Chiral synthesis method of miloabalin intermediate

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a chiral synthesis method of a milobalin intermediate. The method comprises the following steps: by taking (2ZE)-2-((1R, 5S)-3-ethyl bicyclo [3.2. 0] hept-3-ene-6-subunit) acetic acid alkyl ester substances as a raw material, carrying out asymmetric Michael addition reaction on the raw material and nitromethane under the action of a chiral catalyst, and carrying out post-treatment to obtain a chiral target compound. The method is mild in reaction condition, simple and convenient in operation process and low in production cost, and the product is relatively high in purity and yield.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a chiral synthesis method of 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, Mirogabalin besilate developed by Daiichi Sankyo Co., Ltd. was approved for marketing by the Japanese Medical Device Evaluation and Approval Agency (PMDA). The trade name is Tarlige (oral tablets, each containing 2.5mg, 5mg, 10mg, 15mg of Mirogabalin), which is used to treat peripheral neuropathic pain, including diabetic peripheral neuropathy and postherpetic neuralgia. The structural formula of Mirogabalin besilate 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. Then hydrolyze 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, and then react with toluenesulfonic acid monohydrate to form milobarlin benzenesulfonate. The yield obtained by chiral resolution is not high, resulting in high overall production costs, which is not conducive to industrial production, and further improvements are necessary.

[0005]

[0006] Patent CN103562170B reports that aldehyde and propenol are used as starting materials, and a key intermediate is formed through acetal protection, Claisen rearrangement, Knoevenagel condensation reaction, and intramolecular [2+2] reaction; then the key intermediate is subjected to Horner–Wadsworth–Emmons reaction, nitromethane addition reaction, nitro reduction reaction, ester hydrolysis reaction, and chiral resolution to obtain milobarline. This route has the following problems: 1) The intermediate 3-ethylbicyclo[3.2.0]hept-3-ene-6-one obtained is a racemic compound, which is directly reacted with dimethoxyphosphoryl acetate to obtain tert-butyl 3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene acetate, which is reacted with nitromethane under the action of DBU to obtain [3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-ene-6-yl]acetic acid tert-butyl ester, which is reduced by iron powder and ammonium chloride, and then split to obtain [(1R, 5S, 6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-ene-6-yl]acetic acid tert-butyl ester D-mandelate, and the split yield is: 29.4%. The splitting is used in the last step, resulting in waste of early materials and high preparation cost.

[0007]

[0008] In addition, there is a literature (Improved Synthesis Process of Milobarlin Benzene Sulfonate, 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 (Knoevenagel condensationreaction), intramolecular [2+2] reaction to form a key intermediate; the key intermediate is used for subsequent reaction to synthesize milobalin. Similarly, the intermediate 3-ethylbicyclo[3.2.0]hept-3-en-6-one is obtained as a racemic compound, which is directly reacted with dimethoxyphosphoryl acetate to obtain tert-butyl 3-ethylbicyclo[3.2.0]hept-3-en-6-ylidene acetate, which is reacted with nitromethane under the action of DBU to obtain [3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl] acetate tert-butyl ester, which is then reduced with Raney nickel and hydrazine hydrate, and then split to obtain [(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl] acetate tert-butyl ester D-mandelate, which is then hydrolyzed and reacted with benzenesulfonic acid to obtain milobalin benzenesulfonate. It faces problems such as low overall reaction yield and high production cost.

[0009]

[0010] In the existing milobalin synthesis technology, 3-ethylbicyclo[3.2.0]hept-3-en-6-one or its chiral isomer (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one is used as a key intermediate or starting material to synthesize milobalin. Among them, using the chiral isomer (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one as a starting material can reduce the amount of materials used in the subsequent reaction process by half. Therefore, the chiral isomer (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one is selected as the starting material to carry out the synthesis of milobalin; however, in the prior art, another problem is that the chiral resolution is used in the preparation process of milobalin to obtain the isomer with S configuration of C6, i.e., [(1R, 5S, 6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate, and the chiral resolution 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-en-6-yl]acetate), increasing the production cost and being unfavorable for industrial production. Therefore, how to prepare the optically pure milobalin intermediate D with high yield and low cost has become another technical problem in the synthesis process of milobalin benzenesulfonate drug.

[0011]

[0012] [(1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate Summary of the invention

[0013] The purpose of the present invention is to overcome the deficiencies in the prior art and provide a chiral synthesis method for a milobarlin intermediate.

