CN103113177B - Preparation method of amide - Google Patents
Preparation method of amide Download PDFInfo
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- CN103113177B CN103113177B CN201310048323.3A CN201310048323A CN103113177B CN 103113177 B CN103113177 B CN 103113177B CN 201310048323 A CN201310048323 A CN 201310048323A CN 103113177 B CN103113177 B CN 103113177B
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- PODGQCDXLNFETO-DTQDAUPPSA-N CCC(N[C@H](C1)[C@@]1(C1)C1c1cccc2c1CCO2)=O Chemical compound CCC(N[C@H](C1)[C@@]1(C1)C1c1cccc2c1CCO2)=O PODGQCDXLNFETO-DTQDAUPPSA-N 0.000 description 1
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Abstract
The invention discloses a preparation method of amide. The amide contains a structure shown in the specification. The method comprises the following step: carrying out one-step reaction by adopting a corresponding amide type compound as a starting reactant, a reducing agent and a corresponding acid to prepare a final amide product. According to the preparation method disclosed by the invention, the reaction steps are reduced, the cost can be effectively reduced, and the process flow is simplified.
Description
Technical field
The present invention relates to a kind of the field of chemical synthesis, specifically, relate to a kind of preparation method of acid amides, described acid amides is melatonin receptors agonist class acid amides, and the method adopts corresponding amides to prepare final amide product as initial reactant, reductive agent and corresponding acid by single stage method.
Background technology
Melatonin (Melatonin, MT) is a kind of Benzazole compounds, is a kind of amides hormone of pineal gland secretion.
Melatonin receptors is divided into three hypotypes, is respectively MT
1, MT
2and MT
3, research shows to only have MT
1and MT
2hypotype is relevant with adjustment diel rhythm.By activating this several melatonin receptors hypotype, can adenylate cyclase be suppressed and reduce the release of cAMP.Optionally activate the generation that MT1 acceptor can promote to sleep, optionally activating MT2 acceptor then has important relationship with adjustment the length of one's sleep.
A series of benzo ring system derivative has been synthesized in military pharmacy research centre, field under the inspiration of melatonin chemical structure, and its U.S. of China and Sweden is for holding high (Ramelteon) in list marketing in 2005.
Rui Mei is for high (Ramelteon)
In addition as MT
1and MT
2agomelatine (agomelatine) the also list marketing of receptor stimulant.
Agomelatine (Agomelatine)
A kind of new oral melatonin receptor agonist by the Ta Simeiqiong represented with following formula 1, developed by Maryland, USA Wanda drugmaker, unexpected advanced sleep time person's Sleep latency and sleep maintenance situation can be improved, potential treatment circadian rhythm sleep disorders patient transience insomnia simultaneously.
All containing amide group in the chemical structure of above-mentioned melatonin receptor agonist.The general amine that all first composite structure is similar in its preparation process, then makes to be obtained by reacting final product as the amine of presoma and acyl chlorides or acid anhydrides etc.Such as in the preparation of Ta Simeiqiong, (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-base) ring third methylamine usually taking formula 2 to represent as intermediate further with propionyl chloride Reactive Synthesis Ta Simeiqiong.
Formula 2
Prepare in the reaction of final product by aforesaid method, presoma must react further and could prepare final product with propionyl chloride, and therefore reactions steps is long and complicated, economy reduction.
Summary of the invention
For above prior art Problems existing, the present inventor proposes containing of a kind of improvement
the preparation method of the acid amides of structure, the method does not adopt amine conventional in prior art as presoma, but adopts corresponding acid amides directly to synthesize final product as initial reactant one step.
Specifically, preparation method of the present invention can be represented by following reaction formula 1:
Preparation method of the present invention carries out according to following following steps:
Solvent, reductive agent and initial reactant are added in reactor, reflux state is heated under stirring, then in reaction solution, slowly acid is dripped, after dropwising rear maintenance temperature of reaction constant continuation reaction certain hour, be cooled to room temperature stopped reaction, gained mixture is poured in frozen water, adjust ph is to acid, stratification, organic phase, through washing, drying, filtration, precipitation, can obtain final product.
Not necessarily, the final product of gained can also through conventional aftertreatment to be further purified.Described conventional aftertreatment comprises, but be not limited to: crude product methyl tertiary butyl ether/normal hexane mixed solvent is carried out recrystallization or through chromatographic silica gel chromatographic column with methyl tertiary butyl ether/normal hexane mixing solutions drip washing, get leacheate stage casing, desolventizing obtains highly purified product.
