CN106749133A - A kind of method for preparing Ta Simeiqiong - Google Patents
A kind of method for preparing Ta Simeiqiong Download PDFInfo
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- CN106749133A CN106749133A CN201510814397.2A CN201510814397A CN106749133A CN 106749133 A CN106749133 A CN 106749133A CN 201510814397 A CN201510814397 A CN 201510814397A CN 106749133 A CN106749133 A CN 106749133A
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- PTOIAAWZLUQTIO-GXFFZTMASA-N CCC(NC[C@H](C1)[C@@H]1c1cccc2c1CCO2)=O Chemical compound CCC(NC[C@H](C1)[C@@H]1c1cccc2c1CCO2)=O PTOIAAWZLUQTIO-GXFFZTMASA-N 0.000 description 1
- FXYHNSKFBUUONP-GZMMTYOYSA-N NC[C@H](C1)[C@@H]1c1cccc2c1CCO2 Chemical compound NC[C@H](C1)[C@@H]1c1cccc2c1CCO2 FXYHNSKFBUUONP-GZMMTYOYSA-N 0.000 description 1
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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
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Abstract
The present invention provides a kind of preparation method of Ta Simeiqiong; the method is with (S) -4- (oxirane -2- bases) -2; 3- Dihydrobenzofuranes are initiation material; (1R is generated through cyanalation reaction; 2R) -2- (2; 3- Dihydrobenzofuranes -4- bases) formonitrile HCN of ring third, reduction generation ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) cyclopropyl) methylamine and acylation reaction is obtained Ta Simeiqiong again.The inventive method reactions steps are few, simple to operate, and post processing is easy, and product yield is high, and cost of material is low, is conducive to industrialized production, there is larger application value.
Description
Technical field
The present invention relates to pharmaceutical chemistry, and in particular to prepared by the preparation of medicine, more particularly to one kind
The method of Ta Simeiqiong.
Background technology
Ta Simeiqiong, trade name Hetlioz, chemical entitled 1R-trans)-N- [[2- (2,3-
Dihydro -4- benzofuranyls) cyclopropyl] methyl] propionamide, shown in structural formula I.The medicine is by U.S.
Maryland State Vanda drugmakers of state develop, the FDA of on January 31st, 2014 approval listings,
It is a kind of new melatonin (melatonin) receptor stimulating agent, is lost completely for treating
Non- 24- hours sleep arousal disorders (" non-24 ") in bright patient.During " non-24 " is blind person
A kind of length of one's sleep puzzlement that chronic disorders of circadian rhythms causes, light does not enter their eye
Eyeball and its biological clock and 24- hour light and shade cycle synchronisation can not be made, i.e. patient possibility
Sleep is had difficulty in going to sleep or keeps, some patient sleeps' patterns are reversed, need to slept and evening on daytime
It is clear-headed.
At present, the synthetic method about Ta Simeiqiong is substantially by preparing with chiral cylopropyl
With key intermediate (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) first of ring third of amino
Amine II, then intermediate II carry out amidatioon and obtain Ta Simeiqiong.
Patent US5856529 is reported, with (E) -3- (2,3- Dihydrobenzofuranes -4- bases) propylene
Acid is initiation material, with the condensation of (-) -2,10- camphorsulfonic acids lactams, is entered with diazomethane
Row is Cyclopropanated to obtain chiral cylopropyl intermediate, is reduced with lithium aluminium hydride reduction, then pass through
SWERN (polite oxidation reaction) oxidations obtain aldehyde, are then condensed into oxime with hydroxylamine hydrochloride, enter
One step is reduced into amine, and the reaction of last and propionyl chloride obtains Ta Simeiqiong.But the method reaction step
It is rapid more long, and chiral intermediate must be built with diazomethane, it is unfavorable for that safe is operated, it is difficult
To industrialize, specific reactions steps are as follows:
The preparation method of CN102675268 reports:By (1R, 2R) -2- (2,3- dihydrobenzos
Furans -4- bases) cyclopropanecarboxylic acid obtains (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- through chlorination
Base) formyl chloride of ring third, generate (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) through ammonolysis
Ring propyl formamide, most obtains (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- through reduction afterwards
Base) methylamine of ring third this key intermediate.But the initiation material acid chiral cylopropyl of the method
Preparing also will be using reagents such as diazomethanes.
