CN106543119B - Preparation method of optically pure tasimelteon - Google Patents

Preparation method of optically pure tasimelteon Download PDF

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CN106543119B
CN106543119B CN201610841203.2A CN201610841203A CN106543119B CN 106543119 B CN106543119 B CN 106543119B CN 201610841203 A CN201610841203 A CN 201610841203A CN 106543119 B CN106543119 B CN 106543119B
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dihydro
methylamine
benzofuranyl
cyclopropyl
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CN106543119A (en
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张兴贤
宓森阳
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Zhejiang University of Technology ZJUT
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Zhejiang University of Technology ZJUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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Abstract

The invention provides a synthesis method of tasimelteon, which comprises the following steps: the racemic body shown in the formula I is trans- [2- (2, 3-dihydro-4-benzofuranyl) cyclopropyl]Dissolving methylamine and an optically pure resolving agent in a solvent A, stirring and reacting for 2-5 hours at 0-70 ℃, and carrying out aftertreatment on the obtained reaction mixture to obtain (1R, 2R) - [2- (2, 3-dihydro-4-benzofuranyl) cyclopropyl as shown in formula II]A methylamine; dissolving the obtained product in a solvent B, adding triethylamine, adding propionyl chloride under the protection of nitrogen, stirring and reacting for 1-2 hours at 25 ℃, and carrying out aftertreatment on the obtained reaction liquid to obtain the optically pure tasimelteon shown in the formula III. The method has the advantages of mild reaction conditions, simple and convenient operation, high yield, low production cost and good product quality, is suitable for industrial production, and has greater practical application value and social and economic benefits.

Description

A kind of preparation method of optical voidness Ta Simeiqiong
(1) technical field
The present invention relates to the preparation methods of optical voidness anti-insomnia drug Ta Simeiqiong a kind of.
(2) background technique
The present invention is more particularly directed to the synthesis of the anti-insomnia drug Ta Simeiqiong with significant curative effect, the structural formulas of Ta Simeiqiong It is as follows:
The non-24 hours sleep arousal disorders of blind person are chronic circadian rhythm (biological clock) diseases of one kind in blind person Cause sleeping time problem.Non- 24 occur in the crowd having a sleepless night completely, and light does not enter their eyes and they cannot make Its biological clock and 24 hours dark cycle synchronisations.
The Hetlioz (trade name), i.e. Ta Simeiqiong of FDA on January 31 approval Vanda pharmacy in 2014 (Tasimelteon) capsule, melatonin (melatonin) MT1 and MT2 receptor stimulating agent, for treating patient as blind as a bat In non-24- hours sleep arousal disorders (" non-24 ").
The synthetic method of Ta Simeiqiong generally takes optically pure (1R, 2R)-[2- (2,3- dihydro -4- benzene in the prior art And furyl) cyclopropyl] methylamine as intermediate further reacted with propionyl chloride synthesis Ta Simeiqiong.(1R, 2R)-[2- (2,3- Dihydro -4- benzofuranyl) cyclopropyl] methylamine structure is as follows:
U.S. Patent application US5856529, for starting material, is condensed with 2,3- Dihydrobenzofuranes -4- formaldehyde with malonic acid Reaction obtains 2,3- Dihydrobenzofuranes -4- acrylic acid, then with (-) -2,10- camphor sulfonamide combines and is catalysis with palladium acetate Agent carries out Cyclopropanated, constructs chiral cyclopropane using the asymmetric induction of camphorsulfonic acid, obtain through functional group conversions (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, finally reacts to obtain optical voidness Ta Simeiqiong with propionyl chloride.
U.S. Patent application US123389 is starting material using 2,3- diethylene glycol phenol, first obtains important intermediate 4- Asymmetric ring then occurs under the action of chiral rhodium catalyst with ethyl diazoacetate for vinyl-2,3-dihydrobenzofuran It is monocyclopropanated to obtain optically pure (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] Ethyl formate, then through ammonolysis, Reduction obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, finally obtains optical voidness Ta Simeiqiong.
Chinese patent application CN102675268A is then with (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl Base] formic acid be raw material, be directly over chlorination, ammonolysis, functional group's isomerate process of reduction prepares (1R, 2R)-[2- (2,3- bis- Hydrogen -4- benzofuranyl) cyclopropyl] methylamine, the pure Ta Simeiqiong of synthesizing optical.
The purpose of the above method is by obtaining (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] first Amine is as intermediate, the pure Ta Simeiqiong of further synthesizing optical.But there are raw material risk height, reactions for synthetic method The disadvantages of condition is harsh, expensive catalyst, stereoselectivity is not high, it is difficult to realize industry amplification.For of the existing technology Problem, the invention proposes a kind of improved methods to obtain (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] Methylamine, then prepare optical voidness Ta Simeiqiong.
(3) summary of the invention
The purpose of the present invention is to provide the preparation methods of optical voidness Ta Simeiqiong a kind of, and simple process, product are pure Degree is high.
The technical solution adopted by the invention is as follows:
A kind of preparation method of optical voidness Ta Simeiqiong, the method carry out as follows:
(1) by raceme shown in Formulas I it is trans--[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, optical voidness Resolving agent is dissolved in solvent A, is stirred to react at 0~70 DEG C 2~5 hours, and gained reaction mixture is post-treated to obtain Formula II Shown in (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine；Raceme shown in the Formulas I is trans-- The ratio between amount of substance of [2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine and optical voidness resolving agent is 1~3:1；Institute The optical voidness resolving agent stated is D-10- camphorsulfonic acid, D- mandelic acid, D- dibenzoyl tartaric acid, D- tartaric acid, the sweet ammonia of D- benzene Acid, D-phenylalanine or D- bis- are to toluyl tartaric acid；
(2) by (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] first shown in Formula II obtained by step (1) Amine is dissolved in solvent B, and triethylamine is added, propionyl chloride is added under nitrogen protection, 1~2h is stirred to react at 25 DEG C, gained is anti- Answer liquid is post-treated to obtain optical voidness Ta Simeiqiong shown in formula III；(1R, 2R)-shown in the Formula II [2- (2,3- dihydros- 4- benzofuranyl) cyclopropyl] methylamine, triethylamine and propionyl chloride the ratio between the amount of substance be 1:1.6~1.9:1.3~1.6.
