Synthesis method of milobalin intermediate

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of a milobalin intermediate. According to the method, (1R, 5S)-3-ethyl bicyclo [3.2. 0] hept-3-ene-6-ketone is taken as a raw material, and is subjected to a one-step reaction with nitromethane and tert-butyl acetate substances under the action of a chiral catalyst; and performing post-treatment to obtain a chiral target compound. The method has the advantages of mild reaction conditions and simple operation process, and solves the problem of low chiral resolution yield in the prior art. And the obtained product has relatively high purity and yield.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing a milobarlin intermediate. Background Art

[0002] Mirogabalin (DS-5565) is a gabapentinoid developed by Daiichi Sankyo Co., Ltd. Similar to drugs such as gabapentin and pregabalin, it acts on the voltage-gated calcium channel subunit α2δ, and inhibits the release of calcium-mediated neurotransmitters in the dorsal fish by binding to α2δ-1, blocking neuronal excitation and sensory signal transmission. On January 8, 2019, it was approved for marketing by the Japanese Medical Device Evaluation and Approval Agency (PMDA) under the trade name Tarlige (oral tablets, each containing 2.5 mg, 5 mg, 10 mg, 15 mg of Mirogabalin), which is used to treat peripheral neuropathic pain, including diabetic peripheral neuropathy and postherpetic neuralgia. The structural formula of Mirogabalin besylate is as follows:

[0003]

[0004] CN101878193A patent reports the synthesis of milobalin. Among them, (±)-[(1R, 5S, 6S)-3-ethyl-6-(nitromethyl) bicyclo[3.2.0]hept-3-ene-6-yl] tert-butyl acetate is split to obtain [(1R, 5S, 6S)-3-ethyl-6-(nitromethyl) bicyclo[3.2.0]hept-3-ene-6-yl] tert-butyl acetate. Then, [(1R, 5S, 6S)-3-ethyl-6-(aminomethyl) bicyclo[3.2.0]hept-3-ene-6-yl] tert-butyl acetate is obtained by reduction with iron powder and ammonium chloride. The product is then hydrolyzed with hydrochloric acid-ethyl acetate solution to obtain [(1R, 5S, 6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid, which is then reacted with toluenesulfonic acid monohydrate to form milobarlin benzenesulfonate. The yield obtained by chiral resolution is not high, resulting in high overall production costs.

[0005]

[0006] Patent CN103562170B reports that aldehyde and propenol are used as starting materials, and the key intermediate 3-ethylbicyclo[3.2.0]hept-3-en-6-one is formed through acetal protection, Claisen rearrangement, Knoevenagel condensation reaction, and intramolecular [2+2] reaction; and then Horner–Wadsworth–Emmons reaction, nitromethane addition reaction, nitro reduction reaction, chiral resolution, and ester hydrolysis reaction are carried out to obtain milobarline.

[0007]

[0008] In addition, there is a document (Improved Synthesis Process of Milobaline Benzenesulfonate, Zheng Linri et al., Shandong Chemical Industry, 2021, 50, 56) reporting the use of n-butyraldehyde and diisobutylamine as starting materials, dehydration to form an enamine intermediate, and then addition reaction with 3-bromopropylene to form a quaternary ammonium salt, Knoevenagel condensation reaction, and intramolecular [2+2] reaction to form the key intermediate 3-ethylbicyclo[3.2.0]hept-3-en-6-one; the key intermediate is used for subsequent reactions to synthesize Milobaline.

[0009]

[0010] Through the analysis of existing technologies, it is found that an intermediate compound in the preparation process of milobarlin is relatively important. The structure is as follows:

[0011]

[0012] In the preparation process of milobalin, chiral splitting is used to obtain the isomer with S configuration of C6, i.e., [(1R, 5S, 6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-ene-6-yl]acetate, and the chiral splitting yield is not high, resulting in the waste of another configuration substance ([(1R, 5S, 6R)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-ene-6-yl]acetate). Or after the nitro group is reduced to amine, the splitting is also not high, and the production cost is increased, which is not conducive to industrial production. Therefore, how to prepare optically pure milobalin intermediate D with high yield and low cost has become another technical problem in the synthesis process of milobalin benzenesulfonate drug.

[0013]

[0014] [(1R,5S,6S)-3-Ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate Summary of the invention

[0015] The purpose of the present invention is to overcome the deficiencies in the prior art and provide a method for synthesizing a milobarlin intermediate, thereby solving the problem of low chiral separation yield in the prior art.

