CN106749133B - A method of preparing Ta Simeiqiong - Google Patents
A method of preparing Ta Simeiqiong Download PDFInfo
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- CN106749133B CN106749133B CN201510814397.2A CN201510814397A CN106749133B CN 106749133 B CN106749133 B CN 106749133B CN 201510814397 A CN201510814397 A CN 201510814397A CN 106749133 B CN106749133 B CN 106749133B
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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 the preparation method of Ta Simeiqiong a kind of; this method is with (S)-4- (ethylene oxide-2- base)-2; 3- Dihydrobenzofuranes are starting material; (1R is generated through cyanalation reaction; 2R) (2-2-; 3- Dihydrobenzofuranes-4- base) cyclopropyl formonitrile HCN, reduction generate ((1R, 2R)-2- (2,3- Dihydrobenzofuranes-4- base) cyclopropyl) methylamine and Ta Simeiqiong is made in acylation reaction again.The method of the present invention reaction step is few, easy 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 biggish application value.
Description
Technical field
The present invention relates to pharmaceutical chemistry, and in particular to the preparation of drug more particularly to a kind of method for preparing Ta Simeiqiong.
Background technique
Ta Simeiqiong, trade name Hetlioz, the entitled 1R-trans of chemistry)-N- [[2- (2,3- dihydro -4- benzofurans
Base) cyclopropyl] methyl] propionamide, shown in structural formula I.The medicine is developed by Maryland, USA Vanda drugmaker, and 2014 1
The approval listing of the FDA of the moon 31 is a kind of novel melatonin (melatonin) receptor stimulating agent, as blind as a bat for treating
Non- 24- hours sleep arousal disorders in patient (" non-24 ")." non-24 " are that the disorders of circadian rhythms that one kind is chronic in blind person draws
The sleeping time puzzlement risen, light do not enter their eyes and its biological clock and 24- hours light and shade periods cannot be made same
Step, the i.e. patient are likely difficult to sleep of falling asleep or keep, some patient sleeps' modes reverse, and need to sleep and clear at night on daytime
It wakes up.
Currently, the synthetic method in relation to Ta Simeiqiong is substantially to pass through preparation to have in the key of chiral cylopropyl and amino
Mesosome (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl methylamine II, then intermediate II carries out amidation and obtains him
Si Meiqiong.
Patent US5856529 report, with (E) -3- (2,3- Dihydrobenzofuranes -4- base) acrylic acid for starting material, with
(-) -2,10- camphorsulfonic acid lactams condensation, with diazomethane carry out it is Cyclopropanated obtain chiral cylopropyl intermediate, with hydrogenation
Aluminium lithium is restored, then obtains aldehyde by SWERN (polite oxidation reaction) oxidation, then oxime is condensed into hydroxylamine hydrochloride, into one
Step is reduced into amine, and last and propionyl chloride reacts to obtain Ta Simeiqiong.But reactions steps of this method is longer, and must use diazonium first
Alkane constructs chiral intermediate, is unfavorable for safe operation, it is difficult to industrialize, specific reaction step is as follows:
。
The preparation method of CN102675268 report: by (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropanecarboxylic acid
Obtain (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl formyl chloride through chlorination, through ammonolysis generate (1R, 2R) -2- (2,
3- Dihydrobenzofuranes -4- base) cyclopropyl formamide, most (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- are obtained through reduction afterwards
Base) cyclopropyl methylamine this key intermediate.But the preparation of the starting material acid chiral cylopropyl of this method will also use diazonium first
The reagents such as alkane.
Reaction step is as follows:
The method that patent US6214869 reports synthesizing cis 2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl methylamine, should
Method is starting material by (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl-carbinol, protects hydroxyl with mesyl,
Then the mesyl after protection and sodium azide are acted on by azide substitution, and last hydrogenated aluminium lithium restores to obtain cis- 2- (2,3-
Dihydrobenzofuranes -4- base) cyclopropyl methylamine.But the technique of this method requires harshness, uses high-risk reagent N aN3, it is unfavorable for work
Industry metaplasia produces.
