CN102675268A - Method for preparing (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanemethylamine - Google Patents
Method for preparing (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanemethylamine Download PDFInfo
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Abstract
The invention discloses a novel method for synthesizing (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanemethylamine. The method comprises the following steps: chloridizing (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanecarboxylic acid to generate (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropane carbonyl chloride; (2) performing ammonolysis on (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropane carbonyl chloride to generate (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropane formamide; and (3) reducing the (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropane formamide to generate the (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanemethylamine. The method provided by the invention has the advantages of easily available raw materials, simplicity in operation, higher yield in each step, less side reaction, high product purity, simplicity and convenience in post-treatment, and suitability for industrialized production.
Description
Technical field
The present invention relates to the key intermediate of a kind of Ta Simeiqiong of preparation---(1R, 2R)-novel method of 2-(2,3-Dihydrobenzofuranes-4-yl) ring third methylamine.
Background technology
Ta Simeiqiong; It is a kind of new oral melatonin receptor agonist; By Maryland, USA Wanda drugmaker development, can improve suddenly in advance sleep latent period and sleep maintenance situation of the person length of one's sleep simultaneously, potential treatment circadian rhythm sleep disorders patient transience insomnia.
(1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) ring third methylamine is the key intermediate of synthetic Ta Simeiqiong.From present document, (1R, 2R)-2-(2; 3-Dihydrobenzofuranes-4-yl) synthetic route of ring third methylamine mainly be patent US5856529 provide via (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropyl-carbinol is oxidized to aldehyde; Be reacted into oxime with oxammonium hydrochloride then, reduction then generates (1R again; 2R)-method of 2-(2,3-Dihydrobenzofuranes-4-yl) ring third methylamine, shown in the following formula I of reaction process:
Provide among the patent US5856529 synthetic (1R, 2R)-method of 2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropyl-carbinol has multiple; But by (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropyl-carbinol is to (1R; 2R)-and the approach of 2-(2,3-Dihydrobenzofuranes-4-yl) ring third methylamine has only a kind ofly, and do not provide via (1R; 2R)-2-(2; 3-Dihydrobenzofuranes-4-yl) midbody beyond the cyclopropyl-carbinol obtain (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) encircles the method for third methylamine.
In addition, the method (shown in the following formula II of reaction process) of the synthesizing cis 2-that patent US6214869 provides (2,3-Dihydrobenzofuranes-4-yl) ring third methylamine; Also can use for reference and be used for synthesizing (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) encircles third methylamine; Only need to replace with key intermediate cis 2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropyl-carbinol (1R, 2R)-2-(2; 3-Dihydrobenzofuranes-4-yl) cyclopropyl-carbinol gets final product; But this method need use equally (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropyl-carbinol is a key intermediate.
More than two kinds of methods all need use (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropyl-carbinol as synthetic (1R, 2R)-2-(2; 3-Dihydrobenzofuranes-4-yl) key intermediate of ring third methylamine, (1R, 2R)-synthesis step of 2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropyl-carbinol is many; Cost is high, and processing condition are harsh, is difficult to realize the industry amplification; And, from (1R, 2R)-2-(2; 3-Dihydrobenzofuranes-4-yl) cyclopropyl-carbinol to (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) ring third methylamine exists processing condition harsh (low temperature), the dangerous height of raw material (NaN too
3, LiAlH
4) etc. shortcoming, be difficult to realize that industry amplifies.
Summary of the invention
To above-mentioned prior art, the invention provides a kind of synthetic (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) encircles the novel method of third methylamine.
The present invention realizes through following technical scheme:
A kind of preparation (1R, 2R)-method of 2-(2,3-Dihydrobenzofuranes-4-yl) ring third methylamine, may further comprise the steps:
(1) (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropanecarboxylic acid chlorination generate (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) encircles third formyl chloride;
(2) (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) the ring third formyl chloride ammonia separate generation (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) encircles propyl formamide;
(3) (1R, 2R)-reduction of 2-(2,3-Dihydrobenzofuranes-4-yl) ring propyl formamide generate (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) encircles third methylamine.
