-methoxybenzene and the 1, 2-difluoro-3-(4-fluoro-2-methoxyphenoxy methyl)-4-methoxybenzene. Wherein the alkali for providing the alkaline condition is selected from one or more of N, N-diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, diethyl azodicarboxylate and diisopropyl azodicarboxylate; the organic phosphine ligand is selected from one or more of triphenylphosphine, tri-tert-butylphosphine and (1, 2-bis (ethoxycarbonyl) hydrazino) triphenylphosphine trifluoromethanesulfonate, and the organic phosphine ligand is selected from one or more of triphenylphosphine, tri-tert-butylphosphine and (1, 2-bis (ethoxycarbonyl) hydrazino) triphenylphosphine trifluoromethanesulfonate. According to the method, the reaction steps are reduced, the production period is shortened, the total production cost is reduced, and the highest product yield can reach 90% or above.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis and relates to a method for preparing a Linzagolix intermediate, specifically a method for preparing the Linzagolix intermediate 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene (compound C). Background Technology

[0002] Linzagolix is ​​the world's first gonadotropin-releasing hormone (GnRH) receptor antagonist with flexible dosing. In June 2022, Linzagolix tablets were approved for marketing in the EU and the UK for the treatment of moderate to severe uterine fibroids in adult women of reproductive age. On December 16, 2022, the first subject was enrolled in the Phase III clinical trial of Linzagolix in China.

[0003] The original patent WO2014042176 A1 discloses a method for synthesizing Linzagolix intermediates, and the synthetic route is shown below:

[0004]

[0005] 2,3-Difluoro-6-methoxybenzyl alcohol reacts with hydrochloric acid via chlorination to yield an intermediate, which is then subjected to nucleophilic substitution under a phase transfer catalyst to give 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene (compound C). This method has a long reaction time, and the inventors have repeatedly attempted this synthetic route with yields less than 50%. Furthermore, the hydrochloric acid solution used in the first step is highly acidic and easily corrodes the production equipment, causing significant environmental damage.

[0006] WO2022179469 A1 discloses the method of obtaining 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene from 2,3-difluoro-6-methoxybenzyl alcohol via chlorination and nucleophilic substitution reactions.

[0007]

[0008] The inventors repeated the synthesis method with a yield of approximately 52.7%. Furthermore, thionyl chloride was used as the chlorination reagent. Thionyl chloride has dangerous properties such as being flammable, explosive, and easily decomposed when exposed to water and moisture, posing numerous safety hazards in the pharmaceutical production process.

[0009] Therefore, in response to the shortcomings of existing technologies, the inventors have developed a method for preparing Linzagolix intermediates that is simple to operate, safe in process, and has a high yield, in order to meet the needs of scale-up production and quality control. Summary of the Invention

[0010] To overcome the shortcomings of existing technologies, this invention provides a novel synthetic process that uses 2,3-difluoro-6-methoxybenzyl alcohol as a starting material to prepare the target compound 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene via the Mitsunobu reaction. This synthetic route avoids the chlorination process of thionyl chloride, shortens the reaction route, improves reaction efficiency and process safety, and is more suitable for industrial production.

[0011] The objective of this invention is achieved through the following technical solution:

[0012] A method for preparing a Linzagolix intermediate, the synthetic route is as follows:

[0013]

[0014] This includes the following: Under alkaline conditions and with the action of organophosphorus ligands, 2,3-difluoro-6-methoxybenzyl alcohol (compound A) and 2-methoxy-4-fluorophenol (compound B) undergo the Mitsunobu reaction (photo-extending reaction) to give 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene (compound C).

[0015] The molar ratio of 2,3-difluoro-6-methoxybenzyl alcohol to 2-methoxy-4-fluorophenol is 1:1 to 1:2, preferably 1:1 to 1:1.5, more preferably 1:1 to 1:1.2, and most preferably 1:1.05 to 1:1.15.

[0016] The base providing alkaline conditions is selected from one or more of N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), 4-dimethylaminopyridine (DMAP), diethyl azodicarboxylate (DEAD), and diisopropyl azodicarboxylate (DIAD), preferably N,N-diisopropylethylamine or diisopropyl azodicarboxylate.

[0017] The molar ratio of 2,3-difluoro-6-methoxybenzyl alcohol to the base is 1:1 to 1:3, preferably 1:1 to 1:2, and more preferably 1:1 to 1:1.5.

[0018] The organophosphine ligand is selected from one or more of triphenylphosphine (PPh3), tri-tert-butylphosphine (P(n-Bu)3), and (1,2-bis(ethoxycarbonyl)hydrazyl)triphenylphosphine trifluoromethanesulfonate (BEHT triflate), preferably triphenylphosphine.

[0019] The molar ratio of 2,3-difluoro-6-methoxybenzyl alcohol to organophosphorus ligand is 1:1 to 1:3, preferably 1:1 to 1:2, and more preferably 1:1 to 1:1.5.