[0014] In order to achieve the above object, the present invention is implemented by the following scheme:

[0015] Compound A undergoes an asymmetric Michael addition reaction with nitromethane under the action of a chiral catalyst C, and a chiral compound D is obtained after post-treatment. The reaction route is as follows:

[0016]

[0017] Wherein R is one of Me, Et, Pr, iPr, Bu and tBu groups; preferably, R is one of Et and tBu groups, and more preferably, R is tBu group.

[0018] The specific operations include:

[0019] Compound A, catalyst C, nitromethane are added to the reaction container in sequence, and then the reaction solvent is added, and the system is stirred and reacted at the temperature T1, and the reaction is completed after detection. The target product is obtained after post-treatment.

[0020] In a preferred embodiment, the molar ratio of the compound A, nitromethane and catalyst C is: 1:1-10:0.001-0.05; preferably: 1:3-6:0.01-0.03.

[0021] In a preferred embodiment, the reaction solvent is one of tetrahydrofuran, dichloromethane, N-methylpyrrolidone, chloroform, toluene, n-hexane, and 1,4-dioxane, with tetrahydrofuran and dichloromethane being further preferred, and tetrahydrofuran being even more preferred.

[0022] In a preferred embodiment, the reaction temperature T1 is -10 to 50°C, preferably -5 to 35°C, and more preferably 20 to 25°C.

[0023] In a preferred embodiment, the catalyst C is one of catalyst C1, catalyst C2 and catalyst C3. Preferably: catalyst C1.

[0024] The corresponding structure is:

[0025]

[0026] 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.

[0027] In a preferred embodiment, the extractant is one or a combination of ethyl acetate, dichloromethane, methyl tert-butyl ether, n-heptane, and toluene, preferably ethyl acetate or dichloromethane.

[0028] 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.

[0029] Wherein, compound A can be prepared according to the relevant methods in patents CN104755456A, CN102356061A, and CN101878193A. The Wittig-Horner reagent in the method is selected from: tert-ButylO,O-dimethylphosphonoacetate, (diethoxyphosphino)ethyl acetate (EthylDiethylphosphonoacetate), ethyl dimethylphosphonoacetate (Ethyldimethylphosphonoacetate), methyl diethylphosphonoacetate (Methyl diethylphosphonoacetate), isopropyl(dimethylphosphono)acetate, propyl2-dimethoxyphosphorylacetate, and butyl2-dimethoxyphosphorylacetate. The reaction route is as follows:

[0030]

[0031] R is one of Me, Et, Pr, iPr, Bu, and tBu groups, that is, the product obtained by selecting the above-mentioned different Wittig-Horner reagents.

[0032] Compared with the prior art, the technical effects achieved by the present invention are:

[0033] The invention provides a method for preparing an optically pure milobarlin intermediate D by efficiently synthesizing the same. The method can directly synthesize the milobarlin intermediate with high optical purity without chiral separation, and has mild reaction conditions, simple operation, high yield, high chemical purity and high optical purity.

[0034] The intermediate D prepared by the present invention can directly obtain a single chiral milobarlin molecule without chiral separation, with high optical purity and high yield. DETAILED DESCRIPTION

[0035] 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.

[0036] Example 1

[0037] 1) Synthesis of tert-butyl (2ZE)-2-((1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-ylidene)acetate

[0038]

[0039] Potassium tert-butoxide (123.0 g, 1.10 mol) was dissolved in THF (2000 mL). The solution was cooled to 5-10° C., and then tert-butyl dimethoxyphosphonoacetate (246.6 g, 1.10 mol) and (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one (136.2 g, 1.00 mol) were added dropwise thereto, respectively. The mixture was stirred at room temperature for 3 hours, and then ethyl acetate (2000 mL) and water (1500 mL) were added thereto. The aqueous layer was removed, and the organic layer was washed twice with water (1000 mL), then dried over anhydrous sodium sulfate for 3 hours, and dried under reduced pressure. The residue was separated and purified by silica gel column chromatography (volume ratio of petroleum ether: ethyl acetate = 150: 1) to obtain oily (2ZE)-2-((1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene)acetate in a yield of 96.4%; set aside.

[0040] 2) Synthesis of tert-butyl [(1R, 5S, 6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate

[0041]

[0042] In the reaction flask, tert-butyl (2ZE)-2-((1R,5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene)acetate (7.0g, 29.87mmol), catalyst C1 (378.4mg, 0.60mmol), nitromethane (5.5g, 90.16mmol) were added in sequence, and then tetrahydrofuran solvent (50mL) 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, 50mL of water was added, and then ethyl acetate was added for extraction three times (60mL×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 96.8%, a purity of 99.5%, and an optical purity of 99%ee.