Reactions steps are as follows:
Patent US6214869 reports synthesizing cis 2- (2,3- Dihydrobenzofuranes -4- bases)
The method of the methylamine of ring third, the method is by (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases)
Cyclopropyl-carbinol is initiation material, and hydroxyl is protected with mesyl, then the mesyl after protection
With sodium azide effect by azide substitution, last hydrogenated aluminium lithium reduces to obtain cis 2- (2,3-
Dihydrobenzofuranes -4- bases) methylamine of ring third.But the technological requirement of the method is harsh, uses height
Danger reagent N aN3, it is unfavorable for industrialized production.
Reactions steps are as follows:
In a word, the method for prior art report all presence use highly difficult, expensive reagent, work
Skill complex operation, equipment requirement defect high, it is impossible to be suitable to industrial production, needs improvement badly.
The content of the invention
The technical problems to be solved by the invention are to overcome above-mentioned weak point, and research and design is anti-
Should be simple, easy to operate, low cost, the method for preparing Ta Simeiqiong of high income.
The invention provides a kind of method for preparing Ta Simeiqiong, with shown in following reaction equation:
The method of the present invention is comprised the following steps:
(1) (S) -4- (oxirane -2- bases) -2,3- Dihydrobenzofuranes and cyanylation agent are in alkali
In the presence of, cyanalation reaction generation (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases)
The third formonitrile HCN of ring III:
Cyanylation agent described in the step is in cyanogen methyl phosphorodithioate or cyanogen methyl quaternary phosphonium salt
One or more, preferably cyanogen methyl phosphorodithioate, most preferably cyanogen methyl acid phosphate diethylester;
(S) mol ratio of -4- (oxirane -2- bases) -2,3- Dihydrobenzofuranes and cyanylation agent
It is 1:1~5, wherein it is preferred that 1:1~3;
The alkali is selected from sodium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide or caustic alcohol
One or more, preferably sodium hydride;(S) -4- (oxirane -2- bases) -2,3- dihydrobenzos
Furans is 1 with the mol ratio of alkali:1~5, preferably 1:1~3.
Reaction dissolvent is selected from one or more in toluene, paraxylene, n-hexane or hexamethylene,
It is preferred that hexamethylene;The consumption of solvent is (S) -4- (oxirane -2- bases) -2,3- dihydrobenzos
8~50 times of furans quality, preferably 25~30 times.
Reaction temperature is 50~110 DEG C, preferably 70~100 DEG C;Reaction time is 4~12 hours,
It is preferred that 8~10 hours.
Post-reaction treatment:0.5-2 times of reactant solubilization dosage of water quenching is gone out reaction, then
Extracted 3 times through the ethyl acetate of each be quantity of solvent 0.5-2 times successively, use equivalent water again
Extraction, merges organic pressure of subtracting each other and is evaporated (40 DEG C, 0.01MPa rotary evaporations), through column chromatography (post
Type silicagel column 25*500mm glass silica gel posts, silica gel 200-300 mesh, eluting solvent methyl alcohol:
Dichloromethane=1:10) active ingredient is collected, thin layer detection terminal obtains target product III.
(2) (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) formonitrile HCN of ring third is reduced with reducing agent
Reaction generation ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) cyclopropyl) methylamine II:
Reducing agent described in the step is metal hydride, and preferred metal hydride is aluminum hydride
Lithium;(1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) formonitrile HCN of ring third rubs with reducing agent
You are than being 1:1~5, preferably 1:1~3.
Reduction reaction described in the step with metal hydride reducing agent except that can also add road
Lewis acid catalysed promoted is reacted, and described lewis acid is selected from BF3、SnCl4、FeCl3、AlCl3、
ZnCl2Or CuCl2, preferably BF3Or ZnCl2。
Reaction dissolvent be selected from tetrahydrofuran, 2- methyltetrahydrofurans, ether, methyl tertiary butyl ether(MTBE),
One or more in isopropyl ether, glycol dimethyl ether or dioxane, preferably tetrahydrofuran or
Methyltetrahydrofuran;The consumption of solvent is (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4-
Base) 8~60 times, preferably 20~30 times of ring the third formonitrile HCN quality.
