Method for preparing non-azonepan intermediate

Abstract

The invention relates to the technical field of medicinal chemistry, in particular to a method for preparing a fiazonepan intermediate. The method comprises the following steps: (1) carrying out methyl esterification reaction on D-alanine serving as a reaction substrate and a methyl esterification reagent to prepare D-alanine methyl ester; (2) carrying out Boc protection on an amino group of the D-alanine methyl ester by adopting a Boc reagent, so as to obtain N-Boc-D-alanine methyl ester; (3) carrying out an amide exchange reaction on the N-Boc-D-alanine methyl ester and ethanolamine to obtain an ethanolamine derivative IV; and (4) the ethanolamine derivative IV and tetrahydrofuran are subjected to a Mitsunobu reaction for ring closing, and the final product (R)-1-(t-butyloxycarboryl)-2-methyl piperazine-3-ketone is obtained. The method has the advantages of low cost, simplicity in operation, short reaction time and high yield.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemistry, and in particular to a method for preparing a fezonetant intermediate. Background Art

[0002] Fezolinetant, a small molecule oral drug, is used to treat moderate to severe vasomotor syndrome or hot flashes (VMS) caused by menopause. (R)-1-(tert-butyloxycarbonyl)-2-methylpiperazine-3-one is an important intermediate for the synthesis of fezolinetant. The structure of (R)-1-(tert-butyloxycarbonyl)-2-methylpiperazine-3-one is shown in Compound V:

[0003]

[0004] Chinese invention patent publication number CN 107174584 A discloses a method for synthesizing the final product (S)-1-(tert-butyloxycarbonyl)-2-methylpiperazine-3-one, and the specific reaction route is as follows:

[0005]

[0006] The above reaction is carried out in three steps, wherein the yield of the first step is only 49%, and the total yield of the second and third steps is 48%. Therefore, the yields of the three steps are all low, resulting in high batch production costs. In addition, the first step post-treatment requires column chromatography, which cannot be used in industrial production. The second step reaction takes a long time, requiring more than 24 hours, resulting in low production efficiency, which is not conducive to industrial production.

[0007] In addition, a similar scheme (European Journal of Medicinal Chemistry, 2023, 257, 115486) reported a scheme using methanesulfonyl chloride (MsCl), with a total yield of 33.2% in three steps, which is still relatively low. Although the first two steps can be simply processed to obtain a crude product and then directly put it into the next step, the third step still requires column chromatography purification, which is not conducive to commercial scale-up production. The specific reaction route is as follows:

[0008]

[0009] Therefore, it is very necessary to develop a new method for preparing fezonetant intermediates that can solve the above technical problems. Summary of the invention

[0010] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a method for preparing a zonetant intermediate by Mitsunobu reaction ring closure, which has low cost, simple operation, short reaction time and high yield.

[0011] The present invention is achieved through the following technical solutions:

[0012] A method for preparing a fezonetant intermediate by ring closing through a Mitsunobu reaction, wherein the fezonetant intermediate is (R)-1-(tert-butyloxycarbonyl)-2-methylpiperazine-3-one, and the method comprises the following steps:

[0013] (1) using D-alanine as a reaction substrate and performing a methyl esterification reaction with a methyl esterification reagent to prepare D-alanine methyl ester;

[0014] (2) using a Boc reagent to perform Boc protection on the amino group of D-alanine methyl ester to obtain N-Boc-D-alanine methyl ester;

[0015] (3) N-Boc-D-alanine methyl ester undergoes an amide exchange reaction with ethanolamine to obtain ethanolamine derivative IV;

[0016] (4) the ethanolamine derivative IV is subjected to Mitsunobu reaction to obtain the final product (R)-1-(tert-butyloxycarbonyl)-2-methylpiperazine-3-one;

[0017] The structural formula of ethanolamine derivative IV is as follows:

[0018]

[0019] In some embodiments of the present invention, the methyl esterification agent in step (1) includes methanol (MeOH). In addition to being a methyl esterification agent, methanol also serves as a reaction solvent.