Optical voidness resolving agent described in preparation method of the present invention can resolution raceme it is trans--[2- (2,3- bis- Hydrogen -4- benzofuranyl) cyclopropyl] methylamine prepares (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine Solid salt.
Further, the preferably described optical voidness resolving agent is D- camphorsulfonic acid.
Further, preferably described optical voidness resolving agent and raceme it is trans--[2- (2,3- dihydro -4- benzofurans Base) cyclopropyl] the ratio between the amount of substance of methylamine is 1:2.
Further, solvent A described in the step (1) be water, methanol, ethyl alcohol, isopropanol, acetone, methylene chloride or Tetrahydrofuran；Further, preferably methanol, ethyl alcohol.
Further, in the step (1) solvent A volumetric usage with raceme shown in Formulas I it is trans--[2- (2,3- Dihydro -4- benzofuranyl) cyclopropyl] methylamine quality is calculated as 15~100mL/g；Further, preferably 30~50mL/g.
Further, the post-processing approach of step of the present invention (1) reaction mixture are as follows:, will be anti-after fully reacting Mixture is answered to filter to obtain solid salt, the solid salt is soluble in water, inorganic base is added, adjusts pH to 10~12, usually PH is adjusted with the aqueous solution of inorganic base, stirs dissolved clarification later.Add ethyl acetate extraction, be evaporated off after solvent be drying to obtain it is described (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine；The inorganic base is sodium hydroxide, hydroxide Potassium, lithium hydroxide, sodium carbonate or potassium carbonate.
Further, recommend the post-processing approach of reaction mixture in the step (1) are as follows:, will be anti-after fully reacting Mixture is answered first to use the mixed solvent recrystallization of water, methanol, acetone, suction filtration obtains (1R, 2R)-[2- (2,3- dihydro -4- benzos Furyl) cyclopropyl] methylamine solid salt；The mixed solvent is water: methanol: acetone=1~5:0.5~5:50~100；Again Further, the preferably described mixed solvent is water: methanol: acetone=1~3:0.5~2:50~70.Further, preferably described Reaction temperature is 25~40 DEG C in step (2).
Further, solvent B described in the step (2) is methylene chloride, chloroform, toluene, tetrahydrofuran, 2- methyl four Hydrogen furans or acetonitrile.
Further, the volumetric usage of solvent B described in the step (2) with (1R, 2R)-shown in Formula II [2- (2, 3- dihydro -4- benzofuranyl) cyclopropyl] quality of methylamine is calculated as 20~35mL/g.
The present invention recommends the post-processing approach of described step (2) reaction solution are as follows: 1~2mol/L is added in gained reaction solution Dilute hydrochloric acid adjusts pH=5~6, carries out pickling through washing, saturated sodium bicarbonate solution, washes again, solvent is evaporated off i.e. in acquired solution Obtain the optical voidness Ta Simeiqiong.
Specifically, the present invention recommends the method to carry out as follows:
(1) by raceme shown in Formulas I it is trans--[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, optical voidness Resolving agent is dissolved in solvent A, is stirred to react 2~5 hours, after fully reacting at 25~40 DEG C, reaction mixture is filtered To solid salt, is recrystallized, will be recrystallized with 1~5:0.5 of volume ratio~5:50~100 water/methanol/acetone mixed solvent The solid salt arrived addition inorganic alkali solution soluble in water adjusts pH to 10~12, stirs dissolved clarification.Ethyl acetate extraction is added, (1R, 2R)-shown in Formula II [2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine is drying to obtain after solvent is evaporated off；Institute The optical voidness resolving agent stated is D- dibenzoyl tartaric acid；Raceme shown in the Formulas I is trans--[2- (2,3- dihydro -4- benzene And furyl) cyclopropyl] the ratio between the amount of substance of methylamine and optical voidness resolving agent is 1~3:1；The solvent A is water, first Alcohol, ethyl alcohol, isopropanol, acetone, methylene chloride or tetrahydrofuran；The volumetric usage of the solvent A is with raceme shown in Formulas I Trans--[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine quality is calculated as 15~100mL/g；The inorganic base is hydrogen Sodium oxide molybdena, potassium hydroxide, lithium hydroxide, sodium carbonate or potassium carbonate；
(2) by (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] first shown in Formula II obtained by step (1) Amine is dissolved in solvent B, and triethylamine is added, propionyl chloride is added under nitrogen protection, 1~2h is stirred to react at 25 DEG C, gained is anti- It answers liquid that 1~2mol/L dilute hydrochloric acid is added and adjusts pH=5~6, washed, be concentrated to get optical voidness Ta Simeiqiong shown in formula III； (1R, 2R)-shown in the Formula II [2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, triethylamine and propionyl chloride The ratio between amount of substance is 1:1.6~1.9:1.3~1.6；The solvent B is methylene chloride, chloroform, toluene, tetrahydrofuran, 2- first Base tetrahydrofuran or acetonitrile；The volumetric usage of the solvent B is with (1R, 2R)-shown in Formula II [2- (2,3- dihydro -4- benzo furans Mutter base) cyclopropyl] amount of substance of methylamine is calculated as 20~35mL/g.
Compared with prior art, the invention has the benefit that
(1) reaction condition is mild, easy to operate, high income, and selectivity is good；
(2) production cost is low, good product quality, provides a new approach for the synthesis of optical voidness Ta Simeiqiong；
(3) it is suitble to industrialized production, there are biggish practical application value and economic results in society.
(4) specific embodiment
Below by specific embodiment, the invention will be further described, but protection scope of the present invention is not limited in This.
In embodiment, solid yields by resolving agent and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl Base] methylamine molar ratio 1:1~3 on the basis of calculate, (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] first The yield of amine is calculated on the basis of the half of raceme.
