CN102863341A - Chemical synthesis method of (1R, 2S)-2-aryl cyclopropylamine derivative - Google Patents
Chemical synthesis method of (1R, 2S)-2-aryl cyclopropylamine derivative Download PDFInfo
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Abstract
The invention relates to a chemical synthesis method of a (1R, 2S)-2-aryl cyclopropylamine derivative. 3-aryl crylic acid serves as a raw material, the raw material and N,O-dimethyl hydroxy amine hydrochloride are subjected reaction to prepare a corresponding amide intermediate, cyclization reaction is conducted, 2- aryl cyclopropylamine is obtained; and finally D-mandelic acid serves as a resolving agent to obtain the (1R, 2S)-2-aryl cyclopropylamine derivative. The method has the advantages of being high in yield and high in e.e. value.
Description
Technical field
The present invention relates to the chemical synthesis process of a kind of (1R, 2S)-2-aryl rings propanamine derivatives.
Background technology
(1R, 2S)-2-aryl rings propanamine derivatives is the important chiral medicinal intermediate of a class, and many pieces of documents are addressed its modification in new type anticancer medicine molecule, therefore the study on the synthesis of this compounds is had important practical significance.
Although (1R, 2S)-2-aryl rings propanamine derivatives has important function in drug molecule, for synthetic, bibliographical information is very few.Bibliographical information has been arranged take vinylbenzene as raw material, synthesized (1R, 2S)-benzyl ring propylamine through following route.Generally speaking, although this route has directly generated chiral centre, its stereoselectivity is not high.
Summary of the invention
The present invention provides a kind of chemical synthesis process of (1R, 2S)-2-aryl rings propylamine series derivates of high e.e. value in order to overcome the not high defective of existing synthetic method stereoselectivity.
Chemical equation of the present invention is as follows:
The step of (1R, 2S) 2-aryl rings propylamine series derivates chemical synthesis process is as follows:
A, with 3-aromatic substituted acrylic acid, N, O-dimethyl azanol hydrochloride and acid binding agent, stirring and dissolving in organic solvent adds catalyzer subsequently, room temperature reaction, preparation N-methoxyl group-N-methyl-3-aryl acrylamide;
B, get the N-methoxyl group of step gained-N-methyl-3-aryl-acrylamide, be dissolved in the strong polar aprotic solvent, under the nitrogen protection, add highly basic and Trimethylsulfoxonium Iodide, room temperature reaction, preparation N-methoxyl group-N-methyl-2-aryl rings propyl formamide;
C, get step gained N-methoxyl group-N-methyl-2-aryl rings propyl formamide, be dissolved in the solvent, hydrolysis makes 2-aryl cyclopropanecarboxylic acid;
D, with 2-aryl cyclopropanecarboxylic acid, be dissolved in the trimethyl carbinol, under the effect of diphenyl phosphate azide, make N-Boc-2-aryl rings the third methylamine, take off the Boc free amine group under the acidic conditions and react to get 2-aryl rings propylamine;
E, 2-aryl rings the third methylamine is dissolved in the alcoholic solvent, adds the D-amygdalic acid, product makes (1R, 2S)-2-aryl rings propylamine by the ethyl acetate crystallization.
Described chemical synthesis process, in steps A, organic solvent is one of methylene dichloride, trichloromethane, benzene, toluene; Used catalyzer is 1-ethyl (3-dimethylamino-propyl) carbodiimide or dicyclohexylcarbodiimide.In step B, selected strong polar aprotic solvent is one of DMF, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO); Selected alkali is sodium hydride or potassium hydride KH.In the hydrolysis reaction of step C, used solvent is the mixed solvent of water-methanol or water-ethanol.In step D, take off that employed acid is hydrochloric acid or trifluoroacetic acid in the Boc free amine group reaction.Be methyl alcohol or ethanol at the alcohol described in the step e.
Chemical synthesis process of the present invention, its key point are to obtain (1R, 2S)-2-aryl rings propylamine by last chemistry fractionation.This route of synthesis has not only improved the yield of reaction, has also avoided in the existing method racemic risk in the chiral precurser subsequent reactions, thereby has improved the e.e. value of product, is efficiently synthesizing of this compounds to provide a kind of new way.
Embodiment:
In order to deepen understanding of the present invention, the invention will be further described below in conjunction with embodiment, and the following example only is used for explaining the present invention, does not consist of the restriction to protection domain of the present invention.