[0020] In some embodiments of the present invention, step (1) further comprises adding a catalyst, wherein the catalyst is at least one of thionyl chloride (SOCl2) and oxalyl chloride.

[0021] Preferably, in step (1), the molar ratio of the catalyst to D-alanine is 1-2:1, preferably 1.5-2:1.

[0022] In some embodiments of the present invention, the methyl esterification reaction in step (1) comprises one or more of the following reaction conditions:

[0023] 11) the molar ratio of the methyl esterification agent to D-alanine is 5:1-20:1;

[0024] 12) the reaction temperature is 0-30°C, preferably at room temperature (rt);

[0025] 13) The reaction time is 4-8h.

[0026] In some embodiments of the present invention, step (2) comprises one or more of the following reaction conditions:

[0027] 21) The Boc reagent includes Boc2O;

[0028] 22) Step (2) is carried out in one or more solvents such as dichloromethane, acetonitrile, ethyl acetate, etc.; dichloromethane is the preferred reaction solvent;

[0029] 23) The molar ratio of Boc reagent to D-alanine methyl ester is 1.1:1-3.0:1, preferably 1.1:1-2.5:1;

[0030] 24) During the Boc protection process, triethylamine (Et3N) was also added;

[0031] 25) After the reaction materials are added, stir at -10-10°C for 1-2 hours, then heat to 25-30°C and continue stirring for 1-5 hours.

[0032] In some embodiments of the present invention, the amide exchange reaction in step (3) comprises one or more of the following reaction conditions:

[0033] 31) The molar ratio of N-Boc-D-alanine methyl ester to ethanolamine is 1:2-1:5, preferably 1:2-1:3;

[0034] 32) The temperature of the amide exchange reaction is 70-80°C;

[0035] 33) The reaction time of amide exchange is 1-3h.

[0036] After the reaction in step (3) is completed, the reaction solution is washed with saturated brine and then extracted with an extraction reagent.

[0037] The extraction agent is preferably ethyl acetate.

[0038] In some embodiments of the present invention, the Mitsunobu reaction in step (4) further comprises adding an activation reagent.

[0039] In some preferred embodiments of the present invention, the activation reagent includes triphenylphosphine and an azo reagent.

[0040] In some preferred embodiments of the present invention, the azo reagent includes at least one of diisopropyl azodicarboxylate, diethyl azodicarboxylate and di-tert-butyl azodicarboxylate.

[0041] In some preferred embodiments of the present invention, the activation reagent is triphenylphosphine (PPh3) and diisopropyl azodicarboxylate (DIAD).

[0042] In some preferred embodiments of the present invention, in step (4), the molar ratio of ethanolamine derivative IV: triphenylphosphine: azo reagent is 1:1.5-3:1.5-3, preferably 1:1.5-2:1.5-2.

[0043] In some embodiments of the present invention, the Mitsunobu reaction in step (4) comprises one or more of the following reaction conditions:

[0044] 41) the ethanolamine derivative IV is subjected to Mitsunobu reaction ring closure in tetrahydrofuran (THF), the volume ratio of the ethanolamine derivative IV to tetrahydrofuran being 1:15-1:30;

[0045] 42) The temperature of the Mitsunobu reaction is 70-75°C;

[0046] 43) The time of Mitsunobu reaction is 8-16h;

[0047] 44) Mitsunobu reaction is carried out in an inert atmosphere.

