Synthesis method of suvorexant intermediate with high chiral purity

Abstract

The invention belongs to the technical field of synthetic chemistry, and particularly relates to a preparation method of a high-chiral-purity suvorexant intermediate. The preparation method comprises the following steps: by taking (5R)-hexahydro-5-methyl-1-benzyl-1H-1, 4-diazepine as an initial raw material, triethylamine as alkali and dichloromethane as a solvent, carrying out BOC acid anhydride protection to obtain an intermediate 1; dissolving the intermediate 1 in methanol, catalyzing by palladium carbon, and removing benzyl protection to obtain an intermediate 2; performing CBZ protection on the intermediate 2 under an alkaline condition to obtain an intermediate 3; and removing BOC protection from the intermediate 3 under an acidic condition to obtain the suvorexant intermediate with high chiral purity. The synthesis process is simple, the yield is high, the chiral purity reaches 99.8% or above, the solvent and the catalyst can be recycled, and the method is green and environmentally friendly.

Description

Technical Field

[0001] The invention belongs to the technical field of synthetic chemistry, and particularly relates to a method for preparing a suvorexan intermediate with high chiral purity. Background Art

[0002] Insomnia has become a common health problem in modern society, which has long affected the quality of life of the general public. Studies have shown that as people age, insomnia will become more and more common among the population. With the aging of my country's population, the number of elderly people continues to rise, and the number of insomnia patients will further increase. The pace of life in modern society is getting faster and faster, and the life pressure of young and middle-aged people is getting greater and greater. Insomnia symptoms are gradually spreading among young and middle-aged people. It can be seen that there is a huge market demand for drugs to treat insomnia. In recent years, orexin receptors have become a new target for the treatment of insomnia, and orexin receptor antagonists have also become a new type of drug for the treatment of insomnia. Suvorexan is the first orexin receptor antagonist approved for marketing.

[0003] There are many synthetic routes for suvorexant, among which the seven-membered ring chiral intermediate is an inevitable intermediate in the synthetic route. There are few synthetic routes for the CBZ-protected seven-membered ring chiral intermediate reported in the existing literature.

[0004] Patent WO2016020404A1 discloses a method for synthesizing the key intermediate, which uses N-Boc-ethylenediamine and 2,2,6-trimethyl-4H-1,3-dioxin-4-one as starting materials, and obtains compound 1 by high temperature heating reaction. Compound 1 is reduced with sodium borohydride to obtain compound 2. Compound 2 is reduced in the presence of sodium borohydride and a large amount of trifluoroacetic acid to obtain compound 3. Compound 3 is then treated with CBZ to obtain compound 4, compound 4 is oxidized with sodium hypochlorite to obtain compound 5, compound 5 is de-BOCed to obtain compound 6 by methanol-hydrogen chloride, compound 6 is reduced and cyclized with sodium triacetoxyborohydride to obtain compound 7, compound 7 is split by a chiral splitting agent, then refined and freed to obtain the suvorexan intermediate. The reaction route is shown below:

[0005]

[0006] This patented route has expensive starting materials and a long route, resulting in a low overall yield. The preparation of compound 1 needs to be carried out at a high temperature of 150°C. The preparation of compound 2 and compound 3 needs to be carried out at a low temperature of 0°C, and requires the use of explosive reagents such as sodium borohydride and a large amount of trifluoroacetic acid. Compound 4 requires a large amount of sodium hydride for oxidation. Compound 7 needs to be reduced with expensive sodium triacetoxyborohydride. The use of high temperature, explosive reducing agents, oxidants, and a large amount of acid during the reaction process has special requirements for production equipment and is not conducive to industrial production.

[0007] At the same time, the biggest problem of this patent route is that the prepared suvorexan intermediate needs to be split with a splitting agent, the splitting yield is low, and the split product needs to be refined, and the final chiral purity can only reach 97.7% at most. The chiral purity is not significantly improved after refining this product again, and the products produced by this route do not have a market competitive advantage. Summary of the invention

[0008] The technical problem to be solved by the present invention is to overcome the defects of the prior art such as long route, high cost, large amount of explosive reagents, large amount of waste acid, and low chiral purity. The present invention proposes a method for preparing a high chiral purity suvorexan intermediate, which greatly simplifies the synthesis process, improves the yield and purity, reduces the use of explosive reagents and large amounts of acid, and the solvents and catalysts used can be recycled, which is green and environmentally friendly. At the same time, the chiral purity of the suvorexan intermediate produced by this method can reach more than 99.5%, which has a strong market competitive advantage. The reaction route is as follows:

[0009]

