CN116903468B - Preparation method of milbelin intermediate - Google Patents

Preparation method of milbelin intermediate Download PDF

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CN116903468B
CN116903468B CN202310866405.2A CN202310866405A CN116903468B CN 116903468 B CN116903468 B CN 116903468B CN 202310866405 A CN202310866405 A CN 202310866405A CN 116903468 B CN116903468 B CN 116903468B
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hept
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CN116903468A (en
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翟立海
杨宇
王全龙
石莉莉
韩忠丽
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Shandong New Time Pharmaceutical Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
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    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
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    • C07C2602/20—All rings being cycloaliphatic the ring system containing seven carbon atoms

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Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a milabalin intermediate. Reacting (1R, 5S) -3-ethylbicyclo [3.2.0] hept-3-ene-6-one serving as a raw material with nitromethane to obtain (1R, 5S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-ene-6-ol, and further reacting with tert-butyl acetate substances under the action of alkali and a catalyst; the chiral target compound is obtained after post-treatment. The method has mild reaction conditions and simple operation process, solves the problem of low chiral resolution yield in the prior art, and the obtained product has higher purity and yield.

Description

Preparation method of milbelin intermediate
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a milabalin intermediate.
Background
Milobulin (Mirogabalin, DS-5565) is a gabapentin drug developed by the first Sanyo Co., ltd, and acts on the voltage gate calcium channel subunit alpha 2 delta, similar to gabapentin and pregabalin, and by binding to alpha 2 delta-1, inhibits the release of calcium ion mediated neurotransmitters in dorsal fish, blocking neuronal excitation and sensory signaling. Milobulin besylate (Mirogabalin besilate), developed by the first co-product of Japan, was approved by the Japanese medical device review batch Authority (PMDA) and marketed under the trade name Tarlige (oral tablets, each containing 2.5mg, 5mg, 10mg, 15mg of Mirogabalin) for the treatment of peripheral neuropathic pain, including diabetic peripheral neuropathic pain and postherpetic neuralgia. The structural formula of the milbelin benzenesulfonate is as follows:
CN103562170B reports the formation of the key intermediate 3-ethylbicyclo [3.2.0] hept-3-en-6-one via acetal protection, claisen rearrangement, clausiness guerbet condensation (Knoevenagel condensation reaction), intramolecular [2+2] reaction using aldehyde and propenol as starting materials; in addition, the literature (Milobalin besylate synthesis process improvement, zheng Linri, et al, shandong chemical industry, 2021, 50, 56) reports that n-butyraldehyde and diisobutylamine are used as starting materials, an enamine intermediate is formed after dehydration, then an addition reaction is carried out with 3-bromopropene to form a quaternary ammonium salt, a clauygel condensation reaction (Knoevenagel condensation reaction) and an intramolecular [2+2] reaction to form a key intermediate 3-ethylbicyclo [3.2.0] hept-3-en-6-one. Then, the key intermediate is subjected to a Horner-Waxwell-Emmons reaction (Horner-Wadsworth-Emmons reaction), nitromethane addition reaction, nitroreduction reaction, chiral resolution and ester hydrolysis reaction to obtain the Milobalin. Reducing [ 3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester, and resolving to obtain [ (1R, 5S, 6S) -6-aminomethyl-3-ethylbicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester. The yield is low, and the raw materials are wasted.
CN101878193a reports the synthesis of milobalin. Wherein, the (+/-) [ (1R, 5S, 6S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester is resolved to obtain [ (1R, 5S, 6S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester. And reducing with iron powder and ammonium chloride to obtain tert-butyl [ (1R, 5S, 6S) -3-ethyl-6- (aminomethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetate. Hydrolyzing 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 mixing with toluenesulfonic acid monohydrate to obtain the amisulbactam benzenesulfonate. In the route, the [ 3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester is firstly resolved and then reduced to obtain [ (1R, 5S, 6S) -6-aminomethyl-3-ethylbicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester, which is improved compared with the route of the prior reduction and resolution. However, resolution after all affects the yield of the overall route.