In embodiment, enantiomeric excess value (e.e.) is measured by HPLC, and parameter is as follows:
Chiral chromatographic column: Chiralcel OJ-H
Mobile phase: n-hexane: isopropanol=85:15
Detection wavelength: 210nm
Embodiment 1
By D- mandelic acid (0.32g, 2.11mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl Base] methylamine (0.80g, 4.23mmol) is dissolved in 25mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, white solid is precipitated It filters, obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine mandelate.Solid salt is added to In 5mL water, 2mol/L sodium hydroxide solution is added dropwise while stirring, adjusts pH to 10, stirs dissolved clarification.Add 15mL ethyl acetate Extraction, is evaporated to obtain 0.36g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 90.0% is (with list One isomers calculates), in order to unified with the following examples, yield is changed to 45%, with the calculating of raceme total amount.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.36g, 1.90mmol) is dissolved in In 10mL methylene chloride, it is added triethylamine (0.34g, 3.43mmol), nitrogen protection, interpreter addition propionyl chloride (0.26g, 2.83mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (5mL × 2), then use saturated carbon Sour hydrogen sodium washes (5mL × 2), then washes (5mL × 2).Solvent evaporated obtains 0.44g Ta Simeiqiong, yield 94.3%, optical purity For 90%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 2
By D- mandelic acid (0.8g, 5.29mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl Base] methylamine (1.0g, 5.29mmol) is dissolved in 100mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, white solid is precipitated It filters, obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine mandelate.Solid salt is added to In 10mL water, 2mol/L potassium hydroxide solution is added dropwise while stirring, adjusts pH to 12, stirs dissolved clarification.Add 20mL acetic acid second Ester extraction, is evaporated to obtain 0.48g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 48%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.48g, 2.5mmol) is dissolved in In 15mL chloroform, it is added triethylamine (0.43g, 4.30mmol), nitrogen protection, interpreter addition propionyl chloride (0.33g, 3.54mmol), it is stirred to react 1h at 25 DEG C, 1mol/L dilute hydrochloric acid tune pH=5 is added dropwise, washes (5mL × 2), then use saturated carbon Sour hydrogen sodium washes (5mL × 2), then washes (5mL × 2).Solvent evaporated obtains 0.55g Ta Simeiqiong, yield 95%, and optical purity is 86%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 3
By D- mandelic acid (0.21g, 1.41mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl Base] methylamine (0.80g, 4.23mmol) is dissolved in 12mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, white solid is precipitated It filters, obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine mandelate.Solid salt is added to In 5mL water, 2mol/L lithium hydroxide solution is added dropwise while stirring, adjusts pH to 12, stirs dissolved clarification.Add 15mL ethyl acetate Extraction, is evaporated to obtain 0.32g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 40.5%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.32g, 1.68mmol) is dissolved in In 10mL acetonitrile, it is added triethylamine (0.271g, 2.69mmol), nitrogen protection, interpreter addition propionyl chloride (0.2g, 2.18mmol), it is stirred to react 1h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (5mL × 2), then use saturated carbon Sour hydrogen sodium washes (5mL × 2), then washes (5mL × 2).Solvent evaporated obtains 0.40g Ta Simeiqiong, yield 96%, and optical purity is 92%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 4
By D- mandelic acid (0.32g, 2.11mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl Base] methylamine (0.80g, 4.23mmol) is dissolved in 25mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, white solid is precipitated It filters, obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine mandelate.Solid salt is added to In 5mL water, 2mol/L sodium carbonate liquor is added dropwise while stirring, adjusts pH to 10, stirs dissolved clarification.Add 15mL ethyl acetate extraction It takes, is evaporated to obtain 0.35g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 44.0%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.35g, 1.85mmol) is dissolved in In 10mL toluene, it is added triethylamine (0.34g, 3.43mmol), nitrogen protection, interpreter addition propionyl chloride (0.26g, 2.83mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (5mL × 2), then use saturated carbon Sour hydrogen sodium washes (5mL × 2), then washes (5mL × 2).Solvent evaporated obtains 0.42g Ta Simeiqiong, yield 93%, and optical purity is 90%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 5
By D- mandelic acid (0.48g, 3.16mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl Base] methylamine (1.2g, 6.35mmol) is dissolved in 40mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, white solid is precipitated It filters, obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine mandelate.Solid salt is added to In 8mL water, 2mol/L solution of potassium carbonate is added dropwise while stirring, adjusts pH to 12, stirs dissolved clarification.Add 25mL ethyl acetate extraction It takes, is evaporated to obtain 0.55g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 45.5%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.55g, 2.85mmol) is dissolved in In 15mL tetrahydrofuran, it is added triethylamine (0.51g, 5.15mmol), nitrogen protection, interpreter addition propionyl chloride (0.40g, 4.25mmol), it is stirred to react 2h at 25 DEG C, 1mol/L dilute hydrochloric acid tune pH=5 is added dropwise, washes (5mL × 2), then use saturated carbon Sour hydrogen sodium washes (5mL × 2), then washes (5mL × 2).Solvent evaporated obtains 0.68g Ta Simeiqiong, yield 95%, and optical purity is 91%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 6
By D- mandelic acid (0.32g, 2.11mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl Base] methylamine (0.80g, 4.23mmol) is dissolved in 25mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, white solid is precipitated It filters, obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine mandelate.Solid salt is added to In 5mL water, 2mol/L sodium hydroxide solution is added dropwise while stirring, adjusts pH to 12, stirs dissolved clarification.Add 15mL ethyl acetate Extraction, is evaporated to obtain 0.36g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 45.0%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.36g, 1.90mmol) is dissolved in It in 10mL 2- methyltetrahydrofuran, is added triethylamine (0.34g, 3.43mmol), nitrogen protection, propionyl chloride is added in interpreter (0.26g, 2.83mmol) is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, and washes (5mL × 2), then use Saturated sodium bicarbonate washes (5mL × 2), then washes (5mL × 2).Solvent evaporated obtains 0.44g Ta Simeiqiong, yield 94.3%, light Purity is 90%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 7