Reaction step is as follows:
。
In short, the method for prior art report, which all exists, uses highly difficult, expensive reagent, complex operation, equipment
Demanding defect, not can be adapted to industrial production, need to improve.
Summary of the invention
Technical problem to be solved by the present invention lies in above-mentioned shortcoming is overcome, researching and designing reaction is simple, operation letter
Just, at low cost, the method for preparing Ta Simeiqiong of high income.
The present invention provides a kind of methods for preparing Ta Simeiqiong, shown in following reaction equation:
The method of the present invention includes the following steps:
(1) (S) -4- (ethylene oxide -2- base) -2,3- Dihydrobenzofuranes and cyanylation agent in the presence of a base, cyano
Change reaction and generate (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl formonitrile HCN III:
Cyanylation agent described in the step be one of cyanogen methyl phosphorodithioate or cyanogen methyl quaternary phosphonium salt or a variety of, preferably
Cyanogen methyl phosphorodithioate, most preferably cyanogen methyl acid phosphate diethylester；(S) -4- (ethylene oxide -2- base) -2,3- Dihydrobenzofuranes with
The molar ratio of cyanylation agent is 1:1~5, wherein it is preferred that 1:1~3；
The alkali is selected from one of sodium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide or sodium ethoxide or a variety of, preferably
Sodium hydride；(S) molar ratio of -4- (ethylene oxide -2- base) -2,3- Dihydrobenzofuranes and alkali is 1:1~5, preferably 1:1~3.
Reaction dissolvent is selected from one of toluene, paraxylene, n-hexane or hexamethylene or a variety of, preferably hexamethylene；It is molten
The dosage of agent is 8~50 times, preferably 25~30 times of (S) -4- (ethylene oxide -2- base) -2,3- Dihydrobenzofuranes quality.
Reaction temperature is 50~110 DEG C, preferably 70~100 DEG C；Reaction time is 4~12 hours, preferably 8~10 hours.
Post-reaction treatment: being successively then solvent by 0.5-2 times of water quenching reaction of reactant solubilization dosage every time
0.5-2 times of ethyl acetate of amount extracts 3 times, is extracted again with equivalent amount of water, merge it is organic subtract each other pressure be evaporated (40 DEG C, 0.01MPa rotation
Turn evaporation), (column type silicagel column 25*500mm glass silica gel column, silica gel 200-300 mesh, eluting solvent methanol: dichloro are chromatographed through column
Methane=1:10) effective component is collected, thin layer detection terminal obtains target product III.
(2) (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl formonitrile HCN with reducing agent reduction reaction generate ((1R,
2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl) methylamine II:
Reducing agent described in the step is metal hydride, and preferred metal hydride is lithium aluminium hydride reduction；(1R,2R)-2-(2,
3- Dihydrobenzofuranes -4- base) molar ratio of cyclopropyl formonitrile HCN and reducing agent is 1:1~5, preferably 1:1~3.
Reduction reaction described in the step promotes in addition to Louis acid catalysis can also be added with metal hydride reducing agent
Reaction, the lewis acid are selected from BF3、SnCl4、FeCl3、AlCl3、ZnCl2Or CuCl2, preferably BF3Or ZnCl2。
Reaction dissolvent is selected from tetrahydrofuran, 2- methyltetrahydrofuran, ether, methyl tertiary butyl ether(MTBE), isopropyl ether, ethylene glycol two
One of methyl ether or dioxane are a variety of, preferably tetrahydrofuran or methyltetrahydrofuran；The dosage of solvent is (1R, 2R)-
8~60 times, preferably 20~30 times of 2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl formonitrile HCN quality.
Reaction temperature is -50~100 DEG C, and preferably 20~30 DEG C, the reaction time is 0.5~12 hour, and preferably 8~10 is small
When.