Embodiment 1:
Synthesizing of N-methoxyl group-N-methyl-3-Phenyl Acrylamide: with 50.0 g 3-phenylacrylic acids, 30.0 g triethylamine, 31.0 g N-O-dimethyl azanol hydrochloride, 400 ml methylene dichloride add in the 1L reaction flask, add 60.0 g 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride ambient temperature overnight behind mechanical stirring 30 min, methylene dichloride is washed the saturated sodium bicarbonate of rear usefulness mutually twice, ammonium chloride, diluted acid, the sodium chloride aqueous solution washing, dry concentrating obtains faint yellow N-methoxyl group-N methyl-3-Phenyl Acrylamide liquid 52.0 g, and yield is 80.6%.
2-phenyl-ethylene-acetic acid synthetic: under the nitrogen protection with 10.0 g NaH; 250 ml methyl-sulphoxides join in the there-necked flask; add N-methoxyl group-N methyl-3-Phenyl Acrylamide 27.4 g in batches, drip 42.0 g Trimethylsulfoxonium Iodides behind stirring and dissolving 30 min, react under the room temperature.Add shrend and go out that rear organic phase washes with water 3 times with after the methyl tertiary butyl ether extraction, dry concentrated obtain weak yellow liquid 25.0g, yield 85.0%.Yellow product is transferred in the single port bottle, added 200 ml methyl alcohol and 100 ml water, stirring and dissolving adds 10.0 g sodium hydroxide again, and stirring reaction spends the night.React complete after, add entry, use dichloromethane extraction, the concentrated white 2-phenyl of 17.8 g-ethylene-acetic acid solid, the yield 90.1% of obtaining after transferring pH 3-4.
Synthesizing of N-Boc-2-benzyl ring propylamine: with 15.0g 2-phenyl cyclopropanecarboxylic acid, the 150 ml trimethyl carbinols, 11.2 g triethylamines join in the four-hole bottle of 300 ml, and heated and stirred also refluxes.Drip 26.0 g diphenyl phosphate azides, then stirring at room 30 min are heated to 85 ℃ and spend the night.Add the shrend reaction of going out, with the methyl tertiary butyl ether extraction, organic phase washes with water 3 times, and the dry concentrated solid that obtains obtains 19.5 g white solid N-Boc-2-benzyl ring propylamine, yield 90.4% with the mixing solutions recrystallization of methyl tertiary butyl ether and sherwood oil.
Synthesizing of (1R, 2S)-2-benzyl ring propylamine: 15.0 g N-Boc-2-benzyl ring propylamine, the methyl tertiary butyl ether of 100 ml, 30.0 g hydrochloric acid are joined in the four-hole boiling flask of 250 ml, react under 40 ℃ of warm water baths.Reacted rear separatory, water is transferred pH to 12, then uses dichloromethane extraction, concentrates and obtains the faint yellow 2-benzyl ring of 8.2 g propylamine liquid, and yield is 95.7%.With weak yellow liquid obtained in the previous step, 30ml ethanol, 7.0 g D-amygdalic acids join in the 100 ml four-hole boiling flasks, 90 ℃ of constant temperature, backflow 3h.Reaction is used re-crystallizing in ethyl acetate after finishing, and obtains 3.5 g(1R, 2S)-2-benzyl ring propylamine solid, yield 85.4%, e.e. are 99.0%.
1HNMR?in?CDCl
3：
δH?=?2.17?(qn，1H),2.60(s，1H),2.70?(t，1H),2.88?(m，1H),7.23(m，5H)。
Embodiment 2:
N-methoxyl group-N-methyl-3-(4 '-p-methoxy-phenyl) acrylamide is synthetic: with 60.0 g 3-(4 '-p-methoxy-phenyls) vinylformic acid, 33.5 g triethylamine, 32.7 g N-O-dimethyl azanol hydrochloride, 400 ml methylene dichloride add in the 1L reaction flask, add 62.0 g 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride ambient temperature overnight behind mechanical stirring 30 min, methylene dichloride is washed the saturated sodium bicarbonate of rear usefulness mutually twice, ammonium chloride, diluted acid, the sodium chloride aqueous solution washing, dry concentrated yellow N-methoxyl group-N methyl-3-(4 '-p-methoxy-phenyl that obtains) acrylamide liquid 55.3 g, yield is 74.3%.