[0048] In some preferred embodiments of the present invention, the reaction scheme of the method is as follows:

[0049]

[0050] The beneficial effects of the present invention are:

[0051] 1. The starting material of the present invention is D-alanine, which is cheap and easy to obtain, and the production cost is effectively reduced;

[0052] 2. The total reaction time of the present invention is short, which effectively improves the preparation efficiency;

[0053] 3. The reaction conditions of the present invention are relatively mild, and the operation is safe and simple;

[0054] 4. The reaction yield of the present invention is high, and the post-treatment method is simple, and a product of high purity can be obtained without purification by column chromatography;

[0055] 5. The reaction route of the present invention is stable and can be scaled up for production. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 This is the H NMR spectrum data of compound V in Example 1. DETAILED DESCRIPTION

[0057] The present invention will be further described below in conjunction with specific embodiments, and the advantages and features of the present invention will become clearer as the description proceeds. However, these embodiments are exemplary only and do not constitute any limitation to the scope of the present invention. It should be understood by those skilled in the art that the details and forms of the technical solution of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements all fall within the scope of protection of the present invention.

[0058] The "eq." in the examples of the present invention refers to the amount equivalent of a substance.

[0059] Example 1

[0060] A method for preparing a fezonetant intermediate (R)-1-(tert-butyloxycarbonyl)-2-methylpiperazine-3-one comprises the following steps:

[0061] Step 1: Methyl esterification

[0062]

[0063] D-alanine (10.0 g, 96 mmol, 1.0 eq.) and methanol (100 mL) were mixed in a 250 mL three-necked flask, cooled to 0°C, and thionyl chloride (17.1 g, 144 mmol, 1.5 eq.) was added. After the addition was complete, the temperature was raised to 25°C and reacted for 4 h. After the reaction was completed by monitoring by LC-MS, the reaction solution was concentrated under reduced pressure to obtain D-alanine methyl ester (9.4 g, yield 95%).

[0064] Step 2: Boc Protection

[0065]

[0066] D-alanine methyl ester (5.0 g, 49 mmol, 1.0 eq.) and dichloromethane (50 mL) were mixed in a 100 mL three-necked flask, and triethylamine (14.9 g, 147 mmol, 3.0 eq.) was added dropwise thereto after cooling to 0°C. After the addition was complete, the mixture was stirred for 15 min, and then Boc2O (11.8 g, 53.9 mmol, 1.1 eq.) was added thereto. After reacting at 0°C for 1 h, the mixture was heated to room temperature and continued to react for 1 h. After the reaction was completed as monitored by LC-MS, the reaction solution was washed with saturated sodium bicarbonate solution and saturated brine in turn, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain N-Boc-D-alanine methyl ester (8.9 g, yield 90%).

[0067] Step 3: Amide exchange

[0068]

[0069] N-Boc-D-alanine methyl ester (5.0 g, 24.6 mmol, 1.0 eq.) and ethanolamine (4.5 g, 73.8 mmol, 3.0 eq.) were mixed in a 25 mL Shrek tube and reacted at 80°C for 1 h. After the reaction was completed under LC-MS monitoring, the reaction solution was washed with saturated brine, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried and concentrated to obtain ethanolamine derivative IV (5.1 g, yield 90%).

[0070] Step 4: Mitsunobu reaction ring closure

[0071]

[0072] Ethanolamine derivative IV (5.0 g, 21.5 mmol, 1.0 eq.) was mixed with tetrahydrofuran (100 mL) in a 250 mL three-necked flask, and triphenylphosphine (11.3 g, 2.0 eq.) and diisopropyl azodicarboxylate (8.7 g, 2.0 eq.) were added in sequence. The mixture was reacted at 70° C. for 8 h under nitrogen protection. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated under reduced pressure to obtain the final product V (4.2 g, yield 90%). 1 H NMR (400MHz, CDCl3) δ7.52(1H),4.10-4.05(1H),3.43-3.39(1H),3.37-3.20(1H),3.13-3.01(2H),1.43(9H),1.39-1.38(3H).

[0073] The H NMR spectrum data of compound V are as follows Figure 1 shown.