Analysis by prior art has found that an intermediate compound is important in the preparation of milabalin. The structure is as follows:
[ (1R, 5S, 6S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid ester
If the intermediate D can be synthesized, the problem of yield affecting the whole route due to resolution operation can be solved. Therefore, how to prepare the optically pure milabalin intermediate D with high yield and low cost has become another technical problem in the synthesis process of the milabalin benzenesulfonate drug.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides a preparation method of a milobalin intermediate. Solves the problem of low chiral resolution yield in the prior art. The invention has novel route and easily obtained raw materials, has higher yield and ee value compared with the prior art, and is suitable for industrial production.
In order to achieve the above object, the present invention is realized by the following means:
under the action of alkali and catalyst C, the compound A reacts with the compound B, and the chiral compound D is obtained after post-treatment. The reaction route is as follows:
wherein R is one of Me, et, iPr, tBu groups, preferably R is a tBu group.
The method specifically comprises the following operations:
sequentially adding a compound A, alkali, a catalyst C, a reaction solvent and a compound B into a reaction container, stirring the system at a temperature of T1 for reaction, detecting, and performing post-treatment after the reaction is finished to obtain a target product.
In a preferred scheme, the feeding mole ratio of the compound A to the compound B to the catalyst C to the alkali is 1:1-3:0.001-0.005:1-3, preferably 1:1.5:0.002:1.5.
Preferably, the reaction solvent is one of acetonitrile, tetrahydrofuran, N-methylpyrrolidone, toluene, N-hexane and 1, 4-dioxane, preferably one of acetonitrile and tetrahydrofuran, and more preferably tetrahydrofuran.
Preferably, the base is one of potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, N-Diisopropylethylamine (DIPEA), 1, 3-Tetramethylguanidine (TMG), 4-Dimethylaminopyridine (DMAP), 1, 4-diazabicyclo [2.2.2] octane (DABCO), N-methylmorpholine and pyridine, preferably one of sodium carbonate, triethylamine and N-methylmorpholine, and further preferably triethylamine.
Preferably, the reaction temperature T1 is-10 to 50 ℃, preferably 15 to 40 ℃, and more preferably 25 to 35 ℃.
Preferably, the catalyst C is catalyst C1 ([ 1,1' -bis (diphenylphosphine) ferrocene)]Palladium dichloride dichloromethane Complex) (Pd (dppf) Cl 2 .CH 2 Cl 2 ) Catalyst C2 (Tetratriphenylphosphine palladium) (Pd [ P (C) 6 H 5 ) 3 ] 4 ) Catalyst C3 (bis (1, 5-cyclooctadiene) iridium (Ir) chloride dimer) ([ Ir (1, 5-cod) Cl)] 2 ) One of them. Preferably: catalyst C1.
The corresponding structure is as follows:
preferably, the post-treatment comprises: evaporating the organic solvent in the reaction system under reduced pressure, adding water into the concentrate, adding an extractant for extraction, collecting an organic phase, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, removing the organic solvent, and separating and purifying the residue by using a silica gel column chromatography to obtain a colorless oily substance, namely the target product.
Preferably, the extractant is one or more of ethyl acetate, dichloromethane, methyl tertiary butyl ether, n-heptane and toluene; ethyl acetate or dichloromethane are preferred.
In a preferred scheme, the silica gel column chromatographic separation eluent is petroleum ether and ethyl acetate in a volume ratio of 200-400:1.
Wherein, compound a is prepared by the following method. The reaction route is as follows:
the preparation of compound A specifically comprises the following operations:
(1R, 5S) -3-ethylbicyclo [3.2.0]The hept-3-en-6-one is dissolved in an organic solvent, nitromethane and alkali are added, and the temperature T is controlled 2 Stirring for reaction, detecting, determining that the reaction is complete, and performing post-treatment to obtain the compound A.
Preferably, the organic solvent is one of tetrahydrofuran, dichloromethane, acetonitrile, ethyl acetate, toluene and 1, 4-dioxane; preferably: tetrahydrofuran.