2-(4 '-p-methoxy-phenyl)-ethylene-acetic acid synthetic: under the nitrogen protection with 10.0 g NaH; 300 ml methyl-sulphoxides join in the there-necked flask; add N-methoxyl group-N methyl-3-(4 '-p-methoxy-phenyl in batches) acrylamide 31.7 g; drip 42.0 g Trimethylsulfoxonium Iodides behind stirring and dissolving 30 min, react under the room temperature.Adding shrend goes out and washes 3 times dry concentrated obtain yellow liquid 30.0 g, yield 89.0% with water with after the methyl tertiary butyl ether extraction afterwards.Yellow product is transferred in the single port bottle, added 250 ml methyl alcohol and 125 ml water, stirring and dissolving adds 10.0 g sodium hydroxide again, and stirring reaction spends the night.React complete after, add entry, use dichloromethane extraction after transferring pH 3-4, concentrate and obtain the light yellow 2-(4 ' of 22.3 g-p-methoxy-phenyl) the cyclopropanecarboxylic acid solid, yield 91.0%.
N-Boc-2-(4 '-p-methoxy-phenyl) cyclopropylamine is synthetic: with 17.8 g 2-(4 '-p-methoxy-phenyls) cyclopropanecarboxylic acid, the 200 ml trimethyl carbinols, 11.2 g triethylamines join in the four-hole bottle of 300 ml, and heated and stirred also refluxes.Drip 26.0 g diphenyl phosphate azides, then stirring at room 30 min are heated to 85 ℃ and spend the night.Add the shrend reaction of going out, with methyl tertiary butyl ether extraction, water washing 3 times, the dry concentrated solid recrystallization that obtains obtains 21.4 g light yellow solid N-Boc-2-(4 '-p-methoxy-phenyls) cyclopropylamine, yield 87.8%.
(1R, 2S)-and 2-(4 '-p-methoxy-phenyl) cyclopropylamine synthetic: with 17.0 g N-Boc-2-(4 '-p-methoxy-phenyls) cyclopropylamine, the methyl tertiary butyl ether of 125 ml, 30.0 g hydrochloric acid join in the four-hole boiling flask of 250ml, react under 40 ℃ of warm water baths.Reacted rear adding separatory, water is transferred pH to 12, then uses dichloromethane extraction, concentrates and obtains the faint yellow 4 '-p-methoxy-phenyl cyclopropylamine of 9.9 g liquid, and yield is 94.0%.With weak yellow liquid obtained in the previous step, 50 ml ethanol, 7.5 g D-amygdalic acids join in the 100 ml four-hole boiling flasks, 90 ℃ of constant temperature, backflow 3h.Reaction is used re-crystallizing in ethyl acetate after finishing, and obtains 4.0 g(1R, 2S)-2-(4 '-p-methoxy-phenyl) the cyclopropylamine solid, yield 80.8%, e.e. are 98.5%.
1HNMR?in?CDCl
3：
δH?=?1.18–1.31?(m,1H),?1.32–1.43?(m,?1H),?2.28–2.41?(m,?1H),?2.76?(dt,?1H),?3.75?(s,?3H),?6.82–6.91?(m,?2H),?7.04–7.16?(m,?2H)。
Embodiment 3:
N-methoxyl group-N-methyl-3-(4 '-bromophenyl) acrylamide is synthetic: with 75.0 g 3-(4 '-bromophenyls) vinylformic acid, 33.0 g triethylamine, 32.7 g N-O-dimethyl azanol hydrochloride, 400 ml methylene dichloride add in the 1L reaction flask, add 64.0 g 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride ambient temperature overnight behind mechanical stirring 30 min, methylene dichloride is washed the saturated sodium bicarbonate of rear usefulness mutually twice, ammonium chloride, diluted acid, the sodium chloride aqueous solution washing, dry concentrated yellow N-methoxyl group-N methyl-3-(4 '-bromophenyl that obtains) acrylamide liquid 75.4 g, yield is 84.5%.
2-(4 '-bromophenyl)-ethylene-acetic acid synthetic: under the nitrogen protection with 10.0 g NaH; 350 ml methyl-sulphoxides join in the there-necked flask; add N-methoxyl group-N methyl-3-(4 '-bromophenyl in batches) acrylamide 38.7 g; drip 42.0 g Trimethylsulfoxonium Iodides behind stirring and dissolving 30 min, react under the room temperature.Add shrend go out rear with after the methyl tertiary butyl ether extraction, water washing 3 times, dry concentrated obtain yellow liquid 32.3 g, yield 79.3%.Yellow product is transferred in the single port bottle, added 300 ml methyl alcohol and 150 ml water, stirring and dissolving adds 10.0 g sodium hydroxide again, and stirring reaction spends the night.React complete after, use dichloromethane extraction after transferring pH 3-4, concentrates and obtain the faint yellow 2-(4 ' of 24.3 g-bromophenyl) the ethylene-acetic acid solid, yield 88.6%.