[0043] 1H NMR(500MHz,Chloroform-d)δ5.31(s,1H),4.80(d,J=12.4Hz,1H),4.56(d,J=12.5Hz,1H),2.39(m,1H),2.33(m,1H),2.29(m,1H),2.25(d,J= 12.4Hz,1H),2.13(m,2H),2.06(d,J=12.4Hz,1H),1.94(m,1H),1.90(m,1H),1.60(dd,J=13.0,6.8Hz,1H),1.42(s,9H),1.11(t,J=8.0Hz,3H).

[0044] 13 C NMR (125MHz, Chloroform-d) δ172.9,143.2,127.9,84.7,81.4,47.2,46.6,41.2,38.4,35.3,30.0,28.6(3C),23.4,12.3.

[0045] Example 2

[0046]

[0047] In the reaction flask, tert-butyl (2ZE)-2-((11R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene)acetate (prepared according to step 1 in Example 1)) (7.0 g, 29.87 mmol), catalyst C1 (189.2 mg, 0.30 mmol), nitromethane (5.5 g, 90.16 mmol) were added in sequence, and then tetrahydrofuran solvent (50 mL) was added, and the system was stirred and reacted at a temperature of 20 to 25 ° C. After detection, the reaction was completed. The organic solvent in the reaction system was evaporated under reduced pressure, 50 mL of water was added, and then ethyl acetate was added for extraction three times (60 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 94.2%, a purity of 99.3%, and an optical purity of 99%ee.

[0048] Example 3

[0049]

[0050] In the reaction flask, tert-butyl (2ZE)-2-((1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene)acetate (prepared according to step 1 in Example 1)) (7.0 g, 29.87 mmol), catalyst C1 (567.5 mg, 0.90 mmol), nitromethane (5.5 g, 90.16 mmol) were added in sequence, and then tetrahydrofuran solvent (50 mL) was added, and the system was stirred and reacted at a temperature of 20 to 25 ° C. After detection, the reaction was completed. The organic solvent in the reaction system was evaporated under reduced pressure, 50 mL of water was added, and then ethyl acetate was added for extraction three times (60 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 96.3%, a purity of 99.2%, and an optical purity of 99%ee.

[0051] Example 4

[0052]

[0053] In the reaction flask, tert-butyl (2ZE)-2-((1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene)acetate (prepared according to step 1 in Example 1)) (7.0 g, 29.87 mmol), catalyst C1 (18.9 mg, 0.03 mmol), nitromethane (5.5 g, 90.16 mmol) were added in sequence, and then tetrahydrofuran solvent (50 mL) was added, and the system was stirred and reacted at a temperature of 20 to 25 ° C. After detection, the reaction was completed. The organic solvent in the reaction system was evaporated under reduced pressure, 50 mL of water was added, and then ethyl acetate was added for extraction three times (60 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 93.3%, a purity of 99.0%, and an optical purity of 98% ee.

[0054] Example 5

[0055]

[0056] In the reaction flask, tert-butyl (2ZE)-2-((1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene)acetate (prepared according to step 1 in Example 1)) (7.0 g, 29.87 mmol), catalyst C1 (945.9 mg, 1.50 mmol), nitromethane (5.5 g, 90.16 mmol) were added in sequence, and then tetrahydrofuran solvent (50 mL) was added, and the system was stirred and reacted at a temperature of 20 to 25 ° C. After detection, the reaction was completed. The organic solvent in the reaction system was evaporated under reduced pressure, 50 mL of water was added, and then ethyl acetate was added for extraction three times (60 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 96.5%, a purity of 99.0%, and an optical purity of 98%ee.

[0057] Example 6

[0058] 1) Synthesis of ethyl (2ZE)-2-((1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-ylidene)acetate

[0059]

[0060] Sodium tert-butoxide (7.4 g, 77.17 mmol) was dissolved in THF (50 mL). The solution was cooled to 10 ° C or lower. Then, (diethoxyphosphino) ethyl acetate (17.3 g, 77.17 mmol) and (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-one (10.0 g, 73.42 mmol) were added dropwise thereto respectively. The mixture was stirred at room temperature for 3 hours, and then toluene (85 mL) and water (40 mL) were added thereto. The water layer was removed, the organic layer was washed twice with water (20 mL) and concentrated, and the residue was separated and purified by silica gel column chromatography (volume ratio of petroleum ether: ethyl acetate = 150: 1) to obtain oily (2ZE)-2-((1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene) ethyl acetate, with a yield of 93.7%. Set aside.