Post-reaction treatment: 0.5-2 times of the saturated sodium bicarbonate aqueous solution that quantity of solvent is added into reactant is quenched, and takes out
Filter, for filter cake with being every time 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 evaporation),
Effective component is collected through column chromatography (column type 25*500mm, eluting solvent methanol: methylene chloride=1:10), thin layer detects terminal,
Obtain object II.
(3) ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl) methylamine and acylting agent, in acid binding agent
In the presence of, it carries out acylation reaction and generates Ta Simeiqiong:
The reaction of the step is solvent-free or have and carry out under solvent, and the solvent is selected from methylene chloride, chloroform, 1,2- bis-
One of chloroethanes, n-hexane, hexamethylene or methanol are a variety of, preferably methylene chloride；The dosage 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 of propionyl chloride, propionic acid or propionic ester or a variety of, preferably propionyl chloride；It is described
The molar ratio of ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl) methylamine and acylting agent is 1:1~10, excellent
Select 1:1~3.
The acid binding agent is one in triethylamine, diisopropyl ethyl amine, sodium bicarbonate, sodium carbonate, potassium carbonate or pyridine
Kind is a variety of, preferably triethylamine；((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl) methylamine and acid binding agent
Molar ratio be 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, preferably 6~10 hours.
Post-reaction treatment: reactant decompression is spin-dried for (40 DEG C, 0.01MPa rotary evaporation) solvent, and column chromatographs (column type 25*
500mm, eluting solvent methanol: methylene chloride=1:10) effective component is collected, thin layer detects terminal, obtains target product I.
It is a further object of the present invention to provide compound (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl first
Nitrile III, the compound following formula indicate:
It is prepared by following method:
(S) -4- (ethylene oxide -2- base) -2,3- Dihydrobenzofuranes and cyanylation agent are in the presence of a base, cyanalation anti-
(1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl formonitrile HCN III should be generated:
The cyanylation agent is one of cyanogen methyl phosphorodithioate or cyanogen methyl quaternary phosphonium salt or a variety of, preferably cyanogen methyl
Phosphate, most preferably cyanogen methyl acid phosphate diethylester；(S) -4- (ethylene oxide -2- base) -2,3- Dihydrobenzofuranes with it is cyanalation
The molar ratio of reagent is 1:1~5, wherein it is preferred that 1:1~3；
The alkali is selected from one of sodium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide or sodium ethoxide or a variety of, preferably
Sodium hydride；(S) molar ratio of -4- (ethylene oxide -2- base) -2,3- Dihydrobenzofuranes and alkali is 1:1~5, preferably 1:1~3.
Reaction dissolvent is selected from one of toluene, paraxylene, n-hexane or hexamethylene or a variety of, preferably hexamethylene；It is molten
The dosage of agent is 8~50 times, preferably 25~30 times of (S) -4- (ethylene oxide -2- base) -2,3- Dihydrobenzofuranes quality.
Reaction temperature is 50~110 DEG C, preferably 70~100 DEG C；Reaction time is 4~12 hours, preferably 8~10 hours.
Post-reaction treatment: being successively then solvent by 0.5-2 times of water quenching reaction of reactant solubilization dosage every time
0.5-2 times of ethyl acetate of amount extracts 3 times, is extracted again with equivalent amount of water, merge it is organic subtract each other pressure be evaporated (40 DEG C, 0.01MPa rotation
Turn evaporation), (column type silicagel column 25*500mm glass silica gel column, silica gel 200-300 mesh, eluting solvent methanol: dichloro are chromatographed through column
Methane=1:10) effective component is collected, thin layer detection terminal obtains target product III.
Compound (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) the cyclopropyl formonitrile HCN III can be prepared by reduction
Ta Simeiqiong, therefore be the key intermediate of the method for the present invention.
The method of the present invention reaction step is few, easy to operate, and post-processing is easy, and product yield is high, and cost of material is low, is conducive to
Industrialized production has biggish application value.
Specific embodiment
Raw materials and reagents used in following embodiment are commercially available.