Shown in the following formula III of reaction process:
Concrete steps are following:
(1) (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropanecarboxylic acid generate with chlorination reagent B reaction in solvent orange 2 A or under the solvent-free state (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) encircles third formyl chloride; Wherein, solvent orange 2 A is selected from one or more in methylene dichloride, trichloromethane, THF, ether, isopropyl ether, MTBE, the dioxane, preferred methylene dichloride; Chlorination reagent B is selected from one or more in sulfur oxychloride, phosphorus trichloride, POCl3, phosphorus pentachloride, oxalyl chloride, TRIPHOSGENE 99.5, the chlorine, preferred sulfur oxychloride; The consumption of said solvent orange 2 A be (1R, 2R)-0~20 times of 2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropanecarboxylic acid quality; Said (1R, 2R)-mol ratio of 2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropanecarboxylic acid and chlorination reagent B is 1: 1~5; Said temperature of reaction is 0~100 ℃, and the reaction times is 2~12 hours;
(2) (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) ring third formyl chloride in solvent C or solvent-free state under with ammonia separate the reagent react generation (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) encircles propyl formamide; Wherein, solvent C is selected from one or more among THF, dioxane, the DMF, preferred THF; Said ammonia is separated reagent and is selected from a kind of in ammoniacal liquor, ammonia or the liquefied ammonia, preferred ammoniacal liquor; The consumption of said solvent C be (1R, 2R)-0~20 times of 2-(2,3-Dihydrobenzofuranes-4-yl) the ring third formyl chloride quality; Said (1R, 2R)-mol ratio that 2-(2,3-Dihydrobenzofuranes-4-yl) ring third formyl chloride and ammonia are separated reagent is 1: 1~20; Said temperature of reaction is 0~30 ℃; The said reaction times is 2~24 hours;
(3) (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) ring propyl formamide in solvent D, generate with reductive agent E reaction (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) encircles third methylamine; Wherein, said solvent D is selected from one or more in THF, methyl alcohol, ethanol, other water-soluble lower aliphatic alcohols, preferred THF or methyl alcohol; Said reductive agent E is selected from lithium aluminum hydride, Peng Qinghuana, POTASSIUM BOROHYDRIDE 97MIN, Peng Qinghuana and adds acetate, Peng Qinghuana and add trifluoroacetic acid, Peng Qinghuana and add iodine, Peng Qinghuana and add trimethylchlorosilane, Peng Qinghuana and add aluminum chloride, Peng Qinghuana and add magnesium chloride, Peng Qinghuana and add calcium chloride, Peng Qinghuana and add in transition metal chloride, borine, two (methoxy ethoxy) sodium alanate one or more; The consumption of said solvent D be (1R, 2R)-10~20 times of 2-(2,3-Dihydrobenzofuranes-4-yl) ring propyl formamide; Said (1R, 2R)-mol ratio of 2-(2,3-Dihydrobenzofuranes-4-yl) ring propyl formamide and reductive agent E is 1: 2~10; Said temperature of reaction is-40 ℃~100 ℃; The said reaction times is 2~8 hours.
The implication of the describing mode representative of above-mentioned " X adds Y " is " mixture of X and Y ".
In the said step (1), add DMF in the reaction process as catalyzer, (1R, 2R)-mol ratio of 2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropanecarboxylic acid and DMF is 100: 1~5.
In the said step (1), (1R, 2R)-mol ratio of 2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropanecarboxylic acid and chlorination reagent B is preferably 1: 3~and 4.
In the said step (1), temperature of reaction is preferably 40~50 ℃, and the reaction times is preferably 4~6 hours.
In the said step (1), reaction steams solvent with Rotary Evaporators after finishing, and gets the oily product, directly is used for next step reaction.
In the said step (2), (1R, 2R)-mol ratio that 2-(2,3-Dihydrobenzofuranes-4-yl) ring third formyl chloride and ammonia are separated reagent is preferably 1: 10~and 15.
In the said step (2), temperature of reaction is preferably 25 ± 5 ℃ (being room temperature), and the reaction times is preferably 12~24 hours.
In the said step (2), after reaction finishes, in reaction system, add water and also stir, solid is separated out, filter, washing, oven dry gets pale solid, is reaction product, directly is used for next step reaction.
In the said step (3), said reductive agent E is preferably Peng Qinghuana and adds acetate, wherein; (1R; 2R)-and 2-(2,3-Dihydrobenzofuranes-4-yl) ring propyl formamide, Peng Qinghuana, acetate three's mol ratio is 1: 1~5: 1~5, be preferably 1: 3~5: 3~and 5.