Preferably, the alkali is one of sodium hydroxide, cesium carbonate, potassium hydroxide, N-Diisopropylethylamine (DIPEA), 1, 3-Tetramethylguanidine (TMG), 4-Dimethylaminopyridine (DMAP) and 1, 4-diazabicyclo [2.2.2] octane (DABCO); preferably: and (3) sodium hydroxide.
Preferably, the molar ratio of the (1R, 5S) -3-ethylbicyclo [3.2.0] hept-3-en-6-one to nitromethane to the alkali is as follows: 1:1-3:1-5; preferably: 1:1.5:2.
Preferably, the temperature T is controlled 2 The reaction temperature is: 20-80 ℃; preferably: 30-50 ℃.
Preferably, the post-treatment comprises: after the reaction was completed, an extractant and water were added to the reaction system, the aqueous layer was removed, then the organic layer was washed twice with water, dried over anhydrous sodium sulfate, spin-dried under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give compound a.
Preferably, the extractant is one of ethyl acetate and dichloromethane.
Preferably, the silica gel column chromatographic separation eluent is: petroleum ether: ethyl acetate: volume ratio of methanol=50-60:1:0.5.
Compared with the prior art, the invention has the technical effects that:
the invention provides a preparation method for efficiently synthesizing an optically pure milabalin intermediate D, which can directly synthesize the milabalin intermediate with high optical purity without chiral resolution, and has the advantages of easily available raw materials and intermediates, mild reaction conditions, simple process operation, easy purification after post-treatment, high yield, high chemical purity and high optical purity.
Drawings
FIG. 1 Compound A (1R, 5S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0]Hept-3-en-6-ol 1 H-NMR nuclear magnetic pattern.
FIG. 2 Compound A, (1R, 5S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0]Hept-3-en-6-ol 13 C-NMR nuclear magnetic pattern.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
Example 1
1) Synthesis of (1R, 5S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-ol
(1R, 5S) -3-ethylbicyclo [3.2.0] hept-3-en-6-one (500.0 g,3.7 mol) was dissolved in THF (1500 mL), nitromethane (336.0 g,5.5 mol) and sodium hydroxide (293.6 g,7.3 mol) were added, after the addition of the materials, the system was allowed to stand at 40℃and stirred for 3 hours, and after monitoring through a TCL panel, the reaction was determined to be complete, and ethyl acetate (3000 mL) and water (2000 mL) were added thereto. The aqueous layer was removed, the organic layer was washed twice with water (2000 mL), then dried over anhydrous sodium sulfate for 2 hours, dried under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate: methanol volume ratio=50:1:0.5), and the eluate was concentrated to dryness to give (1 r,5 s) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-ol as an oil in a yield of 97.9% and a purity of 99.6%; and (5) standby.
2) Synthesis of [ (1R, 5S, 6S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester
(1R, 5S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-ol (19.7 g,100.0 mmol), triethylamine (15.2 g,150.0 mmol), catalyst C1 (163.2 mg,0.2 mmol) and tetrahydrofuran solvent (250 mL) were added in this order, tert-butyl acetate (17.4 g,150.0 mmol) was added, the system was stirred at 25-35℃for reaction, and the reaction was detected to complete. The organic solvent in the reaction system was distilled off under reduced pressure, water (300 mL) was added, followed by extraction three times (300 mL. Times.3) with ethyl acetate, and the organic phase was collected, washed once with saturated brine, and dried over anhydrous sodium sulfate. Concentrating under reduced pressure, removing organic solvent, separating and purifying the residue by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio=300:1), concentrating the eluent to dryness to obtain colorless oily [ (1R, 5S, 6S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester pure product, wherein the yield is 93.8%, the purity is 99.7%, and the optical purity is 99% ee.
