A method for producing a linzagoli intermediate

Abstract

The present invention solves the problems existing in the prior art and provides a method for preparing a linzagoli intermediate. Compared with the prior art, the method improves production efficiency and reduces total production costs. The reaction is simple and controllable, the yield is high, the side reactions are few, and the subsequent transfer derivatization of isomer impurities that is difficult to remove is avoided. The process operation is simple and more suitable for production scale-up.

Description

1. Technical field

[0001] The invention belongs to the technical field of medicinal chemistry, and particularly relates to the synthesis of a linzagoli intermediate. 2. Background Technology

[0002] Linzagolix is ​​a novel oral GnRH receptor antagonist developed by Kissei Pharmaceutical ("Kissei"), currently under development for the treatment of endometriosis, adenomyosis, and uterine leiomyomata (also known as uterine fibroids). In November 2015, Kissei licensed exclusive global rights to Linzagolix outside of Japan and other Asian countries to ObsEva. In September 2021, Kissei granted Shanghai Biozheng the rights to develop and commercialize Linzagolix in China.

[0003]

[0004] On June 14, 2022, Linzagoli tablets (trade name: Yselty, strengths: 100mg, 200mg) were first approved in the European Union for the treatment of moderate to severe symptoms of uterine fibroids in adult women of childbearing age. Linzagoli tablets are also approved for the treatment of uterine fibroids in Iceland, Liechtenstein, Norway, and the United Kingdom.

[0005] WO2014042176A1 discloses a route for preparing a linzagoli intermediate, as shown below. This synthetic route is a linear design with five steps (total yield 72.0%), resulting in high material costs and a long production time. The fifth reduction step uses Raney-Nickel and hydrogen, which are highly flammable in air, requiring specialized equipment and hindering scale-up.

[0006]

[0007] Therefore, in response to the shortcomings of the existing technology, the present inventors have developed a method for preparing linzagoli intermediates with simple operation, high reaction purity and yield, short production time and lower process cost to meet the needs of scale-up production and quality control. 3. Summary of the invention

[0008] The present invention solves the problems existing in the prior art and provides a method for preparing a linzagoli intermediate. Compared with the prior art, the method improves production efficiency and reduces total production costs. The reaction is simple and controllable, the yield is high, the side reactions are few, and the subsequent transfer derivatization of isomer impurities that is difficult to remove is avoided. The process operation is simple and more suitable for production scale-up.

[0009] The present invention provides a method for preparing a key intermediate compound I of linzagoli, comprising the following steps:

[0010] (1) The compound of formula (VIII) is subjected to hydroxyl protection, nitration, and deprotection reaction to obtain the compound of formula (VII),

[0011]

[0012] (2) The compound of formula (VII) is subjected to a reduction reaction in a solvent to obtain a compound of formula (VI),

[0013]

[0014] (3) protecting the amino group of the compound of formula (VI) in a solvent to obtain the compound of formula (V);

[0015]

[0016] (4) reacting the compound of formula (V) with the compound of formula (III) in a solvent in the presence of a base to obtain the compound of formula (II);

[0017]

[0018] (5) The compound of formula (II) is reacted in a solvent with an acid to obtain the compound of formula (I);

[0019]

[0020] Among them, the R 1 and R 2 are each independently a hydrogen atom, Boc, Cbz, Fmoc, or an acetyl group, and R 1 and R 2 are not hydrogen atoms at the same time. 1 and R 2 are each independently a hydrogen atom or Boc, and R 1 and R 2 Not all hydrogen atoms.

[0021] in,

[0022] In step (1), the compound of formula (VIII) and an acylating agent are subjected to a hydroxyl protection reaction in a solvent to obtain a compound of formula (VIII-1), wherein the solvent is selected from one or more of dichloromethane, tetrahydrofuran, and ethyl acetate, preferably dichloromethane, and the acylating agent is selected from one or both of acetyl chloride and acetic anhydride, preferably acetyl chloride; the compound of formula (VIII-1) is subjected to a nitration reaction in a solvent to obtain a compound of formula (VIII-2), wherein the solvent is selected from one or both of glacial acetic acid and concentrated sulfuric acid, preferably glacial acetic acid, and the nitrating agent is selected from one or both of concentrated nitric acid and fuming nitric acid, preferably concentrated nitric acid; the compound of formula (VIII-2) is subjected to a deprotection reaction in a solvent to obtain a compound of formula (VII), wherein the solvent is selected from one or more of methanol, ethanol, isopropanol, and acetonitrile, preferably methanol; and the deprotection base is selected from one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide, preferably sodium bicarbonate.