[0010] The present invention uses (5R)-hexahydro-5-methyl-1-benzyl-1H-1,4-diazepine (this material is self-made or can be purchased from the market, and the chiral purity reaches 99.8%) as the starting material, triethylamine as the base, dichloromethane as the solvent, and BOC anhydride to react to obtain intermediate 1. The synthesized intermediate 1 is debenzylated by palladium carbon catalysis to obtain intermediate 2, and intermediate 2 is then reacted with a CBZ reagent to obtain intermediate 3, and intermediate 3 is deprotected from BOC protecting groups under acidic conditions to obtain a crude product, which is distilled to obtain a suvorexan intermediate. The present invention has a simple synthesis process, a good yield, a chiral purity of more than 99.8%, and the solvent and catalyst can be recycled, which is green and environmentally friendly.

[0011] The method for preparing a high chiral purity suvorexan intermediate according to the present invention comprises the following steps:

[0012] Step (1): Add (5R)-hexahydro-5-methyl-1-benzyl-1H-1,4-diazepine (SM) to dichloromethane, stir to dissolve, add the first base, cool to -5 to 20°C, dropwise add BOC anhydride, after the reaction is completed, wash the reaction solution with water, and concentrate the organic layer under reduced pressure to dryness to obtain intermediate 1. The structural formula of intermediate 1 is shown in Formula 1;

[0013] Step (2): dissolving the intermediate 1 prepared in step (1) in an alcohol solvent, adding a palladium catalyst, then replacing the atmosphere with nitrogen and hydrogen, and heating to react. After the reaction is completed, filtering and concentrating the reaction solution to obtain an intermediate 2. The structural formula of the intermediate 2 is shown in Formula 2;

[0014] Step (3): dissolving the intermediate 2 prepared in step (2) in an aprotic solvent, adding a second base, cooling, adding a CBZ reagent dropwise, and keeping the temperature to react. After the reaction is completed, washing the reaction solution with water, and concentrating the organic layer to dryness to obtain an intermediate 3. The structural formula of the intermediate 3 is shown in Formula 3;

[0015] Step (4): dissolving the intermediate 3 prepared in step (3) in an organic solvent, adding an acidic reagent, and stirring the mixture at room temperature to react. After the reaction is completed, concentrating the reaction solution to dryness, adding dichloromethane, and adjusting the pH to alkaline with sodium hydroxide. The organic layer is washed with water, concentrated to dryness, and distilled to obtain a suvorexan intermediate with high chiral purity. The suvorexan intermediate is 1-[(5R)-5-methyl-1,4-diazepan-1-yl]benzyl carboxylate (i.e., suvorexan intermediate, with a structural formula as shown in formula a).

[0016] Preferably, in the preparation method according to the present invention, the first base in step (1) can be selected from organic bases: triethylamine, diisopropylethylamine, DBU; or can be selected from inorganic bases: sodium carbonate, potassium carbonate, sodium bicarbonate, etc., preferably the organic base triethylamine.

[0017] Preferably, in the preparation method according to the present invention, the reaction temperature in step (1) is -5 to 20°C, preferably 0 to 10°C.

[0018] Preferably, in the preparation method according to the present invention, the amount of BOC anhydride used in step (1) is 1.0-2.0 equivalents of compound SM, preferably 1.0-1.3 equivalents.

[0019] Preferably, in the preparation method according to the present invention, the alcohol solvent selected in step (2) is selected from methanol, ethanol, isopropanol, or a combination of any two thereof, preferably methanol.

[0020] Preferably, in the preparation method according to the present invention, the palladium catalyst selected in step (2) is selected from 5% palladium on carbon, 10% palladium on carbon, 5% palladium hydroxide, 10% palladium hydroxide, or any combination of two thereof, preferably 10% palladium on carbon.

[0021] Preferably, in the preparation method according to the present invention, the amount of palladium catalyst used in step (2) is 5% to 25% of the amount of intermediate 1, preferably 10% of the amount of intermediate 1.

[0022] Preferably, in the preparation method according to the present invention, the reaction temperature in step (2) is 20-60°C, preferably 40-50°C.

[0023] Preferably, in the preparation method according to the present invention, the aprotic solvent selected in step (3) is selected from dichloromethane, ethyl acetate, toluene, tetrahydrofuran, acetonitrile, or a combination of any two thereof, preferably dichloromethane.

[0024] Preferably, in the preparation method according to the present invention, the second base in step (3) can be selected from organic bases: triethylamine, diisopropylethylamine, DBU; or can be selected from inorganic bases: sodium carbonate, potassium carbonate, sodium bicarbonate, etc., preferably the organic base triethylamine.