[0016] In order to achieve the above object, the present invention is implemented by the following scheme:

[0017] Compound A, nitromethane, compound B, catalyst C and base are added to the reaction container in sequence, and then a reaction solvent is added, and the system is stirred and reacted at a temperature of T. After detection, the reaction is complete, and the target product D is obtained after post-treatment;

[0018]

[0019] Wherein R is one of Me, Et, iPr, and tBu groups, preferably R is a tBu group.

[0020] In a preferred embodiment, the molar ratio of compound A, nitromethane, compound B, catalyst C and base is: 1:1-3:1-3:0.001-0.05:0.05-1; preferably: 1:1.2-2:1-1.5:0.01-0.03:0.2-0.5; further preferably 1:1.5:1.5:0.02:0.5.

[0021] In a preferred embodiment, the reaction solvent is one of acetonitrile, tetrahydrofuran, dichloromethane, N-methylpyrrolidone, chloroform, 1,2-dichloroethane, toluene, n-hexane, and 1,4-dioxane; preferably tetrahydrofuran.

[0022] In a preferred embodiment, the base is one of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, triethylamine, N,N-diisopropylethylamine (DIPEA), 1,1,3,3-tetramethylguanidine (TMG), 4-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO), N-methylmorpholine, and pyridine; preferably sodium carbonate or triethylamine.

[0023] In a preferred embodiment, the reaction temperature T is 10 to 50°C; preferably 20 to 25°C.

[0024] In a preferred embodiment, the catalyst C is one of catalyst C1, catalyst C2, catalyst C3 and catalyst C4; preferably: catalyst C3;

[0025] The corresponding structure is:

[0026]

[0027] The preferred embodiment, the post-treatment is as follows: the organic solvent in the reaction system is evaporated under reduced pressure, water is added to the concentrate, and then an extractant is added for extraction, the organic phase is collected, washed with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure, the organic solvent is removed, and the residue is separated and purified by silica gel column chromatography to obtain a colorless oil, which is the target product.

[0028] In a preferred embodiment, the extractant is one or more of ethyl acetate, dichloromethane, methyl tert-butyl ether, n-heptane, and toluene; preferably ethyl acetate or dichloromethane.

[0029] In a preferred embodiment, the silica gel column chromatography separation eluent is petroleum ether to ethyl acetate in a volume ratio of 200 to 400:1.

[0030] Compared with the prior art, the technical effects achieved by the present invention are:

[0031] The invention provides a method for preparing an optically pure milobarlin intermediate D by a "one-pot" efficient synthesis. The method can directly synthesize the optically pure milobarlin intermediate D without chiral separation, and has mild reaction conditions, simple operation, high yield, high chemical purity and high optical purity, and is suitable for industrial production. DETAILED DESCRIPTION

[0032] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention are all within the scope of protection claimed by the present invention.

[0033] Example 1

[0034] Synthesis of tert-butyl [(1R, 5S, 6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate

[0035]

[0036] In the reaction flask, (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one (13.6 g, 100.0 mmol), nitromethane (9.2 g, 150.0 mmol), tert-butyl acetate (17.4 g, 150.0 mmol), catalyst C3 (826.9 mg, 2.0 mmol) and triethylamine (5.1 g, 50.0 mmol) were added in sequence, and then tetrahydrofuran solvent (250 mL) was added, and the system was stirred and reacted at a temperature of 20-25 ° C. After detection, the reaction was completed. The organic solvent in the reaction system was evaporated under reduced pressure, water (300 mL) was added, and then ethyl acetate was added for extraction three times (300 mL×3), and the organic phase was collected, washed once with saturated brine, and dried over anhydrous sodium sulfate. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, and the residue was separated and purified by silica gel column chromatography (volume ratio of petroleum ether:ethyl acetate=300:1) to obtain pure tert-butyl [(1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate as a colorless oil with a yield of 95.8%, a purity of 99.6%, and an optical purity of 99%ee.

[0037] Example 2

[0038] Synthesis of tert-butyl [(1R, 5S, 6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate

[0039]

[0040] In the reaction flask, (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one (13.6 g, 100.0 mmol), nitromethane (9.2 g, 150.0 mmol), tert-butyl acetate (17.4 g, 150.0 mmol), catalyst C3 (2.1 g, 5.0 mmol) and triethylamine (5.1 g, 50.0 mmol) were added in sequence, and then tetrahydrofuran solvent (250 mL) was added, and the system was stirred and reacted at a temperature of 20-25 ° C. After detection, the reaction was completed. The organic solvent in the reaction system was evaporated under reduced pressure, water (300 mL) was added, and then ethyl acetate was added for extraction three times (300 mL×3), and the organic phase was collected, washed once with saturated brine, and dried over anhydrous sodium sulfate. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, and the residue was separated and purified by silica gel column chromatography (volume ratio of petroleum ether:ethyl acetate=200:1) to obtain pure tert-butyl [(1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate as a colorless oil with a yield of 94.3%, a purity of 99.5%, and an optical purity of 99%ee.