[0023] In step (2), the solvent is selected from one or more of methanol, ethanol, isopropanol, and tetrahydrofuran, preferably methanol; the reducing agent is hydrazine hydrate, activated carbon, and ferric chloride; the reaction temperature is 40-60° C., and the reaction time is 4-8 h.

[0024] In step (3), the solvent is selected from one or more of ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile and toluene, preferably ethyl acetate.

[0025] In step (4), the solvent is selected from one or more of ethyl acetate and acetonitrile, preferably ethyl acetate; the base is selected from one or more of sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide, preferably sodium carbonate; the reaction temperature is 60-80° C., and the reaction time is 6-10 h.

[0026] In step (5), the solvent is selected from one or more of ethyl acetate and acetonitrile, preferably ethyl acetate; the acid is concentrated hydrochloric acid, the reaction temperature is 40-60° C., and the reaction time is 1-4 h.

[0027] Furthermore, the present invention also includes the step of preparing the compound of formula (III) from the compound of formula (IV), wherein the compound of formula (IV) reacts with a chlorination agent in a solvent to obtain the compound of formula (III);

[0028]

[0029] The solvent is DCM; the chlorination agent is selected from one or both of thionyl chloride and phosphorus oxychloride, preferably thionyl chloride; and the reaction temperature is -10 to 10°C.

[0030] The beneficial technical effects of the present invention are:

[0031] 1. The polymerization reaction route is designed. After the second step reaction is completed, the liquid is directly separated. After the liquid separation, the organic phase is directly subjected to the third step reaction. After the reaction is completed, the fourth step reaction is directly subjected to the deprotection reaction to obtain the compound of formula (I). The present application is a convergent reaction, which can prepare the compound of formula (V) and the compound of formula (III) at the same time; the operation is simplified, the production cycle is shortened, the production efficiency is improved, and the total production cost is reduced;

[0032] 2. The preparation of compound (V) from compound (VIII) is mostly done by changing the protecting group. The reaction is simple and controllable with little yield loss. The three-step reaction yield of compound (V) from compound (VIII) to compound (V) is 85.6%.

[0033] 3. Nitration reaction and nitro reduction are both placed at the front end of the route, which reduces the theoretical reaction sites, reduces side reactions, and avoids the difficulty in removing isomer impurities and subsequent derivatization;

[0034] 4. The reaction uses inexpensive and readily available reagents, and the process is simple to operate. The yield of each step is higher than 90%, and the overall yield of the route is 81.4%. The total yield of the second to sixth steps is 86%, which is higher than the total yield of other patented routes (WO2014042176A1, 72.0%).

[0035] 5. This route is reasonably designed, has cost advantages, and is more suitable for production expansion. 4. Description of the accompanying drawings

[0036] Figure 1 The compound of formula (I) prepared in Example 12 1 HNMR. 5. Specific implementation methods

[0037] 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 understood as limiting the present invention.

[0038] Example 1 Preparation of the compound of formula (VII)

[0039] Add 20g of compound (VIII) to 200ml of DCM and triethylamine (17.1g, 1.2eq), cool to 0°C, and dropwise add acetyl chloride (12.1g, 1.1eq). Maintain the temperature at T≤10°C. After addition, maintain the temperature at 0-10°C for 2h. The reaction is complete. Add 200ml of water to the system, stir, separate, and concentrate the organic phase to dryness under reduced pressure at 40°C. Add 100ml of glacial acetic acid, raise the temperature to 60°C, and dropwise add 60% concentrated nitric acid (19.2g, 1.3eq). Maintain the temperature at 55-65°C for 2h. The reaction is complete. Cool to 20°C, add 150ml of water, and a large amount of solid precipitates. Filter and rinse the filter cake with 20ml of water. Add 100ml of methanol to the filter cake, add sodium bicarbonate (23.6g, 2.0eq), and maintain the temperature at 20-25°C for 2.5h. The reaction is complete. 150 ml of water was added to the system, and the pH was adjusted to 5 with concentrated hydrochloric acid. The temperature was controlled at T<30°C. A large amount of solid precipitated and was filtered. The filter cake was rinsed with 20 ml of water and dried to obtain 24.0 g of yellow solid compound (VII) with a yield of 91%.