Reaction temperature is -50~100 DEG C, and preferably 20~30 DEG C, the reaction time is 0.5~12 hour,
It is preferred that 8~10 hours.
Post-reaction treatment:To the saturated sodium bicarbonate of 0.5-2 times that quantity of solvent is added in reactant
The aqueous solution is quenched, suction filtration, filter cake with being every time the 0.1-1 times of methanol rinse 3 times of quantity of solvent,
Filtrate decompression is spin-dried for (40 DEG C, 0.01MPa rotary evaporations), through column chromatography (column type 25*500mm,
Eluting solvent methyl alcohol:Dichloromethane=1:10) active ingredient is collected, thin layer detection terminal obtains mesh
Mark thing II.
(3) ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) cyclopropyl) methylamine and acylation
Reagent, in the presence of acid binding agent, carries out acylation reaction generation Ta Simeiqiong:
The reaction of the step is that solvent-free or carry out under having solvent, the solvent is selected from dichloromethane
One or more in alkane, chloroform, 1,2- dichloroethanes, n-hexane, hexamethylene or methyl alcohol,
It is preferred that dichloromethane;The consumption of solvent is ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4-
Base) cyclopropyl) 0~50 times, preferably 5~15 times of methylamine quality.
The acylting agent is selected from one or more in propionyl chloride, propionic acid or propionic ester, excellent
Select propionyl chloride;((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) cyclopropyl) first
Amine is 1 with the mol ratio of acylting agent:1~10, preferably 1:1~3.
The acid binding agent is triethylamine, diisopropyl ethyl amine, sodium acid carbonate, sodium carbonate, carbon
One or more in sour potassium or pyridine, preferably triethylamine;((1R, the 2R) -2- (2,3-
Dihydrobenzofuranes -4- bases) cyclopropyl) mol ratio of methylamine and acid binding agent is 1:1~8, preferably
1:1~3.
Reaction temperature is -20~80 DEG C, preferably 0~20 DEG C;Reaction time is 0.5~12 hour,
It is preferred that 6~10 hours.
Post-reaction treatment:Reactant decompression is spin-dried for (40 DEG C, 0.01MPa rotary evaporations) solvent,
Column chromatography (column type 25*500mm, eluting solvent methyl alcohol:Dichloromethane=1:10) collect effectively into
Point, thin layer detection terminal obtains target product I.
It is a further object of the present invention to provide compound (1R, 2R) -2- (2,3- dihydrobenzos
Furans -4- bases) the third formonitrile HCN of ring III, the compound is represented with following formula:
Prepared by following method:
(S) -4- (oxirane -2- bases) -2,3- Dihydrobenzofuranes exist with cyanylation agent in alkali
Under, cyanalation reaction generation (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) first of ring third
Nitrile III:
Described cyanylation agent be one kind in cyanogen methyl phosphorodithioate or cyanogen methyl quaternary phosphonium salt or
It is various, preferably cyanogen methyl phosphorodithioate, most preferably cyanogen methyl acid phosphate diethylester;(S) -4- (epoxies
Ethane -2- bases) mol ratio of -2,3- Dihydrobenzofuranes and cyanylation agent is 1:1~5, its
In preferably 1:1~3;
The alkali is selected from sodium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide or caustic alcohol
One or more, preferably sodium hydride;(S) -4- (oxirane -2- bases) -2,3- dihydrobenzos
Furans is 1 with the mol ratio of alkali:1~5, preferably 1:1~3.
Reaction dissolvent is selected from one or more in toluene, paraxylene, n-hexane or hexamethylene,
It is preferred that hexamethylene;The consumption of solvent is (S) -4- (oxirane -2- bases) -2,3- dihydrobenzos
8~50 times of furans quality, preferably 25~30 times.
Reaction temperature is 50~110 DEG C, preferably 70~100 DEG C;Reaction time is 4~12 hours,
It is preferred that 8~10 hours.