[0061] 2) Synthesis of ethyl [(1R, 5S, 6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate

[0062]

[0063] Ethyl (2ZE)-2-((1R,5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene)acetate (8.4g, 40.72mmol), catalyst C2 (522.1mg, 0.81mmol), nitromethane (5.5g, 90.16mmol) were added to the reaction bottle in sequence, and then 1,4-dioxane solvent (50mL) was added, and the system was stirred and reacted at 25-30°C. After detection, the reaction was completed. The organic solvent in the reaction system was evaporated under reduced pressure, 50mL of water was added, and then ethyl acetate was added for extraction three times (60mL×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 ethyl [(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 96.4%, a purity of 99.4%, and an optical purity of 99% ee.

[0064] 1 H NMR(500MHz,Chloroform-d)δ5.47(s,1H),4.72(d,J=12.3Hz,1H),4.59(m,1H) ,4.38(d,J=12.3Hz,1H),4.02(m,1H),2.36(d,J=12.3Hz,1H),2.29(m,1H),2.20 (m,1H),2.15(m,1H),2.09(m,1H),2.06(m,2H),1.90(d,J=12.3Hz,1H),1.76(m, 1H), 1.59 (dd, J=12.8, 6.4Hz, 1H), 1.17 (t, J=8.0Hz, 3H), 1.05 (t, J=8.0Hz, 3H).

[0065] 13 C NMR (125MHz, Chloroform-d) δ173.2,143.2,127.9,84.6,60.1,47.2,46.6,39.4,38.3,35.2,30.04,23.3,14.1,12.4.

[0066] Example 7

[0067] 1) Synthesis of methyl (2ZE)-2-((1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-ylidene)acetate

[0068]

[0069] Sodium tert-butoxide (7.4 g, 77.17 mmol) was dissolved in THF (50 mL), and the solution was cooled to 10°C or lower. Then, (diethoxyphosphino) methyl acetate (16.2 g, 77.17 mmol) and (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-one (10.0 g, 73.42 mmol) were added dropwise thereto respectively. The mixture was stirred at room temperature for 3 hours, and then toluene (85 mL) and water (40 mL) were added thereto. The water layer was removed, the organic layer was washed twice with water (20 mL) and concentrated, and the residue was separated and purified by silica gel column chromatography (volume ratio of petroleum ether: ethyl acetate = 150:1) to obtain oily (2ZE)-2-((1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene) methyl acetate, with a yield of 92.8%. Set aside.

[0070] 2) Synthesis of methyl [(1R, 5S, 6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate

[0071]

[0072] In the reaction flask, (2ZE)-2-((1R,5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene)acetic acid methyl ester (7.8g, 40.57mmol), catalyst C3 (510.8mg, 0.81mmol), nitromethane (5.5g, 90.16mmol) were added in sequence, and then tetrahydrofuran solvent (50mL) was added, and the system was stirred and reacted at -5 to 0°C. After detection, the reaction was completed. The organic solvent in the reaction system was evaporated under reduced pressure, 50mL of water was added, and then ethyl acetate was added for extraction three times (60mL×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=250:1) to obtain pure colorless oily [(1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetic acid methyl ester with a yield of 96.0%, a purity of 99.2%, and an optical purity of 99%ee.

[0073] 1H NMR(500MHz,Chloroform-d)δ5.33(s,1H),4.82(d,J=12.5Hz,1H),4.38(d,J=12.5Hz,1H),3.64(s,3H),2.43(m,1H),2.33(m,2H) ,2.24(m,1H),2.12(m,2H),1.96(dd,J=13.0,6.9Hz,1H),1.91(d,J=12.5Hz,1H),1.85(m,1H),1.57(m,1H),1.09(t,J=8.0Hz,3H).

[0074] 13 C NMR (125MHz, Chloroform-d) δ173.8,143.2,127.9,84.6,51.8,47.2,46.6,38.4,37.2,35.2,30.0,23.3,12.4.

[0075] Example 8

[0076] 1) Synthesis of Isopropyl (2ZE)-2-((1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-ylidene)acetate

[0077]

[0078] Sodium tert-butoxide (7.4 g, 77.17 mmol) was dissolved in THF (50 mL), and the solution was cooled to 10°C or lower. Then, dimethoxyphosphonoacetic acid isopropyl ester (16.2 g, 77.17 mmol) and (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-one (10.0 g, 73.42 mmol) were added dropwise thereto respectively. The mixture was stirred at room temperature for 3 hours, and then toluene (85 mL) and water (40 mL) were added thereto. The water layer was removed, and then the organic layer was washed twice with water (20 mL) and concentrated. The residue was separated and purified by silica gel column chromatography (volume ratio of petroleum ether: ethyl acetate = 150:1) to obtain oily (2ZE)-2-((1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene) acetate isopropyl ester, with a yield of 93.5%. Set aside.