In the said step (3), temperature of reaction is preferably 60~70 ℃, and the reaction times is preferably 6~8 hours.
In the said step (3), reaction is slowly poured reaction mass in the frozen water after finishing, and stirs; The dripping hydrochloric acid adjust pH is 2, stirs, and organic solvent is sloughed in decompression, methylate tertbutyl ether washing organic impurity; Water drips the neutralization of NaOH solution after the layering, and adjust pH is 12, the extraction of methylate tertbutyl ether, and water extracts with MTBE again after the layering; Merge organic phase, washing is revolved the steaming precipitation and is got oily matter, is reaction product.
In said each step, the separation of reaction product is conventional reaction product separation method, is common practise.
In said each step, used solvent, one of ordinary skill in the art also can select other solvent according to practical situation; The used solvent of its effect and the present invention is difference to some extent; But on the whole, do not change design of the present invention, all should include protection scope of the present invention in.
In the above-mentioned compound method, and reaction raw materials (1R, 2R)-2-(2; 3-Dihydrobenzofuranes-4-yl) the cyclopropanecarboxylic acid method that can provide by patent US20070270593 is synthetic, also can be by by Organic Process Research&Development, 2002; 6, the method that 618-620 provides is synthetic.
Preparation of the present invention (1R, 2R)-novel method of 2-(2,3-Dihydrobenzofuranes-4-yl) ring third methylamine, raw material is easy to get, and is simple to operate, and each step yield is all higher, and side reaction is few, and product purity is high, and aftertreatment is easy, is fit to suitability for industrialized production.
Embodiment
Below in conjunction with embodiment the present invention is further described.
Embodiment 1: the preparation of Ta Simeiqiong
Step is following:
(1) (1R, 2R)-preparation of 2-(2,3-Dihydrobenzofuranes-4-yl) ring third formyl chloride
(1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropanecarboxylic acid 5.3g; Be dissolved in the 100ml methylene dichloride, drip thionyl chloride 12.4g, DMF0.02g; (reflux temperature was the boiling point of methylene chloride to reflux in 4 hours; Be routine techniques), sampling adds the methyl alcohol vibration, and the some plate detects the raw material reaction of disappearance to be finished.Steam solvent with Rotary Evaporators, get oily matter 5.8g, directly be used for next step reaction.
(2) (1R, 2R)-preparation of 2-(2,3-Dihydrobenzofuranes-4-yl) ring propyl formamide
Last step gained oily matter 5.8g adds THF 60ml dissolving, dropping ammonia (mass concentration 19%) 25g, stirring at room 18 hours; Add water 200ml, stir 1 hour solid and separate out, filter, washing was dried 4 hours for 60 ℃, got pale solid 4.9g, 99.0%, two step of purity yield 93%.
(3) (1R, 2R)-preparation of 2-(2,3-Dihydrobenzofuranes-4-yl) ring third methylamine
Get step gained pale solid 2.6g, add Peng Qinghuana 2.4g, anhydrous tetrahydro furan 52ml drips acetate 3.8g; Reflux 6 hours (reflux temperature is the boiling point of solvents tetrahydrofurane), sampling spot plate detect the raw material reaction of disappearance and finish, and reduce to room temperature, and material is slowly poured in the 200ml frozen water; Stir, drip the about 26g of hydrochloric acid of mass concentration 10%, adjust pH is 2, stirs; THF is sloughed in decompression, methylate tertbutyl ether 30ml washing, and water drips the NaOH solution neutralization of mass concentration 10% after the layering, and adjust pH is 12; Methylate tertbutyl ether 50ml extraction, water with MTBE 30ml extraction, merges organic phase again after the layering, washing; Revolve the steaming precipitation and get oily matter 2.1g, purity 99.2%, productive rate 92%.
(4) Ta Simeiqiong's is synthetic
Last step product 2.1g, the 75ml that adds methylene chloride, triethylamine 3.5g drips propionyl chloride 1.1g, and stirring at room 8 hours is poured in the 150ml frozen water, adds 10% hydrochloric acid 37g acidifying, layering, organic layer washing, saturated NaHCO
3Solution is washed, washing again, and anhydrous magnesium sulfate drying filters, and revolves steaming, gets oily matter 2.0g, places and solidifies purity 99.5%, productive rate 79%, m.p.