Post-reaction treatment:0.5-2 times of reactant solubilization dosage of water quenching is gone out reaction, then
Extracted 3 times through the ethyl acetate of each be quantity of solvent 0.5-2 times successively, use equivalent water again
Extraction, merges organic pressure of subtracting each other and is evaporated (40 DEG C, 0.01MPa rotary evaporations), through column chromatography (post
Type silicagel column 25*500mm glass silica gel posts, silica gel 200-300 mesh, eluting solvent methyl alcohol:
Dichloromethane=1:10) active ingredient is collected, thin layer detection terminal obtains target product III.
Compound (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) third formonitrile HCN of ring III
Ta Simeiqiong can be prepared by reduction, therefore is the key intermediate of the inventive method.
The inventive method reactions steps are few, simple to operate, and post processing is easy, and product yield is high,
Cost of material is low, is conducive to industrialized production, there is larger application value.
Specific embodiment
Raw material and reagent used by following examples are commercially available.
(S) -4- (oxirane -2- bases) -2,3- Dihydrobenzofuranes for commercially available or
Embodiment 1 prepares Ta Simeiqiong
(1) preparation of (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) third formonitrile HCN of ring III
By sodium hydride (3.9g, 2.0equiv., 98.6mmol) add 80mL hexamethylenes in,
Cyanogen methyl acid phosphate diethylester (9.6g, 1.1 equiv (equivalent), 54.2mmol) is slowly added dropwise,
Completion of dropping, is warmed up to 70 DEG C, then (S) -4- (epoxies for being slowly added dropwise the dissolving of 80mL hexamethylenes
Ethane -2- bases) -2,3- Dihydrobenzofuranes (8.0g, 1.0equiv., 49.3mmol), drop
Add complete, be warmed up to 80 DEG C, after reaction 8 hours, the 50ml that adds water is quenched reaction, Ran Houyi
It is secondary through ethyl acetate 100ml*3, water 100ml extract, merge it is organic subtract each other pressure be evaporated (40 DEG C,
0.01MPa rotary evaporations), through column chromatography (column type silicagel column 25*500mm glass silica gel posts,
Silica gel 200-300 mesh, eluting solvent methyl alcohol:Dichloromethane=1:10) active ingredient is collected, it is thin
Layer detection terminal obtains the oil of (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) third formonitrile HCN of ring III
Shape thing 7.8g, yield 86%.
Confirmation is object III after testing.
1HNMR(CDCl3) δ 7.08 (t, J=8.0Hz, 1H), 6.73 (d, J=8.0Hz,
1H), 6.40 (d, J=8.0Hz, 1H), 4.66 (t, J=8.0Hz, 2H),
3.33-3.29(m,2H),2.58-2.53(m,1H),1.66-1.62(m,1H),
1.59-1.54(m,1H),1.51-1.50(m,1H).13CNMR(CDCl3)δ160.13,
134.20,128.61,126.99,121.06,116.09,108.53,71.16,28.52,
22.86,14.46,5.58.MS(ESI):M/z=285.2,280.0 (M+Na+)。
(2) prepared by ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) cyclopropyl) methylamine II
By (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) formonitrile HCN of ring third (3g, 1.0 equivalents,
16.2mmol) it is dissolved in 120mL2- methyltetrahydrofurans, after bath cooling on the rocks, (0-5 DEG C)
Lithium aluminium hydride reduction (0.92g, 1.5equiv., 24.3mmol) is dividedly in some parts, it is after 3 hours plus full
It is quenched with sodium bicarbonate aqueous solution 100ml, suction filtration, filter cake methanol rinse 3 times is (every time
10ml), filtrate decompression is spin-dried for (40 DEG C, 0.01MPa rotary evaporations), through column chromatography (column type
25*500mm, eluting solvent methyl alcohol:Dichloromethane=1:10) active ingredient, thin layer detection are collected
Terminal obtains 2.95g objects, yield 96%;
(3) N- (((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) cyclopropyl) methyl) propionyl
It is prepared by amine (Ta Simeiqiong) I
((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) cyclopropyl) methylamine (2.48g, 1.0
Equiv., 13.1mmol) it is dissolved in 30mL dichloromethane, bath cooling 0-5OC on the rocks is used
Syringe adds propionyl chloride (1.33g/1.3mL, 1.1equiv., 14.4mmol), has at once white
Color solid is produced, and triethylamine (1.32g/1.8mL, 1.0equiv., 13.1mmol) is then added dropwise,
System becomes clarification immediately, after half an hour, removes ice bath, and (20-25 DEG C) of room temperature is reacted overnight,
Reactant decompression is spin-dried for (40 DEG C, 0.01MPa rotary evaporations) solvent, column chromatography (column type
25*500mm, eluting solvent methyl alcohol:Dichloromethane=1:10) active ingredient, thin layer detection are collected
Terminal get Ta Simeiqiong product 2.8g, yield 88%.