Group A wherein in initial reactant is the aromatic ring of substituted or unsubstituted C6 to C20 and the hetero-aromatic ring of substituted or unsubstituted C6 to C20.
Radicals R is direct key, or be selected from the alkylidene group of the straight or branched of C1 to C8, the alkenylene of the straight or branched of C2 to C8 and the substituted or unsubstituted cycloalkylidene of C3 to C8, the cycloalkylidene of the C3 to C8 of wherein said replacement can be selected from the substituting group of the alkyl of the straight or branched of C1 to C8 containing 1 to 3.
According to a preferred version of the present invention, in described group A, the aromatic ring of described substituted or unsubstituted C6 to C20 is phenyl, naphthyl, anthryl, phenanthryl, indenyl, and the hetero-aromatic ring of described substituted or unsubstituted C6 to C20 is the benzheterocycle of C8 to C20.More preferably, the benzheterocycle of described C8 to C20 is that described heteroatoms is preferably O or N containing one that is selected from O, N and S, the benzheterocycle of two or three heteroatomic C8 to C20.
The substituting group that substituting group on the aromatic ring of the C6 to C20 of wherein said replacement is one, two or three are selected from the alkyl of C1 to C8 or the alkoxyl group of C1 to C8; Preferably, described substituting group is selected from the alkyl of C1 to C4 or the alkoxyl group of C1 to C4.
R is direct key, or be selected from the alkylidene group of the straight or branched of C1 to C4, the alkenylene of the straight or branched of C2 to C4 and the substituted or unsubstituted cycloalkylidene of C3 to C6, the cycloalkylidene of the C3 to C6 of wherein said replacement can be selected from the substituting group of the alkyl of the straight or branched of C1 to C3 containing 1 to 3.
According to further preferred version of the present invention, described group A is selected from described substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, indoles, isoindole, cumarone, diphenylene-oxide, thionaphthene, benzoglyoxaline, quinoline, isoquinoline 99.9 or benzoxazoles.
The substituting group that substituting group on the phenyl of wherein said replacement and the naphthyl of replacement is one, two or three are selected from methyl, ethyl, propyl group, methoxyl group, oxyethyl group and propoxy-.
R is direct key, or be selected from methylene radical, ethylidene, propylidene, isopropylidene, vinylidene, propenylidene, substituted or unsubstituted cyclopropylidene, substituted or unsubstituted sub-cyclobutyl or substituted or unsubstituted cyclopentylidene, the cyclopentylidene of the cyclopropylidene of wherein said replacement, the sub-cyclobutyl of replacement and replacement can be selected from the substituting group of methyl, ethyl, propyl group and butyl containing 1 to 3.
Described sour R ' COOH is organic acid, is selected from the aromatic carboxylic acid of the aliphatic carboxylic acid of C1 to C20, the aromatic carboxylic acid of C6 to C20 or C6 to C20.Preferably, described organic acid is selected from the aromatic carboxylic acid of the aliphatic carboxylic acid of C1 to C10, the aromatic carboxylic acid of C6 to C12 or C6 to C12.More preferably, described organic acid is selected from formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, sad, n-capric acid, undecylenic acid or laurostearic acid.
Described reductive agent be selected from lithium borohydride, sodium borohydride, POTASSIUM BOROHYDRIDE and borine one or more.
Wherein, the mol ratio of initial reactant and reductive agent is 1:2 ~ 1:9, is preferably 1:3 ~ 1:7, is more preferably 1:4.5 ~ 1:6.5.
Reductive agent is 1:1.8 ~ 1:5 with the mol ratio of acid, is preferably 1:3 ~ 1:4.5, is more preferably 1:3 ~ 1:3.5.
Temperature of reaction after acid dropwises controls in room temperature to 100 DEG C, and the reaction times is 2 ~ 12 hours; Preferable reaction temperature is 35 to 85 DEG C, and the reaction times is 3 ~ 10 hours; More preferably temperature of reaction is 44 to 75 DEG C, and the reaction times is 4 ~ 7 hours.
Described solvent is for being selected from methylene dichloride, trichloromethane, tetrahydrofuran (THF), ether, isopropyl ether, methyl tertiary butyl ether, glycol dimethyl ether, dioxane and N, one or more in dinethylformamide (DMF), are preferably methylene dichloride, tetrahydrofuran (THF) or glycol dimethyl ether.
Beneficial effect
Method of the present invention adopts single stage method to prepare acid amides, decreases reactions steps, and technique is simple, improves the utilization ratio of initial reactant, effectively reduces cost, can realize large-scale industrial production.