(S) -4- (ethylene oxide -2- base) -2,3- Dihydrobenzofuranes be it is commercially available or
Embodiment 1 prepares Ta Simeiqiong
(1) preparation of (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl formonitrile HCN III
Sodium hydride (3.9g, 2.0equiv., 98.6mmol) is added in 80mL hexamethylene, cyanogen methyl acid phosphate is slowly added dropwise
Diethylester (9.6g, 1.1 equiv (equivalent), 54.2mmol), is added dropwise, is warming up to 70 DEG C, then 80mL hexamethylene is slowly added dropwise
(S) -4- (ethylene oxide -2- base) -2,3- Dihydrobenzofuranes (8.0g, 1.0equiv., 49.3mmol) of alkane dissolution, are added dropwise
It finishes, after being warming up to 80 DEG C, reaction 8 hours, adds water 50ml quenching reaction, then successively through ethyl acetate 100ml*3, water
100ml extraction, merges organic pressure of subtracting each other and is evaporated (40 DEG C, 0.01MPa rotary evaporation), chromatographs (column type silicagel column 25* through column
500mm glass silica gel column, silica gel 200-300 mesh, eluting solvent methanol: methylene chloride=1:10) collect effective component, thin layer inspection
It surveys terminal and obtains III grease 7.8g of (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl formonitrile HCN, yield 86%.
It is object III through detection confirmation.
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) ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl) methylamine II preparation by (1R, 2R) -2- (2,
3- Dihydrobenzofuranes -4- base) cyclopropyl formonitrile HCN (3g, 1.0 equivalents, 16.2mmol) is dissolved in 120mL2- methyltetrahydrofuran, adds
After ice bath is cooling, (0-5 DEG C) is added portionwise lithium aluminium hydride reduction (0.92g, 1.5equiv., 24.3mmol) and adds saturated carbon after 3 hours
Sour hydrogen sodium water solution 100ml is quenched, and filters, filter cake with methanol rinse 3 times (each 10ml), filtrate decompression be spin-dried for (40 DEG C,
0.01MPa rotary evaporation), through column chromatography (column type 25*500mm, eluting solvent methanol: methylene chloride=1:10) collect effectively at
Point, thin layer detection terminal obtains 2.95g object, yield 96%；
(3) N- (((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl) methyl) propionamide (Ta Simeiqiong) I
Preparation
((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl) methylamine (2.48g, 1.0equiv.,
13.1mmol) be dissolved in 30mL methylene chloride, the cooling 0-5OC of bath on the rocks, with syringe be added propionyl chloride (1.33g/1.3mL,
1.1equiv., 14.4mmol), have white solid generation at once, then be added dropwise triethylamine (1.32g/1.8mL, 1.0equiv.,
13.1mmol), system becomes clarification immediately, after half an hour, removes ice bath, overnight, reactant decompression is revolved for (20-25 DEG C) of room temperature reaction
Dry (40 DEG C, 0.01MPa rotary evaporation) solvent, column chromatograph (column type 25*500mm, eluting solvent methanol: methylene chloride=1:10)
Effective component is collected, thin layer detects terminal get Ta Simeiqiong product 2.8g, yield 88%.
Obtaining product through detection confirmation is Ta Simeiqiong.
MS[M+H]:246.1
Embodiment 2 prepares Ta Simeiqiong
(1) preparation of (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl formonitrile HCN III
Potassium tert-butoxide (16.6g, 2.0equiv., 147.9mmol) is added in 200mL toluene, cyanogen methyl phosphorus is slowly added dropwise
Diethyl phthalate (26.2g, 3 equivalents, 147.9mmol), is added dropwise, is warming up to 100 DEG C, then the dissolution of 100mL toluene is slowly added dropwise
(S) -4- (ethylene oxide -2- base) -2,3- Dihydrobenzofuranes (8.0g, 1.0 equivalents, 49.3mmol), be added dropwise, maintain
After 100 DEG C are reacted 10 hours, add 50ml water quenching reaction, then through extracting ethyl acetate 100*3ml and water 100ml, organic phase
Evaporated under reduced pressure (40 DEG C, 0.01MPa rotary evaporation), through column chromatography (column type 25*500mm, eluting solvent methanol: methylene chloride=
Effective component 1:10) is collected, thin layer detection terminal obtains grease 9.0g, yield 88%.