[0020] The temperature of the Mitsunobu reaction is 20–60°C, preferably 25–40°C; the reaction time is 2–18 hours.

[0021] Specifically, when the organophosphorus ligand is selected from one or more of triphenylphosphine (PPh3) and tri-tert-butylphosphine (P(n-Bu)3), the Mitsunobu reaction time is 2 to 3 hours; when the organophosphorus ligand is selected from (1,2-bis(ethoxycarbonyl)hydrazino)triphenylphosphine trifluoromethanesulfonate, the Mitsunobu reaction time is 10 to 15 hours.

[0022] The reaction solvent is selected from one or more solvents such as tetrahydrofuran, diethyl ether, ethyl acetate, chloroform, dichloromethane, and 1,2-dichloroethane, preferably tetrahydrofuran, dichloromethane, or 1,2-dichloroethane.

[0023] Specifically, a method for preparing a Linzagolix intermediate includes: dissolving 2,3-difluoro-6-methoxybenzyl alcohol and 2-methoxy-4-fluorophenol in a reaction solvent; and under alkaline conditions and the action of an organophosphorus ligand, reacting 2,3-difluoro-6-methoxybenzyl alcohol (compound A) with 2-methoxy-4-fluorophenol (compound B) via a Mitsunobu reaction to obtain 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene.

[0024] A further preferred embodiment of the method for preparing the Linzagolix intermediate includes: after the reaction is complete, adding calcium bromide to the reaction solution, stirring the reaction at room temperature, filtering, obtaining a filtrate, diluting the filtrate with water, extracting with ethyl acetate, combining the organic phases, washing the organic phases with saturated brine, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain pure 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene; or after the reaction is complete, adding saturated sodium bicarbonate aqueous solution, extracting with dichloromethane, combining the organic phases, drying the organic phases with anhydrous sodium sulfate, evaporating to dryness, and performing normal-phase silica gel column chromatography to purify and obtain pure 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene.

[0025] The molar ratio of calcium bromide to 2,3-difluoro-6-methoxybenzyl alcohol is 1:1 to 10:1, preferably 2:1 to 6:1. The phosphine oxy byproduct generated during the reaction is removed with calcium bromide to avoid column chromatography.

[0026] The eluent for the normal-phase silica gel column chromatography is petroleum ether: ethyl acetate = 5:1 V / V.

[0027] The advantages of this invention compared to existing technologies are as follows:

[0028] The Mitsunobu reaction of this invention avoids cumbersome operations such as halogenation reactions, reduces reaction steps, shortens the production cycle, lowers the total production cost, and the product yield can reach more than 90%.

[0029] This invention avoids the use of halogenated reagents that are highly harmful to the environment. The reagents used are inexpensive and readily available, and the process is safe and meets the requirements of green production.

[0030] This invention produces relatively few byproducts, is easy to purify, optimizes the production process, and greatly improves reaction efficiency. Attached Figure Description

[0031] Figure 1 Compound C prepared in Example 1 1 H NMR spectrum.

[0032] Figure 2 The image shows the MS spectrum of compound C prepared in Example 1. Detailed Implementation

[0033] The specific embodiments of the present invention are described in detail below. It should be noted that the embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0034] Example 1

[0035]

[0036] Compound A (10 g, 57.4 mmol) and compound B (8.56 g, 60.26 mmol) were dissolved in tetrahydrofuran, and triphenylphosphine (22.6 g, 86.3 mmol) and DIAD (11.36 mL, 86.8 mmol) were added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, calcium bromide (20 g, 115.5 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for another 6 hours. The mixture was filtered to obtain a filtrate, which was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a pale yellow oil. The oil was cooled at -20 °C for 1 hour to obtain compound C (solid, yield 93.2%).

[0037] 1 H NMR (400MHz, Chloroform-d) δ7.14 (q, J=9.6Hz, 1H), 6.96 (dd, J=8.8, 4.8Hz, 1H), 6.85-6.56 (m, 3H), 5.16 (d, J=2.0Hz, 2H), 3.86 (s, 6H); MS m / z(ESI):321.0[M+Na] + .

[0038] Example 2

[0039] Compared with Example 1, this example only replaces DIAD with an equal amount of DEAD, and all other aspects are the same as in Example 1. The yield of compound C is 91.8%.

[0040] Example 3

[0041] Compared with Example 1, this example replaces DIAD with an equal amount of DEAD and adjusts the amount of compound B so that the molar ratio of compound A to compound B is 1:1.5. All other aspects are the same as in Example 1. The yield of compound C is 83.6%.

[0042] Example 4

[0043] Compared with Example 1, this example replaces DIAD with an equal amount of DEAD and adjusts the amount of compound B so that the molar ratio of compound A to compound B is 1:1.2. All other aspects are the same as in Example 1. The yield of compound C is 87.8%.