[0040] Example 2 Preparation of the compound of formula (VI)

[0041] To 24 g of the compound (VII) prepared in Example 1, 120 ml of methanol, 2.1 g of ferric chloride (0.1 eq), and 2.4 g of activated carbon were added. The temperature was raised to 50°C, and hydrazine hydrate (27.9 g, 3 eq) was added dropwise. After the addition, the mixture was kept at 50-60°C for 5 h to complete the reaction. The mixture was cooled to 40°C, filtered through a pad of diatomaceous earth, and the filter cake was rinsed with 50 ml of 40°C methanol. The filtrate was concentrated under reduced pressure at 40°C, slurried with 100 ml of isopropyl ether, filtered, and dried to obtain 19.3 g of the compound (VI) as a red solid in a yield of 96%.

[0042] Example 3 Preparation of the compound of formula (V)

[0043] To 19.3 g of the compound of formula (VI) prepared in Example 2 was added 100 ml of ethyl acetate and 54 ml of an aqueous solution of sodium hydroxide (5.4 g, 1.1 eq). Di-tert-butyl dicarbonate (32 g, 1.2 eq) was added dropwise. After addition, the mixture was incubated at 20-30°C for 3 h to complete the reaction. The system was separated, washed once with 50 ml of a 10% aqueous citric acid solution, and concentrated under reduced pressure at 40°C to afford 31 g of the compound of formula (V) as a light red solid in a 98% yield.

[0044] Example 4 Preparation of the compound of formula (III)

[0045] 21 g of the compound of formula (IV) and 210 ml of dichloromethane were cooled to 2°C in cold hydrazine, and thionyl chloride (4.5 g, 1.2 eq) was added dropwise, with the temperature controlled at T≤5°C. After the addition was complete, the mixture was kept at 0-5°C for 2 h to complete the reaction. 170 ml of water was added to the system, stirred, and the liquids separated. The organic phase was washed once with 85 ml of saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The dichloromethane was replaced with ethyl acetate to obtain 85 ml of an ethyl acetate solution of the compound of formula (III) (120.61 mmol).

[0046] Example 5 Preparation of the compound of formula (II)

[0047] To 85 ml of an ethyl acetate solution of the compound of formula (III) (120.61 mmol) prepared in Example 4 was added 85 ml of ethyl acetate, followed by the addition of compound V (31 g, 1.0 eq) prepared in Example 3, sodium carbonate (15.4 g, 1.2 eq), and tetrabutylammonium bromide (7.7 g, 0.2 eq). The mixture was heated to reflux for 10 h, and the reaction was complete. The temperature was then lowered, and insoluble salts were removed by filtration to obtain 170 ml of an ethyl acetate solution of compound II (120.61 mmol).

[0048] Example 6 Preparation of the compound of formula (I)

[0049] To a 170ml ethyl acetate solution of the compound of formula (II) (120.61mmol) prepared in Example 5, heat to 40°C and add dropwise 36% concentrated hydrochloric acid (30.6g, 2.5eq). A large amount of white solid precipitated during the addition. After addition, heat to 60°C and allow to react for 1h, which was complete. Cool to 20°C, filter to obtain a white solid, and rinse the filter cake with 10ml of ethyl acetate. Add the filter cake to 100ml of a 1:1 methanol:water solution, adjust the pH to 9-10 with 10% sodium hydroxide solution, stir for 1h, filter, rinse the filter cake with 10ml of water, and dry to obtain 36.2g of compound of formula (I) as a light red solid, with a total yield of 96.1%. Examples 1-6: Total yield 81.4%.