(2) ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl) methylamine II preparation by (1R, 2R) -2- (2,
3- Dihydrobenzofuranes -4- base) cyclopropyl formonitrile HCN (3g, 1.0 equivalent 6.2mmol) is dissolved in 100mL isopropanol, 0-5 DEG C of bath on the rocks
After cooling, lithium aluminium hydride reduction (1.85g, 3 equivalents, 48.6mmol) are added portionwise, after 3 hours, saturated sodium bicarbonate are added to be quenched, takes out
Filter, for filter cake with 10ml isopropyl alcohol 3 times, filtrate decompression is spin-dried for (40 DEG C, 0.01MPa rotary evaporation), chromatographs (column type through column
25*500mm, eluting solvent methanol: methylene chloride=1:10 collect effective component, and thin layer detects terminal, obtains III 2.98g, yield
97%；
(3) N- (((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl) methyl) propionamide (Ta Simeiqiong) I
Preparation
((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl) methylamine (2.48g, 1.0equiv.,
13.1mmol) be dissolved in 50mL n-hexane, (0-5 DEG C) cooling of bath on the rocks, with syringe be added propionyl chloride (1.33g/1.3mL,
1.1 equivalents, 14.4mmol), there is white solid generation at once, potassium carbonate (1.8g, 1.0 equivalents, 13.1mmol) then is added, body
System becomes clarification immediately, after half an hour, removes ice bath, overnight, (40 DEG C, 0.01MPa rotation is steamed for decompression for (20-25 DEG C) of room temperature reaction
Hair) it is spin-dried for solvent, column chromatographs (column type 25*500mm, eluting solvent methanol: methylene chloride=1:10) and collects effective component, thin layer
Terminal is detected, product Ta Simeiqiong 2.9g, yield 90% are obtained.
Obtaining product through detection confirmation is Ta Simeiqiong.
Embodiment 3 prepares (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl formonitrile HCN III
Sodium hydride (3.9g, 2.0 equivalents, 98.6mmol) are added in 100mL n-hexane, cyanogen methyl acid phosphate two is slowly added dropwise
Ethyl ester (8.72g, 1 equivalent, 49.3mmol), is added dropwise, temperature rising reflux, then (S)-of 100mL n-hexane dissolution is slowly added dropwise
4- (ethylene oxide -2- base) -2,3- Dihydrobenzofuranes (8.0g, 1.0 equivalents, 49.3mmol), are added dropwise, back flow reaction 4
After hour, adds 50ml water quenching reaction, then successively extracted (ethyl acetate 100*3ml；Water 100ml), organic phase decompression is steamed
Dry (40 DEG C, 0.01MPa rotary evaporation) are received through column chromatography (column type 25*500mm, eluting solvent methanol: methylene chloride=1:10)
Collect effective component, thin layer detects terminal, obtains III 7.7g of grease, yield 85%.
Obtaining product through detection confirmation is III.
Embodiment 4 prepares ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl) methylamine II
By (1R, 2R) -2- made from embodiment 3 (2,3- Dihydrobenzofuranes -4- base) cyclopropyl formonitrile HCN (3g, 1.0 equivalents,
It 16.2mmol) is dissolved in 120mL tetrahydrofuran, is added portionwise at room temperature lithium aluminium hydride reduction (0.92g, 1.5 equivalents, 24.3mmol), 3
After hour, saturated sodium bicarbonate is added to be quenched, filtered, filter cake is rinsed 3 times with 10ml tetrahydrofuran respectively, and filtrate decompression is spin-dried for
(at 40 DEG C, 0.01MPa rotary evaporation) are received through column chromatography (column type 25*500mm, eluting solvent methanol: methylene chloride=1:10)
Collect effective component, thin layer detects terminal, obtains II 2.85g, yield 93%.
Obtaining product through detection confirmation is II.