Confirmation obtains product for Ta Simeiqiong after testing.
MS[M+H]:246.1
Embodiment 2 prepares Ta Simeiqiong
(1) preparation of (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) third formonitrile HCN of ring III
By potassium tert-butoxide (16.6g, 2.0equiv., 147.9mmol) add 200mL toluene in,
It is slowly added dropwise cyanogen methyl acid phosphate diethylester (26.2g, 3 equivalents, 147.9mmol), completion of dropping,
It is warmed up to 100 DEG C, then (S) -4- (oxirane -2- for being slowly added dropwise the dissolving of 100mL toluene
Base) -2,3- Dihydrobenzofuranes (8.0g, 1.0 equivalents, 49.3mmol), completion of dropping,
After maintaining 100 DEG C of reactions 10 hours, plus 50ml water quenchings are gone out reaction, then through extraction acetic acid second
Ester 100*3ml and water 100ml, organic phase evaporated under reduced pressure (40 DEG C, 0.01MPa rotary evaporations),
Through column chromatography (column type 25*500mm, eluting solvent methyl alcohol:Dichloromethane=1:10) collect effective
Composition, thin layer detection terminal obtains grease 9.0g, yield 88%.
(2) prepared by ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) cyclopropyl) methylamine II
By (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) formonitrile HCN of ring third (3g, 1.0 equivalents
6.2mmol) it is dissolved in 100mL isopropanols, after 0-5 DEG C of cooling of bath on the rocks, is dividedly in some parts hydrogenation
Aluminium lithium (1.85g, 3 equivalents, 48.6mmol), after 3 hours, plus saturated sodium bicarbonate is quenched,
Suction filtration, filter cake 10ml isopropyl alcohols 3 times, filtrate decompression is spin-dried for (40 DEG C, 0.01MPa
Rotary evaporation), through column chromatography (column type 25*500mm, eluting solvent methyl alcohol:Dichloromethane=1:10
Active ingredient is collected, thin layer detection terminal obtains III 2.98g, yield 97%;
(3) N- (((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) cyclopropyl) methyl) propionyl
It is prepared by amine (Ta Simeiqiong) I
((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) cyclopropyl) methylamine (2.48g, 1.0
Equiv., 13.1mmol) it is dissolved in 50mL n-hexanes, (0-5 DEG C) cooling of bath on the rocks is used
Syringe adds propionyl chloride (1.33g/1.3mL, 1.1 equivalents, 14.4mmol), there is white at once
Solid is produced, and is subsequently adding potassium carbonate (1.8g, 1.0 equivalents, 13.1mmol), and system is immediately
Become clarification, after half an hour, remove ice bath, (20-25 DEG C) of room temperature is reacted overnight, decompression (40 DEG C,
0.01MPa rotary evaporations) it is spin-dried for solvent, column chromatography (column type 25*500mm, eluting solvent methyl alcohol:
Dichloromethane=1:10) active ingredient is collected, thin layer detection terminal obtains product Ta Simeiqiong 2.9g,
Yield 90%.
Confirmation obtains product for Ta Simeiqiong after testing.