[0025] Preferably, in the preparation method according to the present invention, the amount ratio of the intermediate 2, triethylamine and CBZ reagent in the step (3) is 1.0:1.1-2.0:1.1-2.0, preferably 1.0:1.2:1.2.

[0026] Preferably, in the preparation method according to the present invention, the solvent selected in step (4) is selected from methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, or a combination of any two thereof, preferably isopropanol.

[0027] Preferably, in the preparation method according to the present invention, the acidic reagent selected in step (4) is selected from concentrated hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanolic hydrogen chloride solution, ethanolic hydrogen chloride solution, isopropanol hydrogen chloride solution, or a combination of any two thereof, preferably isopropanol hydrogen chloride solution.

[0028] Preferably, in the preparation method according to the present invention, in the step (4), after the reaction is completed, post-treatment is performed by adding dichloromethane, adjusting the pH with sodium hydroxide, washing with water, and concentrating the organic layer to dryness to obtain a crude product.

[0029] Preferably, in the preparation method according to the present invention, in the step (4), the crude product is purified by vacuum distillation using an oil pump.

[0030] Technical Effects

[0031] The preparation method of the present invention uses self-made high chiral purity (5R)-hexahydro-5-methyl-1-benzyl-1H-1,4-diazepine (SM) as the starting material, and BOC is added to BOC anhydride to obtain a high-purity intermediate 1. This intermediate does not need to be purified and can be directly used for the next step reaction. Under the catalysis of 10% palladium carbon, the benzyl protecting group of intermediate 1 is removed to obtain intermediate 2. The palladium catalyst used in this process can be repeatedly used, and can also be used for palladium catalyst manufacturers to repurchase metal palladium, which greatly saves costs. Intermediate 2 reacts with a CBZ reagent to obtain intermediate 3. Intermediate 3 is deBOCed under acidic conditions to obtain a crude suvorexan intermediate, without the need for salt separation, and the crude product is directly subjected to oil pump vacuum distillation to obtain a suvorexan intermediate with a chiral purity of 99.8%, and the purity detected by HPLC is 99.3% (the current market purity is 98%). The invention adopts a brand-new synthesis route, uses homemade high chiral purity (5R)-hexahydro-5-methyl-1-benzyl-1H-1,4-diazepine (SM) as a starting material to introduce chirality, and the obtained product has high chiral purity, high reaction conversion rate, low total cost, reusable catalyst, low equipment requirements for the preparation method, and is easy for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 This is the chiral purity liquid phase spectrum of the suvorexan intermediate obtained in Example 1

[0033] Figure 2 This is the chiral purity liquid phase spectrum of the suvorexan intermediate obtained in Example 2 DETAILED DESCRIPTION

[0034] The present invention is further described in detail below by way of examples, but the present invention is not limited to the following examples.

[0035] Embodiment 1:

[0036] Synthesis of intermediate 1:

[0037] At room temperature, 240 mL of dichloromethane, 30 g (147.8 mmol) (5R)-hexahydro-5-methyl-1-benzyl-1H-1,4-diazepine, and 17.9 g (177.4 mmol) of triethylamine were added to a 500 mL three-necked flask in sequence, and the mixture was completely dissolved by stirring. The temperature was lowered by 0-10°C, and 38.7 g (177.4 mmol) of BOC anhydride was added dropwise to the reaction flask. After the addition was completed, stirring was continued for 2-3 hours. TLC showed that there was no obvious residue of the raw material. 100 mL of water was added, and the mixture was allowed to stand for separation after stirring. The lower oil layer was concentrated under reduced pressure until there was no fraction, and a light brown oil intermediate 1 (45.3 g, yield 101.3%) was obtained.

[0038] Synthesis of intermediate 2:

[0039] At room temperature, 270 mL of methanol and 45.3 g (148.8 mmol) of intermediate 1 were added to a 500 mL three-necked flask in sequence, and the mixture was completely dissolved by stirring. Then, 4.53 g (10% W / W) of 10% palladium carbon was added. After the addition was completed, the gas was replaced with nitrogen three times, and then replaced with hydrogen three times. Under normal pressure, the mixture was heated to 40-50 ° C and reacted for 4-6 hours. TLC showed that there was no obvious residue of the raw material. The reaction solution was cooled to room temperature, replaced with nitrogen, filtered, and the filtrate was concentrated under reduced pressure to obtain a colorless transparent oily intermediate 2 (31.7 g, yield 99.4%).