[0079] 2) Synthesis of isopropyl [(1R, 5S, 6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate

[0080]

[0081] In the reaction flask, (2ZE)-2-((1R,5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene)acetic acid isopropyl ester (7.8g, 35.40mmol), catalyst C1 (447.7mg, 0.71mmol), nitromethane (5.5g, 90.16mmol) were added in sequence, and then dichloromethane solvent (50mL) 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, 50mL of water was added, and then ethyl acetate was added for extraction three times (60mL×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=250:1) to obtain pure isopropyl [(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 96.1%, a purity of 99.2%, and an optical purity of 99% ee.

[0082] 1 H NMR(500MHz,Chloroform-d)δ5.47(s,1H),5.03(m,1H),4.72(d,J=12.4Hz,1 H),4.38(d,J=12.3Hz,1H),2.36(d,J=12.5Hz,1H),2.27(m,1H),2.19(m,2H), 2.10(m,3H),1.91(d,J=12.5Hz,1H),1.79(dd,J=17.1,6.6,1.3Hz,1H),1.60 (dd,1H),1.19(d,J=6.8Hz,3H),1.13(d,J=6.8Hz,3H),1.04(t,J=8.0Hz,3H).

[0083] 13 C NMR (125MHz, Chloroform-d) δ173.7,143.2,127.9,84.5,68.3,47.2,46.7,39.7,38.4,35.3,30.0,23.3,21.9(2C),12.4.

[0084] Synthesis of Milobalin Benzenesulfonate

[0085] Step 1:

[0086] Add the compound [(1R, 5S, 6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetic acid tert-butyl ester (5.9 g, 20.00 mmol) into the reaction bottle, then add ammonium chloride (1.6 g, 30.00 mmol), anhydrous ethanol (90 mL) and purified water (30 mL), add reduced iron powder (5.6 g, 100.00 mmol) under stirring, raise the temperature to 70-85 ° C and keep the reaction until the reaction is completed after detection. The reaction solution was filtered with diatomaceous earth, 50 mL of water was added to the filtrate, and the mixture was extracted three times with dichloromethane (60 mL×3). The organic phase was then washed with water (100 mL), saturated sodium bicarbonate (100 mL), and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and dried under reduced pressure to give 4.7 g of oily tert-butyl 2-((1R, 5S, 6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate, which was used for the reaction in step 2.

[0087] Step 2:

[0088] Add tert-butyl 2-((1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate (4.3g, 16.20mmol) to the reaction bottle, then add dichloromethane (50mL), add concentrated hydrochloric acid (8mL, 96.00mmol) under low temperature conditions, after adding, heat to 25°C and stir to react until the reaction is complete as detected by TLC plate. Remove the organic solvent under reduced pressure, add 20% sodium hydroxide solution to adjust the pH value to 4-6, precipitate a large amount of solids, filter under reduced pressure, and then dry to obtain 3.1g of milopalline with an optical purity of 99.5%ee.

[0089] Step 3:

[0090] Weigh milobalin (2.9 g, 13.86 mmol), add acetonitrile (25 mL), stir, then add benzenesulfonic acid (2.3 g, 14.45 mmol), then stir at 25 ° C to form salt for 2 hours, then cool to 10 ° C and stir for crystallization for 1 hour, reduce pressure and filter to obtain 4.9 g milobalin benzenesulfonate, with a purity of 99.5% and an optical purity of 100% ee.

Claims

1. A chiral synthesis method of a milobarlin intermediate, characterized in that: Compound A, catalyst C, and nitromethane are added to the reaction container in sequence, and then the reaction solvent is added, and the system is stirred and reacted at a temperature of T1. After detection, the reaction is complete, and the target product is obtained after post-treatment; the reaction route is as follows: Wherein R is one of Me, Et, Pr, iPr, Bu, tBu groups.

2. The synthesis method according to claim 1, characterized in that The molar ratio of the compound A, nitromethane and catalyst C is: 1:1-10:0.001-0.05; preferably: 1:3-6:0.01-0.

03.

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

4. The synthesis method according to claim 1, characterized in that The reaction temperature T1 is -10 to 50°C; preferably -5 to 35°C.

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

6. 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.

7. The synthesis method according to claim 6, characterized in that The extractant is one or a combination of ethyl acetate, dichloromethane, methyl tert-butyl ether, n-heptane and toluene, preferably ethyl acetate or dichloromethane.

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