By D- mandelic acid (0.64g, 4.22mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl Base] methylamine (1.60g, 8.44mmol) is dissolved in 50mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, white solid is precipitated It filters, obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine mandelate.Solid salt is added to In 10mL water, 2mol/L sodium hydroxide solution is added dropwise while stirring, adjusts pH to 12, stirs dissolved clarification.Add 30mL acetic acid second Ester extraction, is evaporated to obtain 0.7g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 44.0%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.7g, 3.69mmol) is dissolved in In 15mL methylene chloride, it is added triethylamine (0.68g, 6.86mmol), nitrogen protection, interpreter addition propionyl chloride (0.52g, 5.86mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (5mL × 2), then use saturated carbon Sour hydrogen sodium washes (5mL × 2), then washes (5mL × 2).Solvent evaporated obtains 0.89g Ta Simeiqiong, yield 95%, and optical purity is 91%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 8
By D- dibenzoyl tartaric acid (1.00g, 2.79mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzo furans Mutter base) cyclopropyl] methylamine (1.05g, 5.56mmol) is dissolved in 35mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, analysis White solid filters out, obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine Dibenzoyl tartaric Hydrochlorate.Solid salt is added in 5mL water, 2mol/L sodium hydroxide solution is added dropwise while stirring, adjusts pH to 10, is stirred molten Clearly.The extraction of 15mL ethyl acetate is added, 0.46g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl is evaporated to obtain Base] methylamine, yield 43.8%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.46g, 2.43mmol) is dissolved in In 15mL methylene chloride, it is added triethylamine (0.44g, 4.37mmol), nitrogen protection, interpreter addition propionyl chloride (0.34g, 3.65mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (8mL × 2), then use saturated carbon Sour hydrogen sodium washes (8mL × 2), then washes (8mL × 2).Solvent evaporated obtains 0.56g Ta Simeiqiong, yield 93.9%, optical purity For 85%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 9
By D- tartaric acid (0.40g, 2.64mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl Base] methylamine (1.00g, 5.29mmol) is dissolved in 35mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, white solid is precipitated It filters, obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.Solid salt is added to In 5mL water, 2mol/L sodium hydroxide solution is added dropwise while stirring, adjusts pH to 10, stirs dissolved clarification.Add 15mL ethyl acetate Extraction, is evaporated to obtain 0.43g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 43.0%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.43g, 2.27mmol) is dissolved in In 15mL methylene chloride, it is added triethylamine (0.44g, 4.31mmol), nitrogen protection, interpreter addition propionyl chloride (0.33g, 3.63mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (8mL × 2), then use saturated carbon Sour hydrogen sodium washes (8mL × 2), then washes (8mL × 2).0.53g Ta Simeiqiong, yield 95.1%, optics is prepared in solvent evaporated Purity is 92%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 10
By D- camphorsulfonic acid (0.61g, 2.64mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (1.00g, 5.29mmol) is dissolved in 35mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, it is solid that white is precipitated Body filters, and obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine camsilate.By solid salt plus Enter into 5mL water, 2mol/L sodium hydroxide solution is added dropwise while stirring, adjust pH to 10, stirs dissolved clarification.Add 15mL acetic acid Ethyl ester extraction, is evaporated to obtain 0.45g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 45.0%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.45g, 2.38mmol) is dissolved in In 15mL methylene chloride, it is added triethylamine (0.43g, 4.28mmol), nitrogen protection, interpreter addition propionyl chloride (0.33g, 3.57mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (8mL × 2), then use saturated carbon Sour hydrogen sodium washes (8mL × 2), then washes (8mL × 2).Solvent evaporated obtains 0.56g Ta Simeiqiong, yield 96.0%, optical purity For 95.6%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 11
By D- bis- it is trans- to toluyl tartaric acid (1.01g, 2.62mmol) and raceme-[2- (2,3- dihydro -4- Benzofuranyl) cyclopropyl] methylamine (0.99g, 5.24mmol) is dissolved in 35mL methanol, dissolved clarification is stirred at room temperature.It is small to continue stirring 2 When, white solid is precipitated and filters, obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine two to methyl Benzoyltartaric hydrochlorate.Solid salt is added in 5mL water, while stirring be added dropwise 2mol/L sodium hydroxide solution, adjust pH to 10, stir dissolved clarification.The extraction of 15mL ethyl acetate is added, 0.44g (1R, 2R)-[2- (2,3- dihydro -4- benzofurans are evaporated to obtain Base) cyclopropyl] methylamine, yield 44.4%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.44g, 2.33mmol) is dissolved in In 15mL methylene chloride, it is added triethylamine (0.42g, 4.20mmol), nitrogen protection, interpreter addition propionyl chloride (0.32g, 3.49mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (8mL × 2), then use saturated carbon Sour hydrogen sodium washes (8mL × 2), then washes (8mL × 2).Solvent evaporated obtains 0.55g Ta Simeiqiong, yield 96.5%, optical purity For 95%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 12
By D-PG (0.40g, 2.64mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (1.00g, 5.29mmol) is dissolved in 35mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, it is solid that white is precipitated Body filters, and obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.Solid salt is added Into 5mL water, 2mol/L sodium hydroxide solution is added dropwise while stirring, adjusts pH to 10, stirs dissolved clarification.Add 15mL acetic acid second Ester extraction, is evaporated to obtain 0.23g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 23.0%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.23g, 1.22mmol) is dissolved in In 10mL methylene chloride, it is added triethylamine (0.22g, 2.20mmol), nitrogen protection, interpreter addition propionyl chloride (0.17g, 1.82mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (5mL × 2), then use saturated carbon Sour hydrogen sodium washes (5mL × 2), then washes (5mL × 2).0.28g Ta Simeiqiong, yield 94.5%, optics is prepared in solvent evaporated Purity is 70%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 13
By D-phenylalanine (0.44g, 2.64mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (1.00g, 5.29mmol) is dissolved in 35mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, it is solid that white is precipitated Body filters, and obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.Solid salt is added Into 5mL water, 2mol/L sodium hydroxide solution is added dropwise while stirring, adjusts pH to 10, stirs dissolved clarification.Add 15mL acetic acid second Ester extraction, is evaporated to obtain 0.35g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 35%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.35g, 1.87mmol) is dissolved in In 12mL methylene chloride, it is added triethylamine (0.34g, 3.36mmol), nitrogen protection, interpreter addition propionyl chloride (0.26g, 2.80mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (7mL × 2), then use saturated carbon Sour hydrogen sodium washes (7mL × 2), then washes (7mL × 2).0.44g Ta Simeiqiong, yield 96.3%, optics is prepared in solvent evaporated Purity is 65%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 14