Nuclear-magnetism
1HNMR (CDCl
3) 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).Can confirm that resulting product is Ta Simeiqiong; This step is the conventional method for preparing Ta Simeiqiong, confirm that product is Ta Simeiqiong after, can confirm the resulting product of step (3) for (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) encircles third methylamine.
Embodiment 2: the preparation of Ta Simeiqiong
(1) (1R, 2R)-preparation of 2-(2,3-Dihydrobenzofuranes-4-yl) ring third formyl chloride
(1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropanecarboxylic acid 4.3g, be dissolved in the 80ml methylene dichloride, drip thionyl chloride 12.6g, DMF0.02g, stirring at room 12 hours, sampling adds the methyl alcohol vibration, and the some plate detects the raw material reaction of disappearance to be finished.Steam solvent with Rotary Evaporators, get oily matter 4.6g, directly be used for next step reaction.
(2) (1R, 2R)-preparation of 2-(2,3-Dihydrobenzofuranes-4-yl) ring propyl formamide
Last step gained oily matter 4.6g adds THF 50ml dissolving, dropping ammonia (mass concentration 19%) 20g, stirring at room 18 hours.Add water 150ml, stir 1 hour solid and separate out, filter, washing was dried 4 hours for 60 ℃, got pale solid 3.9g, 98.9%, two step of purity rate 91%.
(3) (1R, 2R)-preparation of 2-(2,3-Dihydrobenzofuranes-4-yl) ring third methylamine
Get step gained acid amides 2.6g, add Peng Qinghuana 1.8g, methyl alcohol 52ml drips acetate 2.9g, reflux 6 hours; The sampling spot plate detects the raw material reaction of disappearance to be finished, and reduces to room temperature, and material is slowly poured in the 200ml frozen water, stirs, and drips the about 26g of hydrochloric acid of mass concentration 10%; Adjust pH is 2, stirs, and THF is sloughed in decompression, methylate tertbutyl ether 30ml washing, and water drips the neutralization of mass concentration 10%NaOH solution after the layering; Adjust pH is 12, methylate tertbutyl ether 50ml extraction, and water with MTBE 30ml extraction, merges organic phase again after the layering; Washing is revolved the steaming precipitation and is got oily matter 2.0g, purity 99.1%, productive rate 87.6%.
(4) Ta Simeiqiong's is synthetic
Last step product 2.0g, the 70ml that adds methylene chloride, triethylamine 3.3g drips propionyl chloride 1.0g, and stirring at room 8 hours is poured in the 140ml frozen water, adds the hydrochloric acid 35g acidifying of mass concentration 10%, layering, organic layer washing, saturated NaHCO
3Wash, washing again, anhydrous magnesium sulfate drying filters, and revolves steaming, gets oily matter 1.9g, and place and solidify, purity 99.5%, productive rate 78%, m.p.71-72 ℃,
Embodiment 3: the preparation of Ta Simeiqiong
(1) (1R, 2R)-preparation of 2-(2,3-Dihydrobenzofuranes-4-yl) ring third formyl chloride
(1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropanecarboxylic acid 4.8g, be dissolved in the 96ml MTBE, add POCl3 4.0g, reflux 6 hours, sampling adds the methyl alcohol vibration, and the some plate detects the raw material reaction of disappearance to be finished.Steam solvent with Rotary Evaporators, get oily matter 5.2g, directly be used for next step reaction.
(2) (1R, 2R)-preparation of 2-(2,3-Dihydrobenzofuranes-4-yl) ring propyl formamide
Last step gained oily matter 5.2g adds THF 52ml dissolving, dropping ammonia (mass concentration 19%) 22g, stirring at room 18 hours.Add water 150ml, stir 1 hour solid and separate out, filter, washing was dried 4 hours for 60 ℃, got pale solid 4.4g, 99.2%, two step of purity rate 92%.