[0050] Example 7 Preparation of the compound of formula (VII)

[0051] 80g of compound (VIII) was added to 800ml of DCM and triethylamine (68g, 1.2eq). The temperature was lowered to 0°C, and acetyl chloride (49g, 1.1eq) was added dropwise. The temperature was maintained at 10°C. After addition, the reaction was maintained at 0-10°C for 2h. The reaction was complete. 800ml of water was added to the system, stirred, and separated. The organic phase was concentrated to dryness under reduced pressure at 40°C. 400ml of glacial acetic acid was added, the temperature was raised to 60°C, and 60% concentrated nitric acid (77g, 1.3eq) was added dropwise. The temperature was maintained at 55-65°C for 2h. The reaction was complete. The temperature was lowered to 20°C, and 600ml of water was added. A large amount of solid precipitated. The solid was filtered and the filter cake was rinsed with 80ml of water. 400ml of methanol and sodium bicarbonate (95g, 2.0eq) were added to the filter cake. The reaction was maintained at 20-25°C for 2.5h. The reaction was complete. 600 ml of water was added to the system, and the pH was adjusted to 5 with concentrated hydrochloric acid. The temperature was controlled at T<30°C. A large amount of solid precipitated and was filtered. The filter cake was rinsed with 20 ml of water to obtain 126.4 g (562.86 mmol) of compound (VII) with a yield of 120%.

[0052] Example 8 Preparation of the compound of formula (VI)

[0053] 126.4 g of the compound of formula (VII) prepared in Example 7 (100% yield in the previous step) was added to 632 ml of methanol, ferric chloride (9.1 g, 0.1 eq), and activated carbon (12.6 g). The temperature was raised to 50°C, and hydrazine hydrate (122 g, 3 eq) was added dropwise. After the addition, the mixture was kept at 50-60°C for 5 h to complete the reaction. The temperature was lowered to 20°C, filtered through celite, and the filtrate was concentrated under reduced pressure at 40°C. 400 ml of ethyl acetate was added, and the mixture was washed once with 400 ml of 10% brine to obtain 400 ml of an ethyl acetate solution of the compound of formula (VI) (562.86 mmol).

[0054] Example 9 Preparation of the compound of formula (V)

[0055] To a 400 ml ethyl acetate solution of the compound of formula (VI) (562.86 mmol) prepared in Example 8 was added a 250 ml aqueous solution of sodium hydroxide (25 g, 1.1 eq), and di-tert-butyl dicarbonate (147 g, 1.2 eq) was added dropwise. After addition, the mixture was kept at 20-30°C and allowed to react for 3 h. The reaction was complete. The system was separated and washed once with 200 ml of a 10% aqueous citric acid solution to obtain a 400 ml ethyl acetate solution of the compound of formula (V) (562.86 mmol).

[0056] Example 10 Preparation of the compound of formula (III)

[0057] 98g of the compound of formula (IV) and 980ml of dichloromethane were cooled to 2°C in cold hydrazine, and thionyl chloride (80g, 1.2eq) was added dropwise, with the temperature controlled at T≤5°C. After the addition was complete, the mixture was kept at 0-5°C for 2h to complete the reaction. 800ml of water was added to the system, stirred, and the liquids separated. The organic phase was washed once with 400ml of saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The dichloromethane was replaced with ethyl acetate to obtain 400ml of ethyl acetate solution of the compound of formula (III) (562.86mmol).

[0058] Example 11 Preparation of the compound of formula (II)

[0059] To a 400 ml ethyl acetate solution of the compound of formula (III) (562.86 mmol) prepared in Example 10 was added a 400 ml ethyl acetate solution of the compound of formula (V) (562.86 mmol) prepared in Example 9. Sodium carbonate (72 g, 1.2 eq) and tetrabutylammonium bromide (36 g, 0.2 eq) were then added. The mixture was heated to reflux for 10 h, and the reaction was complete. The temperature was then lowered, and the insoluble salts were filtered to obtain an 800 ml ethyl acetate solution of the compound of formula (II) (562.86 mmol).