By D- camphorsulfonic acid (1.22g, 5.27mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (1.99g, 10.53mmol) is dissolved in 70mL acetone, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, white is precipitated Solid filters, and obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.By solid salt plus Enter into 10mL water, 2mol/L potassium hydroxide solution is added dropwise while stirring, adjust pH to 12, stirs dissolved clarification.Add 30mL second Acetoacetic ester extraction, is evaporated to obtain 0.98g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 49.1%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.98g, 5.18mmol) is dissolved in In 30mL methylene chloride, it is added triethylamine (0.94g, 9.33mmol), nitrogen protection, interpreter addition propionyl chloride (0.71g, 7.76mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (15mL × 2), then use saturated carbon Sour hydrogen sodium washes (15mL × 2), then washes (15mL × 2).Solvent evaporated obtains 1.26g Ta Simeiqiong, yield 99.2%, optical voidness Degree is 87%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 15
By D- camphorsulfonic acid (0.93g, 4.02mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (1.52g, 8.04mmol) is dissolved in 50mL tetrahydrofuran, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, is precipitated white Color solid filters, and obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.By solid salt It is added in 10mL water, 2mol/L sodium hydroxide solution is added dropwise while stirring, adjust pH to 10, stir dissolved clarification.Add 30mL Ethyl acetate extraction, is evaporated to obtain 0.73g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 48%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.73g, 3.86mmol) is dissolved in In 20mL methylene chloride, it is added triethylamine (0.70g, 6.95mmol), nitrogen protection, interpreter addition propionyl chloride (0.53g, 5.79mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (10mL × 2), then use saturated carbon Sour hydrogen sodium washes (10mL × 2), then washes (10mL × 2).Solvent evaporated obtains 0.93g Ta Simeiqiong, yield 98.3%, optical voidness Degree is 89%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 16
By D- camphorsulfonic acid (0.61g, 2.64mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (1.00g, 5.29mmol) is dissolved in 35mL ethyl alcohol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, it is solid that white is precipitated Body filters, and obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.Solid salt is added Into 5mL water, 2mol/L sodium hydroxide solution is added dropwise while stirring, adjusts pH to 10, stirs dissolved clarification.Add 15mL acetic acid second Ester extraction, is evaporated to obtain 0.42g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 42.0%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.42g, 2.24mmol) is dissolved in In 12mL methylene chloride, it is added triethylamine (0.43g, 4.23mmol), nitrogen protection, interpreter addition propionyl chloride (0.33g, 3.58mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (10mL × 2), then use saturated carbon Sour hydrogen sodium washes (10mL × 2), then washes (10mL × 2).0.52g Ta Simeiqiong, yield 95.0%, light is prepared in solvent evaporated Purity is 89%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 17
By D- camphorsulfonic acid (0.61g, 2.64mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (1.00g, 5.29mmol) is dissolved in 35mL isopropanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, white is precipitated Solid filters, and obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.By solid salt plus Enter into 5mL water, 2mol/L sodium hydroxide solution is added dropwise while stirring, adjust pH to 10, stirs dissolved clarification.Add 15mL acetic acid Ethyl ester extraction, is evaporated to obtain 0.45g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 45.0%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.45g, 2.38mmol) is dissolved in In 14mL methylene chloride, it is added triethylamine (0.43g, 4.28mmol), nitrogen protection, interpreter addition propionyl chloride (0.33g, 3.57mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (10mL × 2), then use saturated carbon Sour hydrogen sodium washes (10mL × 2), then washes (10mL × 2).0.54g Ta Simeiqiong, yield 93.2%, light is prepared in solvent evaporated Purity is 87%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 18
By D- camphorsulfonic acid (0.61g, 2.64mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (1.00g, 5.29mmol) is dissolved in 35mL methylene chloride, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, is precipitated white Color solid filters, and obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.By solid salt It is added in 5mL water, 2mol/L sodium hydroxide solution is added dropwise while stirring, adjust pH to 10, stir dissolved clarification.Add 15mL second Acetoacetic ester extraction, is evaporated to obtain 0.50g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 50.0%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.50g, 2.64mmol) is dissolved in In 12mL methylene chloride, it is added triethylamine (0.48g, 4.76mmol), nitrogen protection, interpreter addition propionyl chloride (0.36g, 3.97mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (10mL × 2), then use saturated carbon Sour hydrogen sodium washes (10mL × 2), then washes (10mL × 2).0.64g Ta Simeiqiong, yield 98.8%, light is prepared in solvent evaporated Purity is 82%e.e..Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647, 2926,2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J=7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22- 3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8, 159.6,138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 19
By D- camphorsulfonic acid (0.61g, 2.64mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (1.00g, 5.29mmol) is dissolved in 35mL water, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, white solid is precipitated It filters, obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.Solid salt is added to In 5mL water, 2mol/L sodium hydroxide solution is added dropwise while stirring, adjusts pH to 10, stirs dissolved clarification.Add 15mL ethyl acetate Extraction, is evaporated to obtain 0.55g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 55.0%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.55g, 2.91mmol) is dissolved in In 12mL methylene chloride, it is added triethylamine (0.53g, 5.24mmol), nitrogen protection, interpreter addition propionyl chloride (0.40g, 4.36mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (15mL × 2), then use saturated carbon Sour hydrogen sodium washes (15mL × 2), then washes (15mL × 2).0.69g Ta Simeiqiong, yield 97.1%, light is prepared in solvent evaporated Purity is 42%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 20
By D- camphorsulfonic acid (0.61g, 2.64mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (1.00g, 5.29mmol) is dissolved in 35mL methanol, in 70 DEG C of stirring dissolved clarifications.Continue stirring 2 hours, white is precipitated Solid filters, and obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.By solid salt plus Enter into 5mL water, 2mol/L sodium hydroxide solution is added dropwise while stirring, adjust pH to 10, stirs dissolved clarification.Add 15mL acetic acid Ethyl ester extraction, is evaporated to obtain 0.44g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 44.0%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.44g, 2.33mmol) is dissolved in In 15mL methylene chloride, it is added triethylamine (0.43g, 4.20mmol), nitrogen protection, interpreter addition propionyl chloride (0.32g, 3.50mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (10mL × 2), then use saturated carbon Sour hydrogen sodium washes (10mL × 2), then washes (10mL × 2).0.57g Ta Simeiqiong, yield 99.2%, light is prepared in solvent evaporated Purity is 93%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 21