Embodiment 3 prepares (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) third formonitrile HCN of ring III
By sodium hydride (3.9g, 2.0 equivalents, 98.6mmol) add 100mL n-hexanes in,
It is slowly added dropwise cyanogen methyl acid phosphate diethylester (8.72g, 1 equivalent, 49.3mmol), completion of dropping,
Temperature rising reflux, then it is slowly added dropwise (S) -4- (oxirane -2- of 100mL n-hexane dissolutions
Base) -2,3- Dihydrobenzofuranes (8.0g, 1.0 equivalents, 49.3mmol), completion of dropping,
After back flow reaction 4 hours, plus 50ml water quenchings are gone out reaction, then through extracting (ethyl acetate successively
100*3ml;Water 100ml), organic phase evaporated under reduced pressure (40 DEG C, 0.01MPa rotary evaporations),
Through column chromatography (column type 25*500mm, eluting solvent methyl alcohol:Dichloromethane=1:10) collect effective
Composition, thin layer detection terminal, obtains the 7.7g of grease III, yield 85%.
It is III that confirmation obtains product after testing.
Embodiment 4 is prepared ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) cyclopropyl)
Methylamine II
By (1R, 2R) -2- obtained in embodiment 3 (2,3- Dihydrobenzofuranes -4- bases) ring third
Formonitrile HCN (3g, 1.0 equivalents, 16.2mmol) is dissolved in 120mL tetrahydrofurans, at room temperature in batches
Lithium aluminium hydride reduction (0.92g, 1.5 equivalents, 24.3mmol) is added, after 3 hours, plus saturated carbon
Sour hydrogen sodium is quenched, suction filtration, and filter cake is rinsed 3 times with 10ml tetrahydrofurans respectively, and filtrate subtracts
Pressure is spin-dried for (at 40 DEG C, 0.01MPa rotary evaporations), (column type 25*500mm, is washed through column chromatography
Desolventizing methyl alcohol:Dichloromethane=1:10) active ingredient is collected, thin layer detection terminal obtains II
2.85g, yield 93%.
It is II that confirmation obtains product after testing.
Embodiment 5 prepares ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) cyclopropyl) first
Amine II
By (1R, 2R) -2- obtained in embodiment 3 (2,3- Dihydrobenzofuranes -4- bases) ring third
Formonitrile HCN (3g, 1.0 equivalents, 16.2mmol) is dissolved in 120mL tetrahydrofurans, at room temperature in batches
(0.22g, 0.1 works as to add lithium aluminium hydride reduction (0.92g, 1.5 equivalents, 24.3mmol) and zinc chloride
Amount, 1.62mmol), after 2 hours, plus saturated sodium bicarbonate is quenched, and suction filtration, filter cake uses four
Hydrogen furans is rinsed 3 times, and filtrate decompression is spin-dried for (at 40 DEG C, 0.01MPa rotary evaporations), through post
Chromatography (column type 25*500mm, eluting solvent methyl alcohol:Dichloromethane=1:10) active ingredient is collected,
Thin layer detects terminal, obtains II 2.91g, yield 95%;
It is II that confirmation obtains product after testing.
Embodiment 6
N- (((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) cyclopropyl) methyl) propionamide
It is prepared by (Ta Simeiqiong) I
((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) cyclopropyl) obtained in embodiment 5
Methylamine (2.48g, 1.0equiv., 13.1mmol) is dissolved in 1, the 2- dichloroethanes of 30mL,
With syringe add propionic acid (2.9g, 3equiv., 39.3mmol), back flow reaction 10 hours,
Depressurize and be spin-dried for solvent (40 DEG C, 0.01MPa rotary evaporations), column chromatography (column type 25*500mm,
Eluting solvent methyl alcohol:Dichloromethane=1:10) active ingredient is collected, thin layer detection terminal must be produced
Thing Ta Simeiqiong 2.2g, yield 71%.
Confirmation is Ta Simeiqiong after testing.