Example 2
Synthesis of [ (1R, 5S, 6S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester
(1R, 5S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-ol (19.7 g,100.0 mmol) [ synthesized as in step 1) of example 1 ], triethylamine (10.1 g,100.0 mmol), catalyst C1 (81.6 mg,0.1 mmol) and tetrahydrofuran solvent (250 mL) were sequentially added, tert-butyl acetate (11.6 g,100.0 mmol) was further added, the system was stirred at 25 to 35℃and reacted, and the reaction was detected. The organic solvent in the reaction system was distilled off under reduced pressure, water (300 mL) was added, followed by extraction three times (300 mL. Times.3) with ethyl acetate, and the organic phase was collected, washed once with saturated brine, and dried over anhydrous sodium sulfate. Concentrating under reduced pressure, removing organic solvent, separating and purifying the residue by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio=200:1), concentrating the eluent to dryness to obtain colorless oily [ (1R, 5S, 6S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester pure product, with the yield of 91.2%, the purity of 99.6% and the optical purity of 99% ee.
Example 3
Synthesis of [ (1R, 5S, 6S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester
(1R, 5S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-ol (19.7 g,100.0 mmol) [ synthesized as in step 1) of example 1 ], triethylamine (15.2 g,150.0 mmol), catalyst C1 (408.3 mg,0.5 mmol) and tetrahydrofuran solvent (250 mL) were sequentially added, tert-butyl acetate (17.4 g,150.0 mmol) was further added, the system was stirred at 25 to 35℃to react, and the reaction was detected to complete the reaction. The organic solvent in the reaction system was distilled off under reduced pressure, water (300 mL) was added, followed by extraction three times (300 mL. Times.3) with ethyl acetate, and the organic phase was collected, washed once with saturated brine, and dried over anhydrous sodium sulfate. Concentrating under reduced pressure, removing organic solvent, separating and purifying the residue by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio=300:1), concentrating the eluent to dryness to obtain colorless oily [ (1R, 5S, 6S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester pure product with the yield of 93.7%, the purity of 99.4% and the optical purity of 99% ee.
Example 4
Synthesis of [ (1R, 5S, 6S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester
(1R, 5S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-ol (19.7 g,100.0 mmol) [ synthesized as in step 1) of example 1 ], triethylamine (30.4 g,300.0 mmol), catalyst C1 (163.2 mg,0.2 mmol) and tetrahydrofuran solvent (250 mL) were sequentially added, tert-butyl acetate (17.4 g,150.0 mmol) was further added, the system was stirred at 25-35℃to react, and the reaction was detected to complete the reaction. The organic solvent in the reaction system was distilled off under reduced pressure, water (300 mL) was added, followed by extraction three times (300 mL. Times.3) with ethyl acetate, and the organic phase was collected, washed once with saturated brine, and dried over anhydrous sodium sulfate. Concentrating under reduced pressure, removing organic solvent, separating and purifying the residue by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio=300:1), concentrating the eluent to dryness to obtain colorless oily [ (1R, 5S, 6S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester pure product with the yield of 93.7%, the purity of 99.5% and the optical purity of 99% ee.
Example 5
Synthesis of [ (1R, 5S, 6S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester
(1R, 5S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-ol (19.7 g,100.0 mmol) [ synthesized as in step 1) of example 1 ], triethylamine (15.2 g,150.0 mmol), catalyst C1 (163.2 mg,0.2 mmol) and tetrahydrofuran solvent (250 mL) were sequentially added, tert-butyl acetate (17.4 g,150.0 mmol) was further added, the system was stirred at 40-50℃to react, and the reaction was detected to complete the reaction. The organic solvent in the reaction system was distilled off under reduced pressure, water (300 mL) was added, followed by extraction three times (300 mL. Times.3) with ethyl acetate, and the organic phase was collected, washed once with saturated brine, and dried over anhydrous sodium sulfate. Concentrating under reduced pressure, removing organic solvent, separating and purifying the residue by silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate=300:1), concentrating the eluent to dryness to obtain colorless oily [ (1R, 5S, 6S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester pure product, wherein the yield is 92.4%, the purity is 99.4%, and the optical purity is 98% ee.