[0040] Synthesis of intermediate 3:

[0041] At room temperature, 190 mL of dichloromethane, 31.7 g (147.9 mmol) of intermediate 2, 17.9 g (177.5 mmol) of triethylamine were added to a 500 mL three-necked flask in sequence, and the mixture was completely dissolved by stirring. The mixture was completely dissolved by stirring, and the temperature was lowered by 0-10°C. 30.3 g (177.5 mmol) of Cbz reagent was added dropwise to the reaction flask. After the addition was completed, the mixture was stirred for 2-3 hours. TLC showed that there was no obvious residue of the raw material. 50 mL of water was added, and the mixture was allowed to stand for separation after stirring. The lower oil layer was concentrated under reduced pressure until there was no fraction, and a colorless oil intermediate 3 (50.5 g, yield 98.1%) was obtained.

[0042] Synthesis of Suvorexant Intermediates:

[0043] At room temperature, 100 mL of isopropanol and 50.5 g (144.9 mmol) of intermediate 3 were added to a 500 mL three-necked flask in sequence, and the mixture was stirred until completely dissolved. 54.3 ml (217.3 mmol) of 4 M hydrogen chloride isopropanol was added dropwise to the reaction flask. After the addition was completed, stirring was continued for 4 to 6 hours. TLC showed that there was no obvious residue of the raw material. The reaction solution was concentrated to dryness, 300 ml of dichloromethane was added to the concentrate, the pH was adjusted to alkaline with 10% sodium hydroxide, washed with water, and the organic layer was concentrated under reduced pressure to obtain 29.8 g of crude product, which was distilled under reduced pressure by an oil pump to obtain a colorless oil (24.5 g, yield 68.2%, chiral purity: 99.8%, HPLC: 99.3%).

[0044] Embodiment 2:

[0045] Synthesis of intermediate 1:

[0046] At room temperature, 240 mL of dichloromethane, 30 g (147.8 mmol) (5R)-hexahydro-5-methyl-1-benzyl-1H-1,4-diazepine, and 16.4 g (162.6 mmol) of triethylamine were added to a 500 mL three-necked flask in sequence, and the mixture was completely dissolved by stirring. The temperature was lowered by 0-10°C, and 35.4 g (162.6 mmol) of BOC anhydride was added dropwise to the reaction flask. After the addition was completed, stirring was continued for 2-3 hours. TLC showed that there was no obvious residue of the raw material. 100 mL of water was added, and the mixture was allowed to stand for separation after stirring. The lower oil layer was concentrated under reduced pressure until there was no fraction, and a light brown oil intermediate 1 (44.6 g, yield 99.7%) was obtained.

[0047] Synthesis of intermediate 2:

[0048] At room temperature, 265 mL of methanol and 44.6 g (146.5 mmol) of intermediate 1 were added to a 500 mL three-necked flask in sequence, stirred to dissolve completely, and then 4.46 g (10% W / W) of 10% palladium carbon was added. After the addition was completed, nitrogen was replaced three times, and then replaced with hydrogen three times. Under normal pressure, it was heated to 40-50 ° C and reacted for 4-6 hours. TLC showed that there was no obvious residue of raw materials. The reaction solution was cooled to room temperature, nitrogen was replaced, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a colorless transparent oil intermediate 2 (31.3 g, yield 99.7%).

[0049] Synthesis of intermediate 3:

[0050] At room temperature, 190 mL of dichloromethane, 31.3 g (146.0 mmol) of intermediate 2 were added to a 500 mL three-necked flask in sequence, and the mixture was completely dissolved by stirring. 16.2 g (160.6 mmol) of triethylamine was stirred and completely dissolved. The temperature was lowered by 0-10°C, and 27.4 g (160.6 mmol) of Cbz reagent was added dropwise to the reaction flask. After the addition was completed, stirring was continued for 2-3 hours. TLC showed that there was no obvious residue of the raw material. 50 mL of water was added, and the mixture was allowed to stand for separation after stirring. The lower oil layer was concentrated under reduced pressure until there was no fraction, and a colorless oil intermediate 3 (49.3 g, yield 97.0%) was obtained.

[0051] Synthesis of Suvorexant Intermediates:

[0052] At room temperature, 97 mL of isopropanol and 49.3 g (141.5 mmol) of intermediate 3 were added to a 500 mL three-necked flask in sequence, and the mixture was completely dissolved by stirring. 70.7 ml (283 mmol) of 4 M hydrogen chloride isopropanol was added dropwise to the reaction flask. After the addition was completed, stirring was continued for 4 to 6 hours. TLC showed that there was no obvious residue of the raw material. The reaction solution was concentrated to dryness, 300 ml of dichloromethane was added to the concentrate, the pH was adjusted to alkaline with 10% sodium hydroxide, washed with water, and the organic layer was concentrated under reduced pressure to obtain 30.3 g of crude product, which was distilled under reduced pressure by an oil pump to obtain a colorless oil (24.9 g, yield 71.0%, chiral purity: 99.9%, HPLC: 99.2%).