[0074] Example 2

[0075] A method for preparing a fezonetant intermediate (R)-1-(tert-butyloxycarbonyl)-2-methylpiperazine-3-one comprises the following steps:

[0076] Step 1: Methyl esterification

[0077]

[0078] D-alanine (10.0 g, 96 mmol, 1.0 eq.) and methanol (100 mL) were mixed in a 250 mL three-necked flask, cooled to 0°C, and oxalyl chloride (24.4 g, 192 mmol, 2.0 eq.) was added. After the addition was complete, the temperature was raised to 20°C and the reaction was allowed to proceed for 8 h. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated under reduced pressure to obtain D-alanine methyl ester (9.4 g, yield 95%).

[0079] Step 2: Boc Protection

[0080]

[0081] D-alanine methyl ester (5.0 g, 49 mmol, 1.0 eq.) and acetonitrile (50 mL) were mixed in a 100 mL three-necked flask, and triethylamine (14.9 g, 147 mmol, 3.0 eq.) was added dropwise thereto after cooling to 0°C. After the addition was complete, the mixture was stirred for 15 min, and then Boc2O (26.7 g, 122.5 mmol, 2.5 eq.) was added thereto. After reacting at -10°C for 2 h, the mixture was heated to room temperature and continued to react for 3 h. After the reaction was complete as monitored by LC-MS, the reaction solution was washed with saturated sodium bicarbonate solution and saturated brine in turn, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain N-Boc-D-alanine methyl ester (9.1 g, yield 92%).

[0082] Step 3: Amide exchange

[0083]

[0084] N-Boc-D-alanine methyl ester (5.0 g, 24.6 mmol, 1.0 eq.) and ethanolamine (3.0 g, 49.2 mmol, 2.0 eq.) were mixed in a 25 mL Shrek tube and reacted at 75°C for 2.5 h. After the reaction was completed under LC-MS monitoring, the reaction solution was washed with saturated brine, the aqueous phase was extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain ethanolamine derivative IV (4.6 g, yield 81%).

[0085] Step 4: Mitsunobu reaction ring closure

[0086]

[0087] Ethanolamine derivative IV (5.0 g, 21.5 mmol, 1.0 eq.) was mixed with tetrahydrofuran (150 mL) in a 250 mL three-necked flask, and triphenylphosphine (8.5 g, 1.5 eq.) and diethyl azodicarboxylate (6.5 g, 1.5 eq.) were added in sequence. The mixture was reacted at 75 ° C for 8 h under nitrogen protection. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated under reduced pressure to obtain the final product V (4.0 g, yield 86%).

[0088] Comparative Example 1

[0089] The only difference from Example 1 is that step 4 is different, and the other conditions are the same, as follows:

[0090] Step 4: Mitsunobu reaction ring closure

[0091]

[0092] Ethanolamine derivative IV (5.0 g, 21.5 mmol, 1.0 eq.) was mixed with tetrahydrofuran (100 mL) in a 250 mL three-necked flask, and triphenylphosphine (11.3 g, 43.0 mmol, 2.0 eq.) and di-tert-butyl azodicarboxylate (9.9 g, 43.0 mmol, 2.0 eq.) were added in sequence. The mixture was reacted at 70°C for 8 h under nitrogen protection. The reaction was monitored by LC-MS, and only 5% of compound V was produced.

[0093] The only difference from Example 1 is that in step 4, during the Mitsunobu reaction ring closure process, diisopropyl azodicarboxylate was replaced with di-tert-butyl azodicarboxylate of the same amount, and the result showed only 5% of the target compound. It is speculated that the tert-butyl group in di-tert-butyl azodicarboxylate has a large steric hindrance, which makes the ring formation process difficult.

[0094] Comparative Example 2

[0095] The only difference from Example 1 is that the reaction temperature is different during the Mitsunobu reaction ring-closing process in step 4, and the other conditions are the same, as follows:

[0096]

[0097] The only difference from Example 1 is that in step 4, during the Mitsunobu reaction ring-closure process, the reaction temperature was 30° C. and the reaction was stirred for 8 h. No target compound was generated as monitored by LC-MS.