Example 6
Synthesis of [ (1R, 5S, 6S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester
(1R, 5S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-ol (19.7 g,100.0 mmol) [ synthesized as in step 1) of example 1 ], triethylamine (15.2 g,150.0 mmol), catalyst C1 (163.2 mg,0.2 mmol) and acetonitrile solvent (250 mL) were sequentially added, tert-butyl acetate (17.4 g,150.0 mmol) was further added, the system was stirred at 15℃to react, and the reaction was detected and completed. The organic solvent in the reaction system was distilled off under reduced pressure, water (300 mL) was added, followed by extraction three times (300 mL. Times.3) with ethyl acetate, and the organic phase was collected, washed once with saturated brine, and dried over anhydrous sodium sulfate. Concentrating under reduced pressure, removing organic solvent, separating and purifying the residue by silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate=400:1), concentrating the eluent to dryness to obtain colorless oily [ (1R, 5S, 6S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester pure product, with the yield of 91.7%, the purity of 99.3% and the optical purity of 99% ee.
Example 7
Synthesis of [ (1R, 5S, 6S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester
(1R, 5S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-ol (19.7 g,100.0 mmol) [ synthesized as in step 1) of example 1 ], N-methylmorpholine (15.2 g,150.0 mmol), catalyst C3 (134.3 mg,0.2 mmol) and tetrahydrofuran solvent (250 mL) were sequentially added, tert-butyl acetate (17.4 g,150.0 mmol) was further added, the system was stirred at 25-35℃to react, and the reaction was detected. The organic solvent in the reaction system was distilled off under reduced pressure, water (300 mL) was added, followed by extraction three times (300 mL. Times.3) with ethyl acetate, and the organic phase was collected, washed once with saturated brine, and dried over anhydrous sodium sulfate. Concentrating under reduced pressure, removing organic solvent, separating and purifying the residue by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio=300:1), concentrating the eluent to dryness to obtain colorless oily [ (1R, 5S, 6S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester pure product, wherein the yield is 92.9%, the purity is 99.5%, and the optical purity is 99% ee.
Example 8
Synthesis of [ (1R, 5S, 6S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester
(1R, 5S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-ol (19.7 g,100.0 mmol) [ synthesized as in step 1) of example 1 ], sodium carbonate (15.9 g,150.0 mmol), catalyst C2 (231.1 mg,0.2 mmol) and tetrahydrofuran solvent (250 mL) were sequentially added, tert-butyl acetate (17.4 g,150.0 mmol) was further added, the system was stirred at 25-35℃to react, and the reaction was detected to complete the reaction. The organic solvent in the reaction system was distilled off under reduced pressure, water (300 mL) was added, followed by extraction three times (300 mL. Times.3) with ethyl acetate, and the organic phase was collected, washed once with saturated brine, and dried over anhydrous sodium sulfate. Concentrating under reduced pressure, removing organic solvent, separating and purifying the residue by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio=300:1), concentrating the eluent to dryness to obtain colorless oily [ (1R, 5S, 6S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl ] acetic acid tert-butyl ester pure product, with the yield of 93.3%, the purity of 99.3% and the optical purity of 97% ee.
Example 9
Synthesis of (1R, 5S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-ol
(1R, 5S) -3-ethylbicyclo [3.2.0] hept-3-en-6-one (500.0 g,3.7 mol) was dissolved in THF (1500 mL), nitromethane (336.0 g,5.5 mol) and sodium hydroxide (734.0 g,18.4 mol) were added, after the addition of the materials, the system was allowed to warm to 40℃and stirred for 3 hours, and after monitoring through a TCL panel, it was confirmed that the reaction was complete, and ethyl acetate (3000 mL) and water (2000 mL) were added thereto. The aqueous layer was removed, the organic layer was washed twice with water (2000 mL), then dried over anhydrous sodium sulfate for 2 hours, dried under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate: methanol volume ratio=50:1:0.5), and the eluate was concentrated to dryness to give (1 r,5 s) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-ol as an oil in a yield of 95.4% and a purity of 99.3%.