(3) (1R, 2R)-preparation of 2-(2,3-Dihydrobenzofuranes-4-yl) ring third methylamine
Get step gained acid amides 4.4g, add Peng Qinghuana 3.0g, THF 88ml drips trifluoroacetic acid 9.3g, reflux 2 hours; The sampling spot plate detects the raw material reaction of disappearance to be finished, and reduces to room temperature, and material is slowly poured in the 200ml frozen water, stirs, and drips the about 44g of hydrochloric acid of mass concentration 10%; Adjust pH is 2, stirs, and ethanol is sloughed in decompression, methylate tertbutyl ether 50ml washing, and water drips the neutralization of mass concentration 10%NaOH solution after the layering; Adjust pH is 12, methylate tertbutyl ether 80ml extraction, and water with MTBE 50ml extraction, merges organic phase again after the layering; Washing is revolved the steaming precipitation and is got oily matter 3.6g, purity 99.3%, productive rate 88.8%.
(4) Ta Simeiqiong's is synthetic
Last step product 3.6g, the 72ml that adds methylene chloride, triethylamine 5.9g drips propionyl chloride 1.8g, and stirring at room 8 hours is poured in the 240ml frozen water, adds the hydrochloric acid 64g acidifying of mass concentration 10%, layering, organic layer washing, saturated NaHCO
3Wash, washing again, anhydrous magnesium sulfate drying filters, and revolves steaming, gets oily matter 3.4g, and place and solidify, purity 99.6%, productive rate 72%, m.p.71-72 ℃,
Though above-mentioned combination embodiment specific embodiments of the invention is described; But be not restriction to protection domain of the present invention; One of ordinary skill in the art should be understood that; On the basis of technical scheme of the present invention, those skilled in the art need not pay various modifications that creative work can make or distortion still in protection scope of the present invention.
Claims (10)
- One kind prepare (1R 2R)-method of 2-(2,3-Dihydrobenzofuranes-4-yl) ring third methylamine, is characterized in that: may further comprise the steps:(1) (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropanecarboxylic acid chlorination generate (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) encircles third formyl chloride;(2) (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) the ring third formyl chloride ammonia separate generation (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) encircles propyl formamide;(3) (1R, 2R)-reduction of 2-(2,3-Dihydrobenzofuranes-4-yl) ring propyl formamide generate (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) encircles third methylamine.
- Preparation 2. according to claim 1 (1R, 2R)-method of 2-(2,3-Dihydrobenzofuranes-4-yl) ring third methylamine, it is characterized in that: concrete steps are following:(1) (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropanecarboxylic acid generate with chlorination reagent B reaction in solvent orange 2 A or under the solvent-free state (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) encircles third formyl chloride; Wherein, solvent orange 2 A is selected from one or more in methylene dichloride, trichloromethane, THF, ether, isopropyl ether, MTBE, the dioxane; Chlorination reagent B is selected from one or more in sulfur oxychloride, phosphorus trichloride, POCl3, phosphorus pentachloride, oxalyl chloride, TRIPHOSGENE 99.5, the chlorine; The consumption of said solvent orange 2 A be (1R, 2R)-0~20 times of 2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropanecarboxylic acid quality; Said (1R, 2R)-mol ratio of 2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropanecarboxylic acid and chlorination reagent B is 1: 1~5; Said temperature of reaction is 0~100 ℃, and the reaction times is 2~12 hours;(2) (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) ring third formyl chloride in solvent C or solvent-free state under with ammonia separate the reagent react generation (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) encircles propyl formamide; Wherein, solvent C is selected from one or more among THF, dioxane, the DMF; Said ammonia is separated reagent and is selected from a kind of in ammoniacal liquor, ammonia or the liquefied ammonia; The consumption of said solvent C be (1R, 2R)-0~20 times of 2-(2,3-Dihydrobenzofuranes-4-yl) the ring third formyl chloride quality; Said (1R, 2R)-mol ratio that 2-(2,3-Dihydrobenzofuranes-4-yl) ring third formyl chloride and ammonia are separated reagent is 1: 1~20; Said temperature of reaction is 0~30 ℃; The said reaction times is 2~20 hours;(3) (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) ring propyl formamide in solvent D, generate with reductive agent E reaction (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) encircles third methylamine; Wherein, said solvent D is selected from one or more in THF, methyl alcohol, ethanol, other water-soluble lower aliphatic alcohols; Said reductive agent E is selected from lithium aluminum hydride, Peng Qinghuana, POTASSIUM BOROHYDRIDE 97MIN, Peng Qinghuana and adds acetate, Peng Qinghuana and add trifluoroacetic acid, Peng Qinghuana and add iodine, Peng Qinghuana and add trimethylchlorosilane, Peng Qinghuana and add aluminum chloride, Peng Qinghuana and add magnesium chloride, Peng Qinghuana and add calcium chloride, Peng Qinghuana and add in transition metal chloride, borine, two (methoxy ethoxy) sodium alanate one or more; The consumption of said solvent D be (1R, 2R)-10~20 times of 2-(2,3-Dihydrobenzofuranes-4-yl) ring propyl formamide; Said (1R, 2R)-mol ratio of 2-(2,3-Dihydrobenzofuranes-4-yl) ring propyl formamide and reductive agent E is 1: 2~10; Said temperature of reaction is-40 ℃~100 ℃; The said reaction times is 2~8 hours.