Claims

1. A method for preparing a high chiral purity suvorexan intermediate, characterized in that: The following steps are involved: Step (1): Add (5R)-hexahydro-5-methyl-1-benzyl-1H-1,4-diazepine to dichloromethane, stir to dissolve, add the first base, cool to -5-20°C, dropwise add BOC anhydride, after the reaction is completed, wash the reaction solution with water, and concentrate the organic layer under reduced pressure to dryness to obtain intermediate 1. The structural formula of intermediate 1 is shown in Formula 1; Step (2): dissolving the intermediate 1 prepared in step (1) in an alcohol solvent, adding a palladium catalyst, then replacing the atmosphere with nitrogen and hydrogen, and heating to react. After the reaction is completed, filtering and concentrating the reaction solution to obtain an intermediate 2. The structural formula of the intermediate 2 is shown in Formula 2; Step (3): dissolving the intermediate 2 prepared in step (2) in an aprotic solvent, adding a second base, cooling, adding a CBZ reagent dropwise, and keeping the temperature to react. After the reaction is completed, washing the reaction solution with water, and concentrating the organic layer to dryness to obtain an intermediate 3. The structural formula of the intermediate 3 is shown in Formula 3; Step (4): dissolving the intermediate 3 prepared in step (3) in an organic solvent, adding an acidic reagent, stirring the reaction at room temperature, and after the reaction is completed, concentrating the reaction solution to dryness, adding dichloromethane, and adjusting the pH to alkaline with sodium hydroxide. The organic layer is washed with water, concentrated to dryness, and distilled to obtain a high chiral purity suvorexan intermediate, wherein the suvorexan intermediate is 1-[(5R)-5-methyl-1,4-diazepan-1-yl]benzyl carboxylate.

2. The method for preparing a high chiral purity suvorexan intermediate according to claim 1, wherein: The first base is selected from an organic base or an inorganic base, wherein the organic base is triethylamine, diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene; and the inorganic base is sodium carbonate, potassium carbonate or sodium bicarbonate; and / or, In step (3), the second base is an organic base or an inorganic base, wherein the organic base is triethylamine, diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene; and the inorganic base is sodium carbonate, potassium carbonate or sodium bicarbonate.

3. The method for preparing a high chiral purity suvorexan intermediate according to claim 1, wherein: The reaction temperature in step (1) is 0-10°C.

4. The method for preparing a high chiral purity suvorexan intermediate according to claim 1, wherein: In step (1), the amount of BOC anhydride used is 1.0-2.0 equivalents of (5R)-hexahydro-5-methyl-1-benzyl-1H-1,4-diazepine.

5. The method for preparing a high chiral purity suvorexan intermediate according to claim 1, wherein: The alcohol solvent in step (2) is one or more of methanol, ethanol and isopropanol.

6. The method for preparing a high chiral purity suvorexan intermediate according to claim 1, wherein: The palladium catalyst in step (2) is one or two of palladium carbon with a content of 5%, palladium carbon with a content of 10%, palladium hydroxide with a content of 5%, and palladium hydroxide with a content of 10%.

7. The method for preparing a high chiral purity suvorexan intermediate according to claim 1, wherein: The amount of palladium catalyst used in step (2) is 5% to 25% of the amount of intermediate 1.

8. The method for preparing a high chiral purity suvorexan intermediate according to claim 1, wherein: The reaction temperature in step (2) is 20-60°C.

9. The method for preparing a high chiral purity suvorexan intermediate according to claim 1, wherein: The aprotic solvent in step (3) is selected from one or more of dichloromethane, ethyl acetate, toluene, tetrahydrofuran, and acetonitrile; and / or, The dosage ratio of intermediate 2, triethylamine and CBZ reagent in step (3) is 1.0:(1.1-2.0):(1.1-2.0).

10. The method for preparing a high chiral purity suvorexan intermediate according to claim 1, wherein: The organic solvent used in step (4) is one or more of methanol, ethanol, isopropanol, ethyl acetate, and dichloromethane; and / or, The acidic reagent selected in step (4) is one or more of 36% by mass concentrated hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, and hydrogen chloride methanol solution; and / or, In step (4), after the reaction is completed, post-treatment is performed by adding dichloromethane and sodium hydroxide to adjust the pH, washing with water, and concentrating the organic layer to dryness to obtain a crude product; the crude product is purified by oil pump vacuum distillation.

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