Example 10
Synthesis of (1R, 5S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-ol
(1R, 5S) -3-ethylbicyclo [3.2.0] hept-3-en-6-one (500.0 g,3.7 mol) was dissolved in THF (1500 mL), nitromethane (336.0 g,5.5 mol) and 1, 3-Tetramethylguanidine (TMG) (422.7 g,3.7 mol) were added, after the addition of the materials, the system was allowed to stand at 40℃for 3 hours with stirring, and after monitoring by a TCL panel, the reaction was determined to be complete, and ethyl acetate (3000 mL) and water (2000 mL) were added thereto. The aqueous layer was removed, the organic layer was washed twice with water (2000 mL), then dried over anhydrous sodium sulfate for 2 hours, dried under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate: methanol volume ratio=60:1:0.5), and the eluent was concentrated to dryness to give (1 r,5 s) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-ol as an oil in a yield of 93.9% and a purity of 99.2%.
Example 11
Synthesis of (1R, 5S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-ol
(1R, 5S) -3-ethylbicyclo [3.2.0] hept-3-en-6-one (500.0 g,3.7 mol) was dissolved in THF (1500 mL), nitromethane (336.0 g,5.5 mol) and sodium hydroxide (293.6 g,7.3 mol) were added, after the addition of the materials, the system was allowed to warm to 50℃and stirred for 3 hours, and after monitoring through a TCL panel, it was confirmed that the reaction was complete, and ethyl acetate (3000 mL) and water (2000 mL) were added thereto. The aqueous layer was removed, the organic layer was washed twice with water (2000 mL), then dried over anhydrous sodium sulfate for 2 hours, dried under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate: methanol volume ratio=50:1:0.5), and the eluate was concentrated to dryness to give (1 r,5 s) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-ol as an oil in a yield of 96.9% and a purity of 99.4%.
Example 12
Synthesis of (1R, 5S) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-ol
(1R, 5S) -3-ethylbicyclo [3.2.0] hept-3-en-6-one (500.0 g,3.7 mol) was dissolved in THF (1500 mL), nitromethane (336.0 g,5.5 mol) and sodium hydroxide (293.6 g,7.3 mol) were added, after the addition of the materials, the system was allowed to warm to 30℃and stirred for 3 hours, and after monitoring through a TCL panel, it was confirmed that the reaction was complete, and ethyl acetate (3000 mL) and water (2000 mL) were added thereto. The aqueous layer was removed, the organic layer was washed twice with water (2000 mL), then dried over anhydrous sodium sulfate for 2 hours, dried under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate: methanol volume ratio=50:1:0.5), and the eluate was concentrated to dryness to give (1 r,5 s) -3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-ol as an oil in a yield of 94.3% and a purity of 99.6%.

Claims (17)

1. A preparation method of a milbelin intermediate is characterized in that a compound A, alkali, a catalyst C, a reaction solvent and a compound B are sequentially added into a reaction container, a system temperature T1 is subjected to stirring reaction, detection is carried out, and a target product is obtained after the reaction is finished and post-treatment is carried out; the reaction route is as follows:
；
wherein R is one of Me, et, iPr and tBu groups;
the catalyst C is one of a catalyst C1, namely [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex, a catalyst C2, namely tetraphenylphosphine palladium, and a catalyst C3, namely bis (1, 5-cyclooctadiene) iridium chloride (Ir) dimer;
the corresponding structure is as follows:
；
the reaction temperature T1 is-10-50 ℃.
2. The method of claim 1, wherein R is a tBu group.
3. The preparation method of claim 1, wherein the molar ratio of the compound A to the compound B to the catalyst C to the alkali is 1:1-3:0.001-0.005:1-3.
4. The preparation method according to claim 1, wherein the feeding mole ratio of the compound A to the compound B to the catalyst C to the alkali is 1:1.5:0.002:1.5.
5. The preparation method of claim 1, wherein the base is one of potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, N-diisopropylethylamine, 1, 3-tetramethylguanidine, 4-dimethylaminopyridine, 1, 4-diazabicyclo [2.2.2] octane, N-methylmorpholine, and pyridine.