- 3. preparation (1R according to claim 1; 2R)-and the method for 2-(2,3-Dihydrobenzofuranes-4-yl) ring third methylamine, it is characterized in that: in the said step (1); Add DMF in the reaction process as catalyzer; (1R, 2R)-mol ratio of 2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropanecarboxylic acid and DMF is 100: 1~5.
- 4. preparation (1R according to claim 1; 2R)-2-(2; 3-Dihydrobenzofuranes-4-yl) method of ring third methylamine is characterized in that: in the said step (1), and (1R; 2R)-mol ratio of 2-(2,3-Dihydrobenzofuranes-4-yl) cyclopropanecarboxylic acid and chlorination reagent B is 1: 3~4.
- Preparation 5. according to claim 1 (1R, 2R)-method of 2-(2,3-Dihydrobenzofuranes-4-yl) ring third methylamine, it is characterized in that: in the said step (1), temperature of reaction is 40~50 ℃, and the reaction times is 4~6 hours.
- 6. preparation (1R according to claim 1; 2R)-2-(2; 3-Dihydrobenzofuranes-4-yl) method of ring third methylamine is characterized in that: in the said step (2), and (1R; 2R)-mol ratio that 2-(2,3-Dihydrobenzofuranes-4-yl) ring third formyl chloride and ammonia are separated reagent is 1: 10~15.
- Preparation 7. according to claim 1 (1R, 2R)-method of 2-(2,3-Dihydrobenzofuranes-4-yl) ring third methylamine, it is characterized in that: in the said step (2), temperature of reaction is 25 ± 5 ℃, and the reaction times is 8~12 hours.
- Preparation 8. according to claim 1 (1R, 2R)-method of 2-(2,3-Dihydrobenzofuranes-4-yl) ring third methylamine; It is characterized in that: in the said step (3); Said reductive agent E is that Peng Qinghuana adds acetate, wherein, and (1R; 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) ring propyl formamide, Peng Qinghuana, acetate three's mol ratio is 1: 1~5: 1~5.
- 9. preparation (1R according to claim 8; 2R)-2-(2; 3-Dihydrobenzofuranes-4-yl) method of ring third methylamine; It is characterized in that: said (1R, 2R)-2-(2,3-Dihydrobenzofuranes-4-yl) ring propyl formamide, Peng Qinghuana, acetate three's mol ratio is 1: 3~5: 3~5.
- Preparation 10. according to claim 1 (1R, 2R)-method of 2-(2,3-Dihydrobenzofuranes-4-yl) ring third methylamine, it is characterized in that: in the said step (3), temperature of reaction is 60~70 ℃, and the reaction times is 6~8 hours.
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---|---|---|---|---|
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WO2017193662A1 (en) * | 2016-05-12 | 2017-11-16 | 浙江京新药业股份有限公司 | Crystal form of tasimelteon |
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-
2012
- 2012-05-18 CN CN2012101563086A patent/CN102675268A/en active Pending
Non-Patent Citations (2)
Title |
---|
LI-QIANG SUN, ET AL.: "N-{2-[2-(4-Phenylbutyl)benzofuran-4-yl]cyclopropylmethyl}-acetamide: an orally bioavailable melatonin receptor agonist", 《BIOORG.MED.CHEM.LETT》 * |
SUNG JIN CHO, ET AL.: "Selective 5-Hydroxytryptamine 2C Receptor Agonists Derived from the Lead Compound Tranylcypromine: Identification of Drugs with Antidepressant-Like Action", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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