Embodiment
Adopt single stage method to prepare in the method for acid amides in the present invention, the rate of addition of acid will strictly control, because if rate of addition is too fast, then produces a large amount of bubble, has punching material dangerous; If rate of addition is excessively slow, then the reaction times is long, economical not.According to the dropping principle of above acid, time for adding can be controlled 4 little in 24 hours, preferably 8 is little in 16 hours.But to those skilled in the art, be appreciated that the rate of addition of acid can regulate in real time according to practical situation in the large-scale test of expansion or production.
The mol ratio of initial reactant and reductive agent is 1:2 ~ 1:9, if this mol ratio is less than 1:2, then initial reactant reaction not exclusively, and can remain initial reactant in final product, this not only causes waste, and unfavorable to the purifying of final reacting product; If this mol ratio is greater than 1:9, then reductive agent is excessive causes the consumption that must strengthen acid, economical not.Therefore the mol ratio of initial reactant and reductive agent is preferably 1:3 ~ 1:7, is more preferably 1:4.5 ~ 1:6.5.
Described reductive agent is 1:1.8 ~ 1:5 with the mol ratio of acid, if this mol ratio is less than 1:1.8, then reductive agent reaction is complete not, reacts not thorough; If this mol ratio is greater than 1:5, then propionic acid is excessive too many economical not.Therefore the mol ratio of reductive agent and propionic acid is preferably 1:3 ~ 1:4.5, is more preferably 1:3 ~ 1:3.5.
Described solvent there is no particular restriction, described solvent can not participate in reacting as long as can dissolve the reactant related in method of the present invention simultaneously, but can for being selected from methylene dichloride, trichloromethane, tetrahydrofuran (THF), ether, isopropyl ether, methyl tertiary butyl ether, glycol dimethyl ether, dioxane and N, one or more in dinethylformamide (DMF), are preferably methylene dichloride, tetrahydrofuran (THF) or glycol dimethyl ether.
Following examples are only enumerate as the example of embodiment of the present invention, do not form any restriction to the present invention, it will be appreciated by those skilled in the art that the amendment in the scope not departing from essence of the present invention and design all falls into protection scope of the present invention.
Embodiment 1: compound 1(Ta Simeiqiong) preparation
(compound 1)
By (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-base) the ring propyl formamide of 2.0g (
), (this initial reactant can be prepared according to method disclosed in Chinese patent application CN102675268A), the sodium borohydride of 1.9g adds in 40ml anhydrous tetrahydro furan, reflux, wherein (1R, 2R)-2-(2, 3-Dihydrobenzofuranes-4-base) mol ratio of ring propyl formamide and sodium borohydride is about 1:5, the mixing solutions (mol ratio of sodium borohydride and propionic acid is about 1:3.3) of slow dropping 12.5g propionic acid and 20ml anhydrous tetrahydro furan, within 12 hours, add, then reaction about 6 hours is continued at 70 DEG C, be down to room temperature, material is slowly poured in 100ml frozen water, stir the lower hydrochloric acid dripping mass concentration 10% and be about 20g, adjust pH is about 2.The product obtained is sloughed solvents tetrahydrofurane through underpressure distillation, then the 60ml that adds methylene chloride extracts, aqueous phase extracts once with methylene dichloride 30ml again, merge organic phase, the organic phase obtained is washed through saturated sodium bicarbonate solution, then washes with water, anhydrous magnesium sulfate drying, filter, revolve and steam evaporation and slough solvent and obtain oily matter 2.5g.The oily matter obtained is separated through chromatographic column, wherein with the methyl tertiary butyl ether of 1:1/normal hexane mixing solutions drip washing, gets leacheate stage casing, then slough solvent, obtain white needle-like crystals Ta Simeiqiong 2.2g, purity 99.9%, productive rate 92%.The nuclear magnetic data of gained white needle-like crystals is as follows, proves that the product obtained is Ta Simeiqiong.
M.p.71-72 DEG C, nuclear-magnetism 1HNMR (CDCl3) δ 0.93(m, 2H), 1.18(t, 3H), 1.30(m, 1H), 1.73(m, 1H), 2.22(q, 2H), 3.23(t, 2H), 3.30(q, 2H), 4.58(t, 2H), 5.73(s, 1H), 6.33(d, 1H), 6.60(d, 1H), 7.01(t, 1H).