By D- camphorsulfonic acid (0.61g, 2.64mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (1.00g, 5.29mmol) is dissolved in 35mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 5 hours, it is solid that white is precipitated Body filters, and obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.Solid salt is added Into 5mL water, 2mol/L sodium hydroxide solution is added dropwise while stirring, adjusts pH to 10, stirs dissolved clarification.Add 15mL acetic acid second Ester extraction, is evaporated to obtain 0.41g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 41.0%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.41g, 2.17mmol) is dissolved in In 13mL methylene chloride, it is added triethylamine (0.40g, 3.90mmol), nitrogen protection, interpreter addition propionyl chloride (0.30g, 3.25mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (10mL × 2), then use saturated carbon Sour hydrogen sodium washes (10mL × 2), then washes (10mL × 2).0.52g Ta Simeiqiong, yield 98.1%, light is prepared in solvent evaporated Purity is 95%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 22
By D- camphorsulfonic acid (0.61g, 2.64mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (1.00g, 5.29mmol) is dissolved in 35mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, it is solid that white is precipitated Body filters, and obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.Solid salt is added Into 5mL water, 2mol/L sodium hydroxide solution is added dropwise while stirring, adjusts pH to 10, stirs dissolved clarification.Add 15mL acetic acid second Ester extraction, is evaporated to obtain 0.43g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 43.0%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.43g, 2.27mmol) is dissolved in In 15mL methylene chloride, it is added triethylamine (0.41g, 4.10mmol), nitrogen protection, interpreter addition propionyl chloride (0.31g, 3.41mmol), it is stirred to react 2h at 40 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (8mL × 2), then use saturated carbon Sour hydrogen sodium washes (8mL × 2), then washes (8mL × 2).0.50g Ta Simeiqiong, yield 90.1%, optics is prepared in solvent evaporated Purity is 94%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 23
By D- camphorsulfonic acid (0.75g, 3.23mmol) (0.48g, 3.23mmol) and raceme it is trans--[2- (2,3- bis- Hydrogen -4- benzofuranyl) cyclopropyl] methylamine (1.22g, 6.46mmol) is dissolved in 42mL methanol, and 0 DEG C is stirred 2 hours, is precipitated white Color solid filters, and obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.By solid salt It is added in 10mL water, 2mol/L sodium hydroxide solution is added dropwise while stirring, adjust pH to 10, stir dissolved clarification.Add 20mL Ethyl acetate extraction, is evaporated to obtain 0.70g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 57.0%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.75g, 3.97mmol) is dissolved in In 25mL methylene chloride, it is added triethylamine (0.72g, 7.14mmol), nitrogen protection, interpreter addition propionyl chloride (0.55g, 6.00mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (10mL × 2), then use saturated carbon Sour hydrogen sodium washes (10mL × 2), then washes (10mL × 2).Solvent evaporated obtains 0.97g Ta Simeiqiong, yield 99.8%, optical voidness Degree is 80%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 24
By D- camphorsulfonic acid (0.73g, 3.13mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (1.17g, 6.19mmol) is dissolved in 38mL methanol, is warming up to 50 DEG C and stirs 2 hours, and white solid is precipitated and filters, Heat filters and obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.Solid salt is added Into 7mL water, 2mol/L potassium hydroxide solution is added dropwise while stirring, adjusts pH to 10, stirs dissolved clarification.Add 15mL acetic acid second Ester extraction, is evaporated to obtain 0.48g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 41%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.48g, 2.54mmol) is dissolved in In 15mL methylene chloride, it is added triethylamine (0.46g, 4.57mmol), nitrogen protection, interpreter addition propionyl chloride (0.35g, 3.81mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (8mL × 2), then use saturated carbon Sour hydrogen sodium washes (8mL × 2), then washes (8mL × 2).Solvent evaporated obtains 0.60g Ta Simeiqiong, yield 96.4%, optical purity For 95%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 25
By D- camphorsulfonic acid (0.89g, 3.83mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (1.45g, 7.67mmol) is dissolved in 50mL methanol, in 25 DEG C return stirring 2 hours, white solid is precipitated, heat is taken out Filter obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.Solid salt is added to In 10mL water, 2mol/L sodium hydroxide solution is added dropwise while stirring, adjusts pH to 10, stirs dissolved clarification.Add 25mL acetic acid second Ester extraction, is evaporated to obtain 0.51g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 35%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.51g, 2.70mmol) is dissolved in In 15mL methylene chloride, it is added triethylamine (0.49g, 4.85mmol), nitrogen protection, interpreter addition propionyl chloride (0.37g, 4.05mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (10mL × 2), then use saturated carbon Sour hydrogen sodium washes (10mL × 2), then washes (10mL × 2).Solvent evaporated obtains 0.63g Ta Simeiqiong, yield 95.3%, optical voidness Degree is 91.0%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 26
By D- camphorsulfonic acid (1.22g, 5.28mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (2.00g, 10.58mmol) is dissolved in 70mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, white is precipitated Solid filters, and obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.By 2.30g salt Solid water 1mL, methanol 0.5mL, acetone 50mL recrystallization, the solid salt filtered are added in 10mL water, while stirring 2mol/L sodium hydroxide solution is added dropwise, adjusts pH to 10, stirs dissolved clarification.The extraction of 30mL ethyl acetate is added, 0.84g is evaporated to obtain (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 42.0%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.84g, 4.44mmol) is dissolved in In 25mL methylene chloride, it is added triethylamine (0.81g, 8.00mmol), nitrogen protection, interpreter addition propionyl chloride (0.61g, 6.66mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (15mL × 2), then use saturated carbon Sour hydrogen sodium washes (15mL × 2), then washes (15mL × 2).Solvent evaporated obtains 1.07g Ta Simeiqiong, yield 99.2%, optical voidness Degree is 95.5%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 27