Claims (10)
1. a kind of method for preparing Ta Simeiqiong, it is characterised in that the method reaction equation:
Comprise the following steps:
(1) (S) -4- (oxirane -2- bases) -2,3- Dihydrobenzofuranes and cyanylation agent are in alkali
In the presence of, reaction generation (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) formonitrile HCN of ring third
Ⅲ:
(2) (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) formonitrile HCN of ring third is reduced with reducing agent
Generation ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) cyclopropyl) methylamine II:
(3) ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) cyclopropyl) methylamine and acylation
Reagent, reacts generation Ta Simeiqiong I in the presence of acid binding agent:
2. the method for preparing Ta Simeiqiong according to claim 1, it is characterised in that
Step (1) the cyanalation reagent for using that reacts is cyanogen methyl phosphorodithioate or cyanogen methyl season phosphine
One or more in salt;(S) -4- (oxirane -2- bases) -2,3- Dihydrobenzofuranes with
The mol ratio of cyanylation agent is 1:1~5;The alkali is selected from sodium hydride, sodium tert-butoxide, tertiary fourth
One or more in potassium alcoholate, sodium methoxide or caustic alcohol;(S) -4- (oxirane -2- bases) -2,
3- Dihydrobenzofuranes are 1 with the mol ratio of alkali:1~5;
Reaction dissolvent is selected from one or more in toluene, paraxylene, n-hexane or hexamethylene;
The consumption of solvent is (S) -4- (oxirane -2- bases) -2,3- Dihydrobenzofuranes quality
8~50 times;
Reaction temperature is 50~110 DEG C;Reaction time is 4~12 hours.
3. the method for preparing Ta Simeiqiong according to claim 2, it is characterised in that
The reagent that cyanalation reaction described in step (1) is used is cyanogen methyl phosphorodithioate, most preferably cyanogen
Methyl acid phosphate diethylester;(S) -4- (oxirane -2- bases) -2,3- Dihydrobenzofuranes and cyanogen
The mol ratio of base reagent is 1:1~3;
The alkali is sodium hydride;(S) -4- (oxirane -2- bases) -2,3- Dihydrobenzofuranes
It is 1 with the mol ratio of alkali:1~3;
Reaction dissolvent is hexamethylene;The consumption of solvent is (S) -4- (oxirane -2- bases) -2,
25~30 times of 3- Dihydrobenzofuranes quality;
Reaction temperature is 70~100 DEG C;Reaction time is 8~10 hours.
4. the method for preparing Ta Simeiqiong according to claim 1, it is characterised in that
Step (2) described reducing agent is metal hydride, and preferred metal hydride is lithium aluminium hydride reduction;
The mol ratio of (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) formonitrile HCNs of ring third and reducing agent
It is 1:1~5;
Reaction dissolvent be selected from tetrahydrofuran, 2- methyltetrahydrofurans, ether, methyl tertiary butyl ether(MTBE),
One or more in isopropyl ether, glycol dimethyl ether or dioxane;The consumption of solvent for (1R,
2R) 8~60 times of -2- (2,3- Dihydrobenzofuranes -4- bases) ring the third formonitrile HCN quality;
Reaction temperature is -50~100 DEG C;Reaction time is 0.5~12 hour.
5. the method for preparing Ta Simeiqiong according to claim 4, it is characterised in that
Step (2) described reducing agent is that metal hydride is lithium aluminium hydride reduction;(1R,2R)-2-(2,3-
Dihydrobenzofuranes -4- bases) mol ratio of the formonitrile HCN of ring third and reducing agent is 1:1~3;
Reaction dissolvent is selected from tetrahydrofuran or methyltetrahydrofuran;The consumption of solvent for (1R,
2R) 20~30 times of -2- (2,3- Dihydrobenzofuranes -4- bases) ring the third formonitrile HCN quality.