[0041] Example 3

[0042] Synthesis of tert-butyl [(1R, 5S, 6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate

[0043]

[0044] In the reaction flask, (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one (13.6 g, 100.0 mmol), nitromethane (9.2 g, 150.0 mmol), tert-butyl acetate (17.4 g, 150.0 mmol), catalyst C3 (41.3 mg, 0.1 mmol) and triethylamine (5.1 g, 50.0 mmol) were added in sequence, and then tetrahydrofuran solvent (250 mL) was added, and the system was stirred and reacted at a temperature of 20-25 ° C. After detection, the reaction was completed. The organic solvent in the reaction system was evaporated under reduced pressure, water (30 mL) was added, and then ethyl acetate was added for extraction three times (300 mL×3), and the organic phase was collected, washed once with saturated brine, and dried over anhydrous sodium sulfate. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, and the residue was separated and purified by silica gel column chromatography (volume ratio of petroleum ether:ethyl acetate=400:1) to obtain pure tert-butyl [(1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate as a colorless oil with a yield of 93.8%, a purity of 99.4%, and an optical purity of 98%ee.

[0045] Example 4

[0046] Synthesis of tert-butyl [(1R, 5S, 6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate

[0047]

[0048] In the reaction flask, (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one (13.6 g, 100.0 mmol), nitromethane (9.2 g, 150.0 mmol), tert-butyl acetate (17.4 g, 150.0 mmol), catalyst C3 (826.8 mg, 2.0 mmol) and triethylamine (5.1 g, 50.0 mmol) were added in sequence, and then tetrahydrofuran solvent (250 mL) was added, and the system was stirred and reacted at 30-35 ° C. After detection, the reaction was completed. The organic solvent in the reaction system was evaporated under reduced pressure, water (300 mL) was added, and then ethyl acetate was added for extraction three times (300 mL×3), and the organic phase was collected, washed once with saturated brine, and dried over anhydrous sodium sulfate. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, and the residue was separated and purified by silica gel column chromatography (volume ratio of petroleum ether:ethyl acetate=200:1) to obtain pure tert-butyl [(1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate as a colorless oil with a yield of 94.6%, a purity of 99.3%, and an optical purity of 98%ee.

[0049] Example 5

[0050] Synthesis of tert-butyl [(1R, 5S, 6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate

[0051]

[0052] In the reaction flask, (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one (13.6 g, 100.0 mmol), nitromethane (9.2 g, 150.0 mmol), tert-butyl acetate (17.4 g, 150.0 mmol), catalyst C1 (1.2 g, 2.0 mmol) and triethylamine (5.1 g, 50.0 mmol) were added in sequence, and then tetrahydrofuran solvent (250 mL) was added, and the system was stirred and reacted at a temperature of 10-15 ° C. After detection, the reaction was completed. The organic solvent in the reaction system was evaporated under reduced pressure, water (300 mL) was added, and then ethyl acetate was added for extraction three times (300 mL×3), and the organic phase was collected, washed once with saturated brine, and dried over anhydrous sodium sulfate. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, and the residue was separated and purified by silica gel column chromatography (volume ratio of petroleum ether:ethyl acetate=200:1) to obtain pure tert-butyl [(1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate as a colorless oil with a yield of 93.6%, a purity of 99.4%, and an optical purity of 99%ee.

[0053] Example 6

[0054] Synthesis of tert-butyl [(1R, 5S, 6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate

[0055]

[0056] In the reaction flask, (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one (13.6 g, 100.0 mmol), nitromethane (9.2 g, 150.0 mmol), tert-butyl acetate (17.4 g, 150.0 mmol), catalyst C2 (1.13 g, 2.0 mmol) and sodium carbonate (2.1 g, 20.0 mmol) were added in sequence, and then tetrahydrofuran solvent (250 mL) was added, and the system was stirred and reacted at a temperature of 20-25 ° C. After detection, the reaction was completed. The organic solvent in the reaction system was evaporated under reduced pressure, water (300 mL) was added, and then ethyl acetate was added for extraction three times (300 mL×3), and the organic phase was collected, washed once with saturated brine, and dried over anhydrous sodium sulfate. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, and the residue was separated and purified by silica gel column chromatography (volume ratio of petroleum ether:ethyl acetate=300:1) to obtain pure tert-butyl [(1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate as a colorless oil with a yield of 93.9%, a purity of 99.7%, and an optical purity of 99%ee.