By D- camphorsulfonic acid (1.22g, 5.27mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (1.99g, 10.53mmol) is dissolved in 70mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, white is precipitated Solid filters, and obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.By 2.33g salt Solid water 1mL, methanol 1.5mL, acetone 50mL recrystallization, the solid salt filtered are added in 10mL water, while stirring 2mol/L sodium hydroxide solution is added dropwise, adjusts pH to 10, stirs dissolved clarification.The extraction of 30mL ethyl acetate is added, 0.80g is evaporated to obtain (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 40%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.80g, 4.23mmol) is dissolved in In 25mL methylene chloride, it is added triethylamine (0.77g, 7.62mmol), nitrogen protection, interpreter addition propionyl chloride (0.58g, 6.34mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (15mL × 2), then use saturated carbon Sour hydrogen sodium washes (15mL × 2), then washes (15mL × 2).Solvent evaporated obtains 0.97g Ta Simeiqiong, yield 93.6%, optical voidness Degree is 96.8%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 28
By D- camphorsulfonic acid (1.22g, 5.27mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (1.99g, 10.53mmol) is dissolved in 70mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, white is precipitated Solid filters, and obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.By 2.32g salt Solid water 1mL, methanol 5mL, acetone 50mL recrystallization, the solid salt filtered are added in 10mL water, drip while stirring Add 2mol/L sodium hydroxide solution, adjust pH to 10, stirs dissolved clarification.The extraction of 30mL ethyl acetate is added, 0.98g is evaporated to obtain (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 49.0%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.98g, 5.18mmol) is dissolved in In 30mL methylene chloride, it is added triethylamine (0.94g, 9.32mmol), nitrogen protection, interpreter addition propionyl chloride (0.71g, 7.76mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (18mL × 2), then use saturated carbon Sour hydrogen sodium washes (18mL × 2), then washes (20mL × 2).Solvent evaporated obtains 1.18g Ta Simeiqiong, yield 93.5%, optical voidness Degree is 95.8%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 29
By D- camphorsulfonic acid (1.22g, 5.27mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (1.99g, 10.53mmol) is dissolved in 70mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, white is precipitated Solid filters, and obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.By 2.30g salt Solid water 1mL, methanol 0.5mL, acetone 50mL recrystallization, the solid salt filtered are added in 10mL water, while stirring 2mol/L sodium hydroxide solution is added dropwise, adjusts pH to 10, stirs dissolved clarification.The extraction of 30mL ethyl acetate is added, 0.80g is evaporated to obtain (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 40.0%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.80g, 4.23mmol) is dissolved in In 25mL methylene chloride, it is added triethylamine (0.77g, 7.62mmol), nitrogen protection, interpreter addition propionyl chloride (0.58g, 6.34mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (15mL × 2), then use saturated carbon Sour hydrogen sodium washes (15mL × 2), then washes (15mL × 2).Solvent evaporated obtains 0.97g Ta Simeiqiong, yield 93.6%, optical voidness Degree is 95.2%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 30
By D- camphorsulfonic acid (1.22g, 5.27mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (1.99g, 10.53mmol) is dissolved in 70mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, white is precipitated Solid filters, and obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.2.32 salt are consolidated Body water 5mL, methanol 1.5mL, acetone 50mL recrystallization, the solid salt filtered are added in 10mL water, drip while stirring Add 2mol/L sodium hydroxide solution, adjust pH to 10, stirs dissolved clarification.The extraction of 30mL ethyl acetate is added, 0.85g is evaporated to obtain (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 42.7%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.85g, 4.50mmol) is dissolved in In 25mL methylene chloride, it is added triethylamine (0.82g, 8.10mmol), nitrogen protection, interpreter addition propionyl chloride (0.62g, 6.75mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (15mL × 2), then use saturated carbon Sour hydrogen sodium washes (15mL × 2), then washes (15mL × 2).Solvent evaporated obtains 1.05g Ta Simeiqiong, yield 95.5%, optical voidness Degree is 95.8%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 31
By D- camphorsulfonic acid (1.22g, 5.27mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (1.99g, 10.53mmol) is dissolved in 70mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, white is precipitated Solid filters, and obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.2.31 salt are consolidated Body water 5mL, methanol 1.5mL, acetone 50mL recrystallization, the solid salt filtered are added in 10mL water, drip while stirring Add 2mol/L sodium hydroxide solution, adjust pH to 10, stirs dissolved clarification.The extraction of 30mL ethyl acetate is added, 0.88g is evaporated to obtain (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 44.2%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.88g, 4.70mmol) is dissolved in In 28mL methylene chloride, it is added triethylamine (0.85g, 8.46mmol), nitrogen protection, interpreter addition propionyl chloride (0.65g, 7.05mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (17mL × 2), then use saturated carbon Sour hydrogen sodium washes (17mL × 2), then washes (18mL × 2).Solvent evaporated obtains 1.08g Ta Simeiqiong, yield 95.0%, optical voidness Degree is 95.1%e.e..
Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985,1230,1459,1590,1613,1647,2926, 2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J =7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR(125MHz,CDCl3): δ=173.8,159.6, 138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7,28.6,21.7,19.7,13.4,9.9.
Embodiment 32
By D- camphorsulfonic acid (1.22g, 5.27mmol) and raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) ring Propyl] methylamine (1.98g, 10.47mmol) is dissolved in 70mL methanol, dissolved clarification is stirred at room temperature.Continue stirring 2 hours, white is precipitated Solid filters, and obtains (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine tartrate.By 2.32g salt Solid water 1.5mL, methanol 2.0mL, acetone 50mL recrystallization, the solid salt filtered are added in 10mL water, side stirring 2mol/L sodium hydroxide solution is added dropwise in side, adjusts pH to 10, stirs dissolved clarification.The extraction of 30mL ethyl acetate is added, is evaporated 0.75g (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, yield 37.9%.
(1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine (0.75g, 3.97mmol) is dissolved in In 20mL methylene chloride, it is added triethylamine (0.72g, 7.15mmol), nitrogen protection, interpreter addition propionyl chloride (0.55g, 6.00mmol), it is stirred to react 2h at 25 DEG C, 2mol/L dilute hydrochloric acid tune pH=6 is added dropwise, washes (15mL × 2), then use saturated carbon Sour hydrogen sodium washes (15mL × 2), then washes (15mL × 2).Solvent evaporated obtains 0.95g Ta Simeiqiong, yield 97.7%, optical voidness Degree is 98.8%e.e..
[α]=- 37.08 ° of (c=10.0mg/mL, CHCl3).Rf=0.39 (PE-EtOAc, 1:1) .IR (KBr): 985, 1230,1459,1590,1613,1647,2926,2974,3070cm-1.1H NMR(500MHz,CDCl3): δ=0.91-0.94 (m, 1H), 0.95-1.00 (m, 1H), 1.18 (t, J=7.6Hz, 3H), 1.32-1.36 (m, 1H), 1.73-1.76 (m, 1H), 2.22 (q, J=7.6Hz, 2H), 3.22-3.26 (m, 2H), 3.28-3.37 (m, 2H), 4.60 (t, J=8.7Hz, 2H), 5.72 (br d, 1H), 6.35 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.03 (t, J=7.9Hz, 1H)13C NMR (125MHz,CDCl3): δ=173.8,159.6,138.9,128.2,126.0,115.7,106.8,71.0,43.5,29.7, 28.6,21.7,19.7,13.4,9.9.