Embodiment 5 prepares ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl) methylamine II
By (1R, 2R) -2- made from embodiment 3 (2,3- Dihydrobenzofuranes -4- base) cyclopropyl formonitrile HCN (3g, 1.0 equivalents,
16.2mmol) be dissolved in 120mL tetrahydrofuran, be added portionwise at room temperature lithium aluminium hydride reduction (0.92g, 1.5 equivalents, 24.3mmol) and
Zinc chloride (0.22g, 0.1 equivalent, 1.62mmol), after 2 hours, adds saturated sodium bicarbonate to be quenched, and filters, filter cake tetrahydrofuran
Rinsing 3 times, filtrate decompression is spin-dried for (at 40 DEG C, 0.01MPa rotary evaporation), chromatographs (column type 25*500mm, eluting solvent first through column
Alcohol: methylene chloride=1:10) effective component is collected, thin layer detects terminal, obtains II 2.91g, yield 95%；
Obtaining product through detection confirmation is II.
Embodiment 6
N- (((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl) methyl) propionamide (Ta Simeiqiong) I system
It is standby
((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl) methylamine made from embodiment 5 (2.48g,
1.0equiv., 13.1mmol) be dissolved in 1, the 2- dichloroethanes of 30mL, with syringe be added propionic acid (2.9g, 3equiv.,
39.3mmol), back flow reaction 10 hours, decompression are spin-dried for solvent (40 DEG C, 0.01MPa rotary evaporation), and column chromatographs (column type 25*
500mm, eluting solvent methanol: methylene chloride=1:10) effective component is collected, thin layer detects terminal, obtains product Ta Simeiqiong
2.2g, yield 71%.
It is Ta Simeiqiong through detection confirmation.
Claims (11)
1. a kind of method for preparing Ta Simeiqiong, it is characterised in that this method reaction equation:
The following steps are included:
(1) in the presence of a base, reaction generates for (S) -4- (ethylene oxide -2- base) -2,3- Dihydrobenzofuranes and cyanylation agent
(1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl formonitrile HCN III:
；
(2) (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl formonitrile HCN is restored with reducing agent and generates ((1R, 2R) -2-
(2,3- Dihydrobenzofuranes -4- base) cyclopropyl) methylamine II:
；
(3) ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl) methylamine and acylting agent exist in acid binding agent
Lower reaction generates Ta Simeiqiong I:
。
2. the method according to claim 1 for preparing Ta Simeiqiong, which is characterized in that step (1) the cyanalation reaction
The reagent used is one of cyanogen methyl phosphorodithioate or cyanogen methyl quaternary phosphonium salt or a variety of；(S) -4- (ethylene oxide -2- base) -2,
The molar ratio of 3- Dihydrobenzofuranes and cyanylation agent is 1:1~5；The alkali is selected from sodium hydride, sodium tert-butoxide, the tert-butyl alcohol
One of potassium, sodium methoxide or sodium ethoxide are a variety of；(S) -4- (ethylene oxide -2- base) -2,3- Dihydrobenzofuranes and alkali
Molar ratio is 1:1~5；
Reaction dissolvent is selected from one of toluene, paraxylene, n-hexane or hexamethylene or a variety of；The dosage of solvent is (S) -4-
8~50 times of (ethylene oxide -2- base) -2,3- Dihydrobenzofuranes quality；
Reaction temperature is 50~110 DEG C；Reaction time is 4~12 hours.
3. the method according to claim 2 for preparing Ta Simeiqiong, which is characterized in that cyanalation anti-described in step (1)
The reagent that should be used is cyanogen methyl acid phosphate diethylester；(S) -4- (ethylene oxide -2- base) -2,3- Dihydrobenzofuranes with it is cyanalation
The molar ratio of reagent is 1:1~3；
The alkali is sodium hydride；(S) molar ratio of -4- (ethylene oxide -2- base) -2,3- Dihydrobenzofuranes and alkali be 1:1~
3；
Reaction dissolvent is hexamethylene；The dosage of solvent is (S) -4- (ethylene oxide -2- base) -2,3- Dihydrobenzofuranes quality
25~30 times；
Reaction temperature is 70~100 DEG C；Reaction time is 8~10 hours.