[0044] Example 5

[0045] Compared with Example 1, this example uses an equal amount of tri-tert-butylphosphine to replace triphenylphosphine, and all other aspects are the same as in Example 1. The yield of compound C is 79.4%.

[0046] Example 6

[0047] 2,3-Difluoro-6-methoxybenzyl alcohol (compound A, 5 g, 28.7 mmol, 1.0 eq) and 2-methoxy-4-fluorophenol (compound B, 4.08 g, 28.7 mmol, 1.0 eq) were dissolved in 1,2-dichloroethane, and (1,2-bis(ethoxycarbonyl)hydrazyl)triphenylphosphine trifluoromethanesulfonate (BEHT) was added. Triflate (20.2 g, 34.45 mmol, 1.2 eq) and N,N-diisopropylethylamine (DIPEA, 4.95 mL, 28.7 mmol, 1.0 eq) were reacted at room temperature for 15 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and subjected to normal-phase silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 V / V). The purified product was an oily substance, cooled, and compound C (solid, yield 64.2%) was obtained.

[0048] Example 7

[0049] Compared with Example 6, the amount of DIPEA was adjusted in this example, while the rest were the same as in Example 6, and the yield of compound C was 71.4%.

[0050] Table 1. Effect of reaction process on the yield of compound C

[0051]

Claims

1. A method for preparing a Linzagolix intermediate, characterized in that: The synthesis route is as follows: This includes: under alkaline conditions and with the action of organophosphorus ligands, 2,3-difluoro-6-methoxybenzyl alcohol reacts with 2-methoxy-4-fluorophenol via the Mitsunobu reaction to give 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene; The base providing the alkaline conditions is selected from one or more of N,N-diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, diethyl azodicarboxylate, and diisopropyl azodicarboxylate. The organophosphine ligand is selected from one or more of triphenylphosphine, tri-tert-butylphosphine, and (1,2-bis(ethoxycarbonyl)hydrazyl)triphenylphosphine trifluoromethane sulfonate.

2. The method for preparing the Linzagolix intermediate according to claim 1, characterized in that: The molar ratio of 2,3-difluoro-6-methoxybenzyl alcohol to 2-methoxy-4-fluorophenol is 1:1 to 1:2, preferably 1:1 to 1:1.5, more preferably 1:1 to 1:1.2, and most preferably 1:1.05 to 1:1.

15.

3. The method for preparing the Linzagolix intermediate according to claim 1, characterized in that: The base is N,N-diisopropylethylamine or diisopropyl azodicarboxylic acid.

4. The method for preparing the Linzagolix intermediate according to claim 1, characterized in that: The molar ratio of 2,3-difluoro-6-methoxybenzyl alcohol to the base is 1:1 to 1:3, preferably 1:1 to 1:2, and more preferably 1:1 to 1:1.

5.

5. The method for preparing the Linzagolix intermediate according to claim 1, characterized in that: The organophosphine ligand is triphenylphosphine.

6. The method for preparing the Linzagolix intermediate according to claim 1, characterized in that: The molar ratio of 2,3-difluoro-6-methoxybenzyl alcohol to organophosphorus ligand is 1:1 to 1:3, preferably 1:1 to 1:2, and more preferably 1:1 to 1:1.

5.

7. The method for preparing the Linzagolix intermediate according to claim 1, characterized in that: The temperature of the Mitsunobu reaction is 20–60°C, preferably 25–40°C; the reaction time is 2–18 hours.

8. The method for preparing the Linzagolix intermediate according to claim 1, characterized in that: The reaction solvent is selected from one or more solvents such as tetrahydrofuran, diethyl ether, ethyl acetate, chloroform, dichloromethane, and 1,2-dichloroethane, preferably tetrahydrofuran, dichloromethane, or 1,2-dichloroethane.

9. A method for preparing a Linzagolix intermediate, characterized in that: include: 2,3-Difluoro-6-methoxybenzyl alcohol and 2-methoxy-4-fluorophenol were dissolved in a reaction solvent. Under alkaline conditions and with the action of an organophosphorus ligand, 2,3-difluoro-6-methoxybenzyl alcohol and 2-methoxy-4-fluorophenol underwent a Mitsunobu reaction to give 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene.

10. The method for preparing the Linzagolix intermediate according to claim 1 or 9, characterized in that: After the reaction was complete, calcium bromide was added to the reaction solution, the mixture was stirred at room temperature, filtered, and the filtrate was diluted with water, extracted with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain pure 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene; or after the reaction was complete, saturated sodium bicarbonate aqueous solution was added, the mixture was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by normal-phase silica gel column chromatography to obtain pure 1,2-difluoro-3-(4-fluoro-2-methoxyphenoxymethyl)-4-methoxybenzene. The molar ratio of calcium bromide to 2,3-difluoro-6-methoxybenzyl alcohol is 1:1 to 10:1, preferably 2:1 to 6:1.

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