6. The preparation method of claim 1, wherein the base is one of sodium carbonate, triethylamine and N-methylmorpholine.
7. The process of claim 1 wherein the base is triethylamine.
8. The process according to claim 1, wherein the reaction temperature T1 is 15 to 40 ℃.
9. The process according to claim 1, wherein the reaction temperature T1 is 25 to 35 ℃.
10. The preparation method according to claim 1, wherein the catalyst C is a catalyst C1, namely [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex;
the corresponding structure is as follows:
。
11. the method according to claim 1, wherein the post-treatment: evaporating the organic solvent in the reaction system under reduced pressure, adding water into the concentrate, adding an extractant for extraction, collecting an organic phase, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, removing the organic solvent, and separating and purifying the residue by using a silica gel column chromatography to obtain a colorless oily substance, namely the target product.
12. The preparation method according to claim 1, wherein the compound a is prepared by the following method:
(1R, 5S) -3-ethylbicyclo [3.2.0]The hept-3-en-6-one is dissolved in an organic solvent, nitromethane and alkali are added, and the temperature T is controlled 2 Stirring for reaction, detecting, determining that the reaction is complete, and performing post-treatment to obtain a compound A; the reaction route is as follows:
；
the temperature T is controlled 2 The reaction temperature is: 20-80 ℃.
13. The preparation method according to claim 12, wherein the molar ratio of (1 r,5 s) -3-ethylbicyclo [3.2.0] hept-3-en-6-one, nitromethane and base: 1:1-3:1-5.
14. The preparation method according to claim 12, wherein the molar ratio of (1 r,5 s) -3-ethylbicyclo [3.2.0] hept-3-en-6-one, nitromethane and base: 1:1.5:2.
15. The method according to claim 12, wherein the temperature is controlled T 2 The reaction temperature is: 30-50 ℃.
16. The method according to claim 12, wherein the base is one of sodium hydroxide, cesium carbonate, potassium hydroxide, N-diisopropylethylamine, 1, 3-tetramethylguanidine, 4-dimethylaminopyridine, and 1, 4-diazabicyclo [2.2.2] octane.
17. The method of claim 12, wherein the base is sodium hydroxide.
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CN101878193A (en) * 2007-09-28 2010-11-03 第一三共株式会社 Bicyclic gamma-amino acid derivative
CN103562170A (en) * 2011-06-08 2014-02-05 第一三共株式会社 Method for producing bicyclic compound via claisen rearrangement
CN103987687A (en) * 2011-12-15 2014-08-13 第一三共株式会社 Optical resolution method for bicyclic compound using asymmetric catalyst
CN104245951A (en) * 2012-04-10 2014-12-24 第一三共株式会社 Optical resolution method for bicyclic compound using enzyme
CN107667097A (en) * 2015-05-27 2018-02-06 诺瓦色生物公司 The separation of the enantiomer of the bicyclic ketone of 3 alkene in [3.2.0] heptan 6 of 3 ethyls
CN115745764A (en) * 2022-12-08 2023-03-07 重庆华森制药股份有限公司 Preparation method of milobalin intermediate

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101878193A (en) * 2007-09-28 2010-11-03 第一三共株式会社 Bicyclic gamma-amino acid derivative
WO2010084798A1 (en) * 2009-01-21 2010-07-29 第一三共株式会社 Tricyclic compound
CN103562170A (en) * 2011-06-08 2014-02-05 第一三共株式会社 Method for producing bicyclic compound via claisen rearrangement
CN103987687A (en) * 2011-12-15 2014-08-13 第一三共株式会社 Optical resolution method for bicyclic compound using asymmetric catalyst
CN104245951A (en) * 2012-04-10 2014-12-24 第一三共株式会社 Optical resolution method for bicyclic compound using enzyme
CN107667097A (en) * 2015-05-27 2018-02-06 诺瓦色生物公司 The separation of the enantiomer of the bicyclic ketone of 3 alkene in [3.2.0] heptan 6 of 3 ethyls
CN115745764A (en) * 2022-12-08 2023-03-07 重庆华森制药股份有限公司 Preparation method of milobalin intermediate

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