It is pointed out that the design and feature of above-mentioned EXPERIMENTAL EXAMPLE only to illustrate the invention, it is familiar the purpose is to allow People of the invention understands this experiment and implements accordingly, can not limit the scope of the invention.All spirit according to the present invention is real The equivalent change or modification that matter is made, should be covered by the scope of protection of the present invention.

Claims (10)

1. a kind of preparation method of optical voidness Ta Simeiqiong, it is characterised in that the method carries out as follows:
(1) by raceme shown in Formulas I it is trans--[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, optical voidness split Agent is dissolved in solvent A, is stirred to react at 0~70 DEG C 2~5 hours, and gained reaction mixture is post-treated to be obtained shown in Formula II (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine；Raceme shown in the Formulas I is trans--[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] the ratio between the amount of substance of methylamine and optical voidness resolving agent is 1~3:1；Described Optical voidness resolving agent is D-10- camphorsulfonic acid, D- mandelic acid, D- dibenzoyl tartaric acid, D- tartaric acid, D-PG, D- Phenylalanine or D- bis- are to toluyl tartaric acid；
(2) (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine shown in Formula II obtained by step (1) is molten In solvent B, triethylamine is added, propionyl chloride is added under nitrogen protection, 1~2h, gained reaction solution are stirred to react at 25 DEG C It is post-treated to obtain optical voidness Ta Simeiqiong shown in formula III；(1R, 2R)-shown in the Formula II [2- (2,3- dihydro -4- benzene And furyl) cyclopropyl] methylamine, triethylamine and propionyl chloride the ratio between the amount of substance be 1:1.6~1.9:1.3~1.6,
2. the method as described in claim 1, it is characterised in that solvent A described in the step (1) be water, methanol, ethyl alcohol, Isopropanol, acetone, methylene chloride or tetrahydrofuran.
3. the method as described in claim 1, it is characterised in that the volumetric usage of solvent A described in the step (1) is with Formulas I Shown in raceme it is trans--[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine quality is calculated as 15~100mL/g.
4. the method as described in claim 1, it is characterised in that the post-processing approach of described step (1) reaction mixture are as follows: After fully reacting, reaction mixture is filtered to obtain solid salt, the solid salt is soluble in water, inorganic base is added and adjusts PH To 10~12, dissolved clarification is stirred, ethyl acetate extraction is added, is drying to obtain described (1R, 2R)-[2- (2,3- after solvent is evaporated off Dihydro -4- benzofuranyl) cyclopropyl] methylamine.
5. method as claimed in claim 4, it is characterised in that alkali is sodium hydroxide, potassium hydroxide, hydrogen in the step (1) Lithia, sodium carbonate or potassium carbonate.
6. method as claimed in claim 4, it is characterised in that the post-processing approach of reaction mixture in the step (1) Are as follows: after fully reacting, reaction mixture is first used the mixing of 1~5:0.5 of volume ratio~5:50~100 water/methanol/acetone molten Agent recrystallization, then recrystallization is filtered and obtains solid salt.
7. the method as described in claim 1, it is characterised in that solvent B described in the step (2) is methylene chloride, chlorine Imitative, 1,2- dichloroethanes, toluene, tetrahydrofuran, 2- methyltetrahydrofuran or acetonitrile.
8. the method as described in claim 1, it is characterised in that the volumetric usage of solvent B described in the step (2) is with formula The quality of (1R, 2R)-shown in II [2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine is calculated as 20~35mL/g.
9. the method as described in claim 1, it is characterised in that the post-processing approach of described step (2) reaction solution are as follows: by institute It obtains reaction solution and 1~2mol/L dilute hydrochloric acid adjusting pH=5~6 is added, washed, be concentrated to get the optical voidness Ta Simeiqiong.
10. the method as described in one of claim 1~9, it is characterised in that the method carries out as follows:
(1) by raceme shown in Formulas I it is trans--[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, optical voidness split Agent is dissolved in solvent A, is stirred to react at 25~40 DEG C 2~5 hours, after fully reacting, by reaction mixture with volume ratio 1~ Water/methanol/acetone mixed solvents of 5:0.5~5:50~100 recrystallizes, by the solid salt being recrystallized to give it is soluble in water plus Enter inorganic alkali solution, adjust pH to 10~12, stir dissolved clarification, adds ethyl acetate extraction, be drying to obtain formula after solvent is evaporated off (1R, 2R)-shown in II [2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine；The optical voidness resolving agent is D- Dibenzoyl tartaric acid；Raceme shown in the Formulas I is trans--[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine It is 1~3:1 with the ratio between the amount of substance of optical voidness resolving agent；The solvent A is water, methanol, ethyl alcohol, isopropanol, acetone, two Chloromethanes or tetrahydrofuran；The volumetric usage of the solvent A with raceme shown in Formulas I it is trans--[2- (2,3- dihydro -4- benzene And furyl) cyclopropyl] methylamine quality is calculated as 15~100mL/g；The inorganic base is sodium hydroxide, potassium hydroxide, hydroxide Lithium, sodium carbonate or potassium carbonate；
(2) (1R, 2R)-[2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine shown in Formula II obtained by step (1) is molten In solvent B, triethylamine is added, propionyl chloride is added under nitrogen protection, 1~2h, gained reaction solution are stirred to react at 25 DEG C 1~2mol/L dilute hydrochloric acid is added and adjusts PH=5~6, washed, be concentrated to get optical voidness Ta Simeiqiong shown in formula III；It is described The substance of (1R, 2R)-shown in Formula II [2- (2,3- dihydro -4- benzofuranyl) cyclopropyl] methylamine, triethylamine and propionyl chloride The ratio between amount be 1:1.6~1.9:1.3~1.6；The solvent B is methylene chloride, chloroform, toluene, tetrahydrofuran, 2- methyl four Hydrogen furans, acetonitrile；The volumetric usage of the solvent B is with (1R, 2R)-shown in Formula II [2- (2,3- dihydro -4- benzofuranyl) Cyclopropyl] amount of substance of methylamine is calculated as 20~35mL/g.
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