[0098] Comparative Example 3

[0099] The only difference from Example 1 is that the reaction temperature is different during the Mitsunobu reaction ring-closing process in step 4, and the other conditions are the same, as follows:

[0100]

[0101] The only difference from Example 1 is that in the ring-closing process of the Mitsunobu reaction in step 4, the reaction temperature was 50° C. and the reaction was stirred for 8 h. No target compound was generated as monitored by LC-MS.

[0102] The above detailed description is a specific description of one feasible embodiment of the present invention. The embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not deviate from the present invention should be included in the scope of the technical solution of the present invention.

Claims

1. A method for preparing a fezonetant intermediate, wherein the fezonetant intermediate is (R)-1-(tert-butyloxycarbonyl)-2-methylpiperazine-3-one, characterized in that: The method comprises the following steps: (1) using D-alanine as a reaction substrate and performing a methyl esterification reaction with a methyl esterification reagent to prepare D-alanine methyl ester; (2) using a Boc reagent to perform Boc protection on the amino group of D-alanine methyl ester to obtain N-Boc-D-alanine methyl ester; (3) N-Boc-D-alanine methyl ester undergoes an amide exchange reaction with ethanolamine to obtain ethanolamine derivative IV; (4) the ethanolamine derivative IV is subjected to Mitsunobu reaction to obtain the final product (R)-1-(tert-butyloxycarbonyl)-2-methylpiperazine-3-one; 2. The method according to claim 1, characterized in that The methyl esterification agent in step (1) includes methanol.

3. The method according to claim 1, characterized in that Step (1) also includes adding a catalyst, wherein the catalyst is at least one of thionyl chloride and oxalyl chloride.

4. The method according to claim 3, characterized in that The methyl esterification reaction in step (1) includes one or more of the following reaction conditions: 11) the molar ratio of the methyl esterification agent to D-alanine is 5:1-20:1; 12) The molar ratio of the catalyst to D-alanine is 1-2:1; 13) The reaction temperature is 0-30°C; 14) The reaction time is 4-8h.

5. The method according to claim 1, characterized in that Step (2) comprises one or more of the following reaction conditions: 21) The Boc reagent includes Boc2O; 22) step (2) is carried out in at least one solvent selected from the group consisting of dichloromethane, acetonitrile and ethyl acetate; 23) The molar ratio of the Boc reagent to D-alanine methyl ester is 1.1:1-3.0:1; 24) During the Boc protection process, triethylamine was also added; 25) After the reaction materials are added, stir at -10-10°C for 1-2 hours, then heat to 25-30°C and continue stirring for 1-5 hours.

6. The method according to claim 1, characterized in that The amide exchange reaction in step (3) includes one or more of the following reaction conditions: 31) The molar ratio of N-Boc-D-alanine methyl ester to ethanolamine is 1:2-1:5; 32) The temperature of the amide exchange reaction is 70-80°C; 33) The reaction time of amide exchange is 1-3h.

7. The method according to claim 1, characterized in that The Mitsunobu reaction in step (4) further comprises adding an activation reagent, wherein the activation reagent comprises triphenylphosphine and an azo reagent, wherein the azo reagent comprises at least one of diisopropyl azodicarboxylate, diethyl azodicarboxylate and di-tert-butyl azodicarboxylate.

8. The method according to claim 7, characterized in that The activation reagents are triphenylphosphine and diisopropyl azodicarboxylate.

9. The method according to claim 7, characterized in that: In step (4), the molar ratio of ethanolamine derivative IV: triphenylphosphine: azo reagent is 1:1.5-3:1.5-3.

10. The method according to claim 1, characterized in that The Mitsunobu reaction in step (4) includes one or more of the following reaction conditions: 41) the ethanolamine derivative IV is subjected to Mitsunobu reaction ring closure in tetrahydrofuran, wherein the volume ratio of the ethanolamine derivative IV to tetrahydrofuran is 1:15-1:30; 42) The temperature of the Mitsunobu reaction is 70-75°C; 43) The time of Mitsunobu reaction is 8-16h; 44) Mitsunobu reaction is carried out in an inert atmosphere.

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