Embodiment 2: the auspicious U.S. of compound 2(is for high) preparation
(compound 2)
By the compound of 3.2g
as initial reactant (preparation method that this initial reactant can describe according to patent JP11080106 obtains), 1.9g sodium borohydride add in 40ml anhydrous tetrahydro furan, reflux, wherein the mol ratio of initial reactant and sodium borohydride is about 1:5, the mixing solutions (mol ratio of sodium borohydride and propionic acid is about 1:3.8) of slow dropping 12.5g propionic acid and 20ml anhydrous tetrahydro furan, within 12 hours, add, then reaction about 6 hours is continued at 70 DEG C, be down to room temperature, material is slowly poured in 100ml frozen water, stir the lower hydrochloric acid dripping mass concentration 10% and be about 20g, adjust pH is about 2.The product obtained is sloughed solvents tetrahydrofurane through underpressure distillation, then the 60ml that adds methylene chloride extracts, aqueous phase extracts once with methylene dichloride 30ml again, merge organic phase, the organic phase obtained is washed through saturated sodium bicarbonate solution, then washes with water, anhydrous magnesium sulfate drying, filter, revolve and steam evaporation and slough solvent and obtain oily matter 2.3g.The oily matter obtained is separated through chromatographic column, wherein with the methyl tertiary butyl ether of 1:1/normal hexane mixing solutions drip washing, gets leacheate stage casing, then slough solvent, obtain white needle-like crystals 2.7g, purity 97.6%, productive rate 91%.The nuclear magnetic data of gained white needle-like crystals is as follows:
m.p.112-113℃
1HNMR(CDCl3)δ:1.14(t,J=7.6Hz,3H),1.58-1.72(m,1H),1.75-19.0(m,1H),1.98-2.09(m,1H),2.17(q,J=7.6Hz,2H),2.23-2.35(m,1H),2.71-2.98(m,2H),3.03-3.29(m,3H),3.30-3.40(m,2H),4.45-4.65(m,2H),5.41(brs,1H),6.61(d,J=7.98Hz,1H),6.95(d,J=7.98Hz,1H)。
Embodiment 3: compound 3(melatonin) preparation
(compound 3)
By the compound of 3.5g
as initial reactant, (this initial reactant can according to document Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; Vol.251; (1960); P.394 the preparation method described obtains), the sodium borohydride of 1.9g adds in 40ml anhydrous tetrahydro furan, reflux, wherein the mol ratio of initial reactant and sodium borohydride is about 1:5, the mixing solutions (mol ratio of sodium borohydride and acetic acid is about 1:3.5) of slow dropping 20.9g acetic acid and 20ml anhydrous tetrahydro furan, within 12 hours, add, then reaction about 6 hours is continued at 70 DEG C, be down to room temperature, material is slowly poured in 100ml frozen water, stir the lower hydrochloric acid dripping mass concentration 10% and be about 20g, adjust pH is about 2.The product obtained is sloughed solvents tetrahydrofurane through underpressure distillation, then the 60ml that adds methylene chloride extracts, aqueous phase extracts once with methylene dichloride 30ml again, merge organic phase, the organic phase obtained is washed through saturated sodium bicarbonate solution, then washes with water, anhydrous magnesium sulfate drying, filter, revolve and steam evaporation and slough solvent and obtain oily matter 2.7g.The oily matter obtained is separated through chromatographic column, wherein with the methyl tertiary butyl ether of 1:1/normal hexane mixing solutions drip washing, gets leacheate stage casing, then slough solvent, obtain white needle-like crystals 2.9g, purity 96%, productive rate 89%.The nuclear magnetic data of gained white needle-like crystals is as follows:
m.p.116℃～117℃
1HNMR(CDCl
3)δ:1.93(s,3H,CH
3),2.94(t,2H,CH
2CH
2NH),3.59(dd,2H,CH
2CH
2NH),3.86(s,3H,OCH
3),5.58(s,1H,NH),6.86-7.26(m,4H,Ph-H&Indol-H),8.02(s,1H,Indol-NH)
Embodiment 4: compound 4(Agomelatine (Agomelatine)) preparation
(compound 4)
By the compound of 3.4g
as initial reactant (this initial reactant can be prepared according to method disclosed in patent application US5194614), the sodium borohydride of 1.9g adds in 40ml anhydrous tetrahydro furan, reflux, wherein the mol ratio of initial reactant and sodium borohydride is about 1:5, the mixing solutions (mol ratio of sodium borohydride and acetic acid is about 1:2.9) of slow dropping 18.7g acetic acid and 20ml anhydrous tetrahydro furan, within 12 hours, add, then reaction about 6 hours is continued at 70 DEG C, be down to room temperature, material is slowly poured in 100ml frozen water, stir the lower hydrochloric acid dripping mass concentration 10% and be about 20g, adjust pH is about 2.The product obtained is sloughed solvents tetrahydrofurane through underpressure distillation, then the 60ml that adds methylene chloride extracts, aqueous phase extracts once with methylene dichloride 30ml again, merge organic phase, the organic phase obtained is washed through saturated sodium bicarbonate solution, then washes with water, anhydrous magnesium sulfate drying, filter, revolve and steam evaporation and slough solvent and obtain oily matter 2.6g.The oily matter obtained is separated through chromatographic column, wherein with the methyl tertiary butyl ether of 1:1/normal hexane mixing solutions drip washing, gets leacheate stage casing, then slough solvent, obtain white crystal 3.0g, purity 97%, productive rate 98%.Gained white crystal, m.p.107-108 DEG C.