[0057] Example 7

[0058] Synthesis of tert-butyl [(1R, 5S, 6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate

[0059]

[0060] In the reaction flask, (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one (13.6 g, 100.0 mmol), nitromethane (9.2 g, 150.0 mmol), tert-butyl acetate (17.4 g, 150.0 mmol), catalyst C4 (1.3 g, 2.0 mmol) and 4-dimethylaminopyridine (DMAP) (610.8 mg, 5.0 mmol) were added in sequence, and then tetrahydrofuran solvent (250 mL) was added, and the system was stirred and reacted at a temperature of 20-25 ° C. After detection, the reaction was completed. The organic solvent in the reaction system was evaporated under reduced pressure, water (300 mL) was added, and then dichloromethane was added for extraction three times (300 mL×3), and the organic phase was collected, washed once with saturated brine, and dried with anhydrous sodium sulfate. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, and the residue was separated and purified by silica gel column chromatography (volume ratio of petroleum ether:ethyl acetate=200:1) to obtain pure tert-butyl [(1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate as a colorless oil with a yield of 94.2%, a purity of 99.3%, and an optical purity of 99%ee.

[0061] Example 8

[0062]

[0063] In the reaction flask, (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one (13.6 g, 100.0 mmol), nitromethane (6.7 g, 110.0 mmol), tert-butyl acetate (17.4 g, 150.0 mmol), catalyst C3 (826.8 mg, 2.0 mmol) and triethylamine (5.1 g, 50.0 mmol) were added in sequence, and then tetrahydrofuran solvent (250 mL) was added, and the system was stirred and reacted at a temperature of 20-25 ° C. After detection, the reaction was completed. The organic solvent in the reaction system was evaporated under reduced pressure, water (300 mL) was added, and then ethyl acetate was added for extraction three times (300 mL×3), and the organic phase was collected, washed once with saturated brine, and dried over anhydrous sodium sulfate. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, and the residue was separated and purified by silica gel column chromatography (volume ratio of petroleum ether:ethyl acetate=300:1) to obtain pure tert-butyl [(1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate as a colorless oil with a yield of 92.8%, a purity of 97.6%, and an optical purity of 98%ee.

Claims

1. A method for synthesizing a milobarlin intermediate, characterized in that: Compound A, nitromethane, compound B, catalyst C and base are added to the reaction container in sequence, and then a reaction solvent is added, and the system is stirred and reacted at a temperature of T. After detection, the reaction is complete, and the target product D is obtained after post-treatment; Wherein R is one of Me, Et, iPr, and tBu groups, preferably R is a tBu group.

2. The synthesis method according to claim 1, characterized in that The molar ratio of compound A, nitromethane, compound B, catalyst C and base is: 1:1-3:1-3:0.001-0.05:0.05-1; preferably: 1:1.2-2:1-1.5:0.01-0.03:0.2-0.

5.

3. The synthesis method according to claim 1, characterized in that The reaction solvent is one of acetonitrile, tetrahydrofuran, dichloromethane, N-methylpyrrolidone, chloroform, 1,2-dichloroethane, toluene, n-hexane and 1,4-dioxane; preferably tetrahydrofuran.

4. The synthesis method according to claim 1, characterized in that The base is one of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, triethylamine, N,N-diisopropylethylamine (DIPEA), 1,1,3,3-tetramethylguanidine (TMG), 4-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO), N-methylmorpholine and pyridine; preferably sodium carbonate or triethylamine.

5. The synthesis method according to claim 1, characterized in that The reaction temperature T is 10-50°C, preferably 20-25°C.

6. The synthesis method according to claim 1, characterized in that The catalyst C is one of catalyst C1, catalyst C2, catalyst C3 and catalyst C4; preferably: catalyst C3; The corresponding structure is:

7. The synthesis method according to claim 1, characterized in that The post-treatment is as follows: the organic solvent in the reaction system is evaporated under reduced pressure, water is added to the concentrate, and then an extractant is added for extraction, the organic phase is collected, washed with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure, the organic solvent is removed, and the residue is separated and purified by silica gel column chromatography to obtain a colorless oil, which is the target product.

8. The synthesis method according to claim 7, characterized in that The extractant is one or more of ethyl acetate, dichloromethane, methyl tert-butyl ether, n-heptane and toluene; preferably ethyl acetate or dichloromethane.

9. The synthesis method according to claim 7, characterized in that: The silica gel column chromatography separation eluent is petroleum ether and ethyl acetate in a volume ratio of 200 to 400:1.

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