6. the method for preparing Ta Simeiqiong according to claim 3 or 4, its feature exists
In the reduction reaction of step (2) is except with metal hydride reducing agent, being additionally added Louis
Acid catalysis promotes reaction, and described lewis acid is selected from BF3、SnCl4、FeCl3、AlCl3、
ZnCl2Or CuCl2, preferably BF3Or ZnCl2。
7. the method for preparing Ta Simeiqiong according to claim 6, it is characterised in that
The reduction reaction of step (2) is except with metal hydride reducing agent, being additionally added lewis acid and urging
Change and promote reaction, described lewis acid is selected from BF3Or ZnCl2。
8. the method for preparing Ta Simeiqiong according to claim 1, it is characterised in that
Solvent-free or carry out under having solvent, the solvent is selected from two to the acylation reaction of step (3)
One kind in chloromethanes, chloroform, 1,2- dichloroethanes, n-hexane, hexamethylene or methyl alcohol or
It is various;The consumption of solvent is ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) cyclopropyl)
0~50 times of methylamine quality;
The acylting agent is selected from one or more in propionyl chloride, propionic acid or propionic ester;Institute
State ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- bases) cyclopropyl) methylamine and be acylated examination
The mol ratio of agent is 1:1~10;
The acid binding agent be selected from triethylamine, diisopropyl ethyl amine, sodium acid carbonate, sodium carbonate,
One or more in potassium carbonate or pyridine;((1R, 2R) -2- (2,3- dihydrobenzo furans
Mutter -4- bases) cyclopropyl) methylamine and the mol ratio of acid binding agent be 1:1~8;
Reaction temperature is -20~80 DEG C;Reaction time is 0.5~12 hour.
9. the method for preparing Ta Simeiqiong according to claim 8, it is characterised in that
Solvent described in acylation reaction described in step (3) is dichloromethane;The consumption of solvent for ((1R,
2R) -2- (2,3- Dihydrobenzofuranes -4- bases) cyclopropyl) 5~15 times of methylamine quality.;
The acylting agent is propionyl chloride;((1R, 2R) -2- (2,3- dihydrobenzo furans
Mutter -4- bases) cyclopropyl) methylamine and the mol ratio of acylting agent be 1:1~3.
The acid binding agent is triethylamine;((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4-
Base) cyclopropyl) mol ratio of methylamine and acid binding agent is 1:1~3.
Reaction temperature is 0~20 DEG C;Reaction time is 6~10 hours.
10. compound (1R, 2R) -2- (2, the 3- Dihydrobenzofuranes -4- bases) formonitrile HCN of ring third,
Characterized in that, the compound is represented with following formula:
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5753709A (en) * | 1995-06-07 | 1998-05-19 | Bristol-Myers Squibb Company | N-acyl-2 aryl cyclopropylmethylamine derivatives as melatonergics |
CN102675268A (en) * | 2012-05-18 | 2012-09-19 | 济南志合医药科技有限公司 | Method for preparing (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanemethylamine |
CN103664697A (en) * | 2012-09-07 | 2014-03-26 | 博瑞生物医药技术(苏州)有限公司 | Chemical method used for preparing aromatic cyclopropanecarbonitrile and cyclopropylamine |
CN104327022A (en) * | 2014-10-17 | 2015-02-04 | 苏州明锐医药科技有限公司 | Preparation method of tasimelteon |
-
2015
- 2015-11-23 CN CN201510814397.2A patent/CN106749133B/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5753709A (en) * | 1995-06-07 | 1998-05-19 | Bristol-Myers Squibb Company | N-acyl-2 aryl cyclopropylmethylamine derivatives as melatonergics |
CN102675268A (en) * | 2012-05-18 | 2012-09-19 | 济南志合医药科技有限公司 | Method for preparing (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanemethylamine |
CN103664697A (en) * | 2012-09-07 | 2014-03-26 | 博瑞生物医药技术(苏州)有限公司 | Chemical method used for preparing aromatic cyclopropanecarbonitrile and cyclopropylamine |
CN104327022A (en) * | 2014-10-17 | 2015-02-04 | 苏州明锐医药科技有限公司 | Preparation method of tasimelteon |
Non-Patent Citations (1)
Title |
---|
J.SIVA PRASAD ET AL.,: "Development of Jacobsen Asymmetric Epoxidation and Sharpless Asymmetric Dihydroxylation Methods for the Large-Scale Preparation of a Chiral Dihydrobenzofuran Epoxide", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105949153A (en) * | 2016-05-10 | 2016-09-21 | 浙江工业大学 | Synthesis method of tasimelteon |
CN105949153B (en) * | 2016-05-10 | 2018-03-02 | 浙江工业大学 | A kind of Ta Simeiqiong synthetic method |
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