[0060] Example 12 Preparation of the compound of formula (I)

[0061] To an 800ml solution of the compound of formula (II) (562.86mmol) prepared in Example 11 in ethyl acetate, heat to 40°C and add dropwise 36% concentrated hydrochloric acid (143g, 2.5eq). A large amount of white solid precipitates during the addition. After addition, heat to 60°C and allow to react for 1h, which completes the reaction. Cool to 20°C, filter to obtain a white solid, and rinse the filter cake with 50ml of ethyl acetate. Add the filter cake to 400ml of a 1:1 methanol:water solution, adjust the pH to 9-10 with 10% (mass fraction) sodium hydroxide solution, stir for 1h, filter, rinse the filter cake with 50ml of water, and dry to obtain 151g of a light red solid, with a total yield of 86%. 1 H NMR (400MHz, DMSO-d6) δ9.61 (s, 2H), 7.48 (q, J = 9.7Hz, 1H), 7.19 (d, J = 7.7Hz, 1H), 7.11 (d ,J=12.0Hz,1H),6.92(ddd,J=9.4,3.7,1.9Hz,1H),5.00(s,2H),3.82(s,3H),3.75(s,3H).

Claims

1. A method for preparing a compound of formula (I), a key intermediate of Linzagoli, characterized in that: The following steps are involved: (1) The compound of formula (VIII) is subjected to hydroxyl protection, nitration, and deprotection reaction to obtain the compound of formula (VII): ； (2) The compound of formula (VII) is subjected to a reduction reaction in a solvent to obtain a compound of formula (VI): ； (3) Protecting the amino group of the compound of formula (VI) in a solvent to obtain a compound of formula (V): ； (4) The compound of formula (V) reacts with the compound of formula (III) in a solvent in the presence of a base to obtain the compound of formula (II): ； (5) The compound of formula (II) is treated in a solvent with an acid to obtain the compound of formula (I): ； Among them, the R 1 and R 2 are each independently a hydrogen atom, Boc, and R 1 and R 2 Not all hydrogen atoms.

2. The preparation method according to claim 1, characterized in that The hydroxyl protection reaction in step (1) is a reaction of the compound of formula (VIII) with an acylating agent in a solvent to obtain a compound of formula (VIII-1), wherein the solvent is selected from one or more of dichloromethane, tetrahydrofuran, and ethyl acetate; and the acylating agent is selected from one or both of acetyl chloride and acetic anhydride.

3. The preparation method according to claim 1, characterized in that The nitration reaction in step (1) is a nitration reaction of the compound of formula (VIII-1) in a solvent to obtain the compound of formula (VIII-2), wherein the solvent is selected from one or both of glacial acetic acid and concentrated sulfuric acid; and the nitration reagent is selected from one or both of concentrated nitric acid and fuming nitric acid.

4. The preparation method according to claim 1, characterized in that The deprotection reaction in step (1) is a deprotection reaction of the compound of formula (VIII-2) in a solvent to obtain a compound of formula (VII), wherein the solvent is selected from one or more of methanol, ethanol, isopropanol, and acetonitrile; and the deprotection base is selected from one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide.

5. The preparation method according to claim 1, characterized in that In the step (2), the solvent is selected from one or more of methanol, ethanol, isopropanol, and tetrahydrofuran; the reducing reagent is hydrazine hydrate, activated carbon, and ferric chloride; the reaction temperature is 40-60° C., and the reaction time is 4-8 hours.

6. The preparation method according to claim 1, characterized in that In the step (3), the solvent is selected from one or more of ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, and toluene.

7. The preparation method according to claim 1, characterized in that The compound of formula (III) in step (4) is obtained by reacting the compound of formula (IV) with a chlorination reagent in a solvent: ， The solvent is DCM; the chlorination agent is selected from one or two of thionyl chloride and phosphorus oxychloride; and the reaction temperature is -10 to 10°C.

8. The preparation method according to claim 1, characterized in that In the step (4), the solvent is selected from one or both of ethyl acetate and acetonitrile; the base is selected from one or more of sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide; the reaction temperature is 60-80° C., and the reaction time is 6-10 h.

9. The preparation method according to claim 1, characterized in that In the step (5), the solvent is selected from one or both of ethyl acetate and acetonitrile; the acid is concentrated hydrochloric acid; the reaction temperature is 40-60° C., and the reaction time is 1-4 h.

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