Embodiment 5: the preparation of compound 5
(compound 5)
By (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-base) the ring propyl formamide of 2.0g (
, this initial reactant can be prepared according to method disclosed in Chinese patent application CN102675268A), the sodium borohydride of 1.9g adds in 40ml anhydrous tetrahydro furan, reflux, wherein (1R, 2R)-2-(2, 3-Dihydrobenzofuranes-4-base) mol ratio of ring propyl formamide and sodium borohydride is about 1:5, the mixing solutions (mol ratio of sodium borohydride and acetic acid is about 1:3.5) of slow dropping 16.4g acetic acid and 20ml anhydrous tetrahydro furan, within 12 hours, add, then reaction about 6 hours is continued at 70 DEG C, be down to room temperature, material is slowly poured in 100ml frozen water, stir the lower hydrochloric acid dripping mass concentration 10% and be about 20g, adjust pH is about 2.The product obtained is sloughed solvents tetrahydrofurane through underpressure distillation, then the 60ml that adds methylene chloride extracts, aqueous phase extracts once with methylene dichloride 30ml again, merge organic phase, the organic phase obtained is washed through saturated sodium bicarbonate solution, then washes with water, anhydrous magnesium sulfate drying, filter, revolve and steam evaporation and slough solvent and obtain oily matter 2.6g.The oily matter obtained is separated through chromatographic column, wherein with the methyl tertiary butyl ether of 1:1/normal hexane mixing solutions drip washing, gets leacheate stage casing, then slough solvent, obtain white needle-like crystals 2.2g, purity 98.7%, productive rate 92%.Gained white needle-like crystals, m.p.69-70 DEG C.
Embodiment 6: the preparation of compound 6
(compound 6)
By the compound of 3.6g
as initial reactant (preparation method that this initial reactant can describe according to US6160134 obtains), the sodium borohydride of 1.9g adds in 40ml anhydrous tetrahydro furan, reflux, wherein the mol ratio of initial reactant and sodium borohydride is about 1:5, the mixing solutions (mol ratio of sodium borohydride and propionic acid is about 1:2.9) of slow dropping 11.9g propionic acid and 20ml anhydrous tetrahydro furan, within 12 hours, add, then reaction about 6 hours is continued at 70 DEG C, be down to room temperature, material is slowly poured in 100ml frozen water, stir the lower hydrochloric acid dripping mass concentration 10% and be about 20g, adjust pH is about 2.The product obtained is sloughed solvents tetrahydrofurane through underpressure distillation, then the 60ml that adds methylene chloride extracts, aqueous phase extracts once with methylene dichloride 30ml again, merge organic phase, the organic phase obtained is washed through saturated sodium bicarbonate solution, then washes with water, anhydrous magnesium sulfate drying, filter, revolve and steam evaporation and slough solvent and obtain oily matter 2.4g.The oily matter obtained is separated through chromatographic column, wherein with the methyl tertiary butyl ether of 1:1/normal hexane mixing solutions drip washing, gets leacheate stage casing, then slough solvent, obtain white powder 2.8g, purity 96%, productive rate 91%.Gained white powder, m.p.77-78 DEG C.
In terms of existing technologies, preparation method of the present invention decreases reactions steps, can effectively reduce costs, simplification of flowsheet.