4. the method according to claim 1 for preparing Ta Simeiqiong, which is characterized in that step (2) reducing agent is gold
Belong to hydride；The molar ratio of (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl formonitrile HCN and reducing agent is 1:1~5；
Reaction dissolvent is selected from tetrahydrofuran, 2- methyltetrahydrofuran, ether, methyl tertiary butyl ether(MTBE), isopropyl ether, glycol dimethyl ether
Or one of dioxane or a variety of；The dosage of solvent is (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl first
8~60 times of nitrile quality；
Reaction temperature is -50~100 DEG C；Reaction time is 0.5~12 hour.
5. the method according to claim 4 for preparing Ta Simeiqiong, which is characterized in that step (2) described metal hydride
For lithium aluminium hydride reduction.
6. the method according to claim 4 for preparing Ta Simeiqiong, which is characterized in that step (2) reducing agent is gold
Category hydride is lithium aluminium hydride reduction；The molar ratio of (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl formonitrile HCN and reducing agent
For 1:1~3；
Reaction dissolvent is selected from tetrahydrofuran or 2- methyltetrahydrofuran；The dosage of solvent is (1R, 2R) -2- (2,3- dihydrobenzo
Furans -4- base) 20~30 times of cyclopropyl formonitrile HCN quality.
7. the method according to claim 3 or 4 for preparing Ta Simeiqiong, which is characterized in that the reduction reaction of step (2) is removed
Metal hydride reducing agent is used, Louis acid catalysis is additionally added and promotes reaction, the lewis acid is selected from BF3、SnCl4、
FeCl3、AlCl3、ZnCl2Or CuCl2。
8. the method according to claim 7 for preparing Ta Simeiqiong, which is characterized in that the reduction reaction of step (2) in addition to
With metal hydride reducing agent, it is additionally added Louis acid catalysis and promotes reaction, the lewis acid is selected from BF3Or ZnCl2。
9. the method according to claim 1 for preparing Ta Simeiqiong, which is characterized in that the acylation reaction of step (3) exists
Solvent-free or have and carry out under solvent, the solvent is selected from methylene chloride, chloroform, 1,2- dichloroethanes, n-hexane, hexamethylene or first
One of alcohol is a variety of；The dosage of solvent is ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl) methylamine matter
0~50 times of amount；
The acylting agent is selected from one of propionyl chloride, propionic acid or propionic ester or a variety of；((1R, the 2R) -2- (2,3-
Dihydrobenzofuranes -4- base) cyclopropyl) molar ratio of methylamine and acylting agent is 1:1~10；
The acid binding agent is selected from one of triethylamine, diisopropyl ethyl amine, sodium bicarbonate, sodium carbonate, potassium carbonate or pyridine
Or it is a variety of；The molar ratio of ((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl) methylamine and acid binding agent is 1:1
~8；
Reaction temperature is -20~80 DEG C；Reaction time is 0.5~12 hour.
10. the method according to claim 9 for preparing Ta Simeiqiong, which is characterized in that
Solvent described in acylation reaction described in step (3) is methylene chloride；The dosage of solvent is ((1R, 2R) -2- (2,3- bis-
Hydrogen benzofuran -4- base) cyclopropyl) 5~15 times of methylamine quality；
The acylting agent is propionyl chloride；((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl) methylamine
Molar ratio with acylting agent is 1:1~3；
The acid binding agent is triethylamine；((1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl) methylamine with tie up
The molar ratio of sour agent is 1:1~3；
Reaction temperature is 0~20 DEG C；Reaction time is 6~10 hours.
Compound 11. (1R, 2R) -2- (2,3- Dihydrobenzofuranes -4- base) cyclopropyl formonitrile HCN, which is characterized in that the compound
Following formula indicates:
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| 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 |
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| 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 |
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