Claims (9)
1. a preparation method for acid amides, described preparation method is represented by following reaction formula 1 and carries out according to following following steps:
Solvent, reductive agent and initial reactant are added in reactor, reflux state is heated under stirring, then in reaction solution, slowly drip sour R ' OOH, after dropwising rear maintenance temperature of reaction constant continuation reaction certain hour, be cooled to room temperature stopped reaction, gained mixture is poured in frozen water, adjust ph is extremely acid, stratification, and organic phase is through washing, drying, filtration, precipitation, final product can be obtained
Group A wherein in initial reactant is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, indoles, isoindole, cumarone, diphenylene-oxide, thionaphthene, benzoglyoxaline, quinoline, isoquinoline 99.9 or benzoxazoles;
The substituting group that substituting group on the phenyl of wherein said replacement and the naphthyl of replacement is one, two or three are selected from methyl, ethyl, propyl group, methoxyl group, oxyethyl group and propoxy-;
R is direct key, or be selected from methylene radical, ethylidene, propylidene, isopropylidene, vinylidene, propenylidene, substituted or unsubstituted cyclopropylidene, substituted or unsubstituted sub-cyclobutyl or substituted or unsubstituted cyclopentylidene, the cyclopentylidene of the cyclopropylidene of wherein said replacement, the sub-cyclobutyl of replacement and replacement contains the substituting group that 1 to 3 is selected from methyl, ethyl, propyl group and butyl;
Described sour R ' OOH is selected from formic acid, acetic acid, propionic acid, butyric acid, valeric acid or caproic acid;
Described reductive agent be selected from lithium borohydride, sodium borohydride, POTASSIUM BOROHYDRIDE and borine one or more;
The mol ratio of described initial reactant and reductive agent is 1:2 ~ 1:9, and reductive agent is 1:1.8 ~ 1:5 with the mol ratio of acid.
2. the preparation method of acid amides according to claim 1, it is characterized in that, the final product of gained can also through conventional aftertreatment to be further purified, described conventional aftertreatment comprises, but be not limited to: crude product methyl tertiary butyl ether/normal hexane mixed solvent is carried out recrystallization or through chromatographic silica gel chromatographic column with methyl tertiary butyl ether/normal hexane mixing solutions drip washing, get leacheate stage casing, desolventizing obtains highly purified product.
3. the preparation method of acid amides according to claim 1, is characterized in that, the mol ratio of described initial reactant and reductive agent is 1:3 ~ 1:7, and reductive agent is 1:3 ~ 1:4.5 with the mol ratio of acid.
4. the preparation method of acid amides according to claim 1, is characterized in that, the mol ratio of described initial reactant and reductive agent is 1:4.5 ~ 1:6.5, and reductive agent is 1:3 ~ 1:3.5 with the mol ratio of acid.
5. the preparation method of acid amides according to claim 1, is characterized in that, the temperature of reaction after acid dropwises controls in room temperature to 100 DEG C, and the reaction times is 2 ~ 12 hours.
6. the preparation method of acid amides according to claim 5, is characterized in that, the temperature of reaction after acid dropwises controls at 35 to 85 DEG C, and the reaction times is 3 ~ 10 hours.
7. the preparation method of acid amides according to claim 5, is characterized in that, the temperature of reaction after acid dropwises controls at 44 to 75 DEG C, and the reaction times is 4 ~ 7 hours.
8. the preparation method of acid amides according to claim 1, it is characterized in that, one or more for being selected from methylene dichloride, trichloromethane, tetrahydrofuran (THF), ether, isopropyl ether, methyl tertiary butyl ether, glycol dimethyl ether, dioxane and DMF (DMF) of described solvent.
9. the preparation method of acid amides according to claim 8, is characterized in that, described solvent is selected from methylene dichloride, tetrahydrofuran (THF) or glycol dimethyl ether.
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| EP3105212A1 (en) | 2014-02-12 | 2016-12-21 | Vanda Pharmaceuticals Inc. | Highly purified pharmaceutical grade tasimelteon |
| CN105949153B (en) * | 2016-05-10 | 2018-03-02 | 浙江工业大学 | synthesis method of tasimelteon |
| CN107365288A (en) * | 2016-05-12 | 2017-11-21 | 浙江京新药业股份有限公司 | Ta Simeiqiong crystal formation |
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| ATE180491T1 (en) * | 1993-02-19 | 1999-06-15 | Hoffmann La Roche | RACEMIZATION-FREE PRODUCTION OF AMIDES AND PEPTIDES IN THE PRESENCE OF CATALYTIC AMOUNTS OF AN N-HYDROXY COMPOUND |
| JP3803185B2 (en) * | 1997-11-13 | 2006-08-02 | 住友化学株式会社 | Production method of amines |
| 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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