N-Boc-2-(4 '-bromophenyl) cyclopropylamine is synthetic: with 22.3 g 2-(4 '-bromophenyls) cyclopropanecarboxylic acid, the 250 ml trimethyl carbinols, 11.2 g triethylamines join in the four-hole bottle of 300 ml, and heated and stirred also refluxes.Drip 26.0 g diphenyl phosphate azides, then stirring at room 30 min are heated to 85 ℃ and spend the night.Add the shrend reaction of going out, with methyl tertiary butyl ether extraction, water washing 3 times, the dry concentrated solid that obtains obtains 26.7 g white solid N-Boc-2-(4 '-bromophenyls with the mixing solutions recrystallization of methyl tertiary butyl ether and sherwood oil) cyclopropylamine, yield 92.5%.
(1R, 2S)-2-(4 '-bromophenyl) synthesizing of cyclopropylamine: with 20.0 g N-Boc-2-(4 '-bromophenyls) cyclopropylamine, the methyl tertiary butyl ether of 200 ml, 30.0 g hydrochloric acid join in the four-hole boiling flask of 500 ml, react under 40 ℃ of warm water baths.Reacted rear adding MTBE separatory, water is transferred pH to 12, then uses dichloromethane extraction, the concentrated faint yellow 2-(4 ' of the 12.7 g-bromophenyl that obtains) cyclopropylamine, yield is 93.5 %.With weak yellow liquid obtained in the previous step, 70 ml ethanol, 7.5 g D-amygdalic acids join in the 100 ml four-hole boiling flasks, 90 ℃ of constant temperature, backflow 3h.Reaction obtains 5.6 g(1R, 2S with the EA recrystallization after finishing)-2-(4 '-bromophenyl) the cyclopropylamine solid, yield 88.2%, e.e. are 98.5%.
1HNMR?in?CDCl
3：
δH?=?1.39?(m,?1H),1.49?(ddd,?1H),?2.42?(ddd,?1H),?2.90?(dt,?1H),?7.16?(d,?2H),?7.51?(d,?2H)。
Chemical synthesis process of the present invention, its key point are to obtain (1R, 2S)-2-aryl rings propylamine by last chemistry fractionation.This route of synthesis has not only improved the yield of reaction, has also avoided in the existing method racemic risk in the chiral precurser subsequent reactions, thereby has improved the e.e. value of product, is efficiently synthesizing of this compounds to provide a kind of new way.
Claims (8)
1. the chemical synthesis process of one kind (1R, 2S)-2-aryl rings propanamine derivatives, it is characterized in that: chemical equation is as follows:
, (1R, the 2S) of gained-2-aryl rings propylamine series derivates
, wherein R independently is selected from: hydrogen, C
1-6Alkyl, C
1-6Alkoxyl group or phenyl and substituted-phenyl, X independently is selected from: F, Cl, Br, I;
Described (1R, 2S)-2-aryl rings propylamine series derivates chemical synthesis process is:
A, with 3-aromatic substituted acrylic acid, N, O-dimethyl azanol hydrochloride and acid binding agent, stirring and dissolving in organic solvent adds catalyzer subsequently, room temperature reaction, preparation N-methoxyl group-N-methyl-3-aryl acrylamide;
B, get the N-methoxyl group of step gained-N-methyl-3-aryl-acrylamide, be dissolved in the strong polar aprotic solvent, under the nitrogen protection, add highly basic and Trimethylsulfoxonium Iodide, room temperature reaction, preparation N-methoxyl group-N-methyl-2-aryl rings propyl formamide;
C, get step gained N-methoxyl group-N-methyl-2-aryl rings propyl formamide, be dissolved in the solvent, hydrolysis makes 2-aryl cyclopropanecarboxylic acid;
D, with 2-aryl cyclopropanecarboxylic acid, be dissolved in the trimethyl carbinol, under the effect of diphenyl phosphate azide, make N-Boc-2-aryl rings the third methylamine, take off the Boc free amine group under the acidic conditions and react to get 2-aryl rings propylamine;
E, 2-aryl rings the third methylamine is dissolved in the alcoholic solvent, adds the D-amygdalic acid, product makes (1R, 2S)-2-aryl rings propylamine by the ethyl acetate crystallization.
2. the chemical synthesis process of (1R, 2S) according to claim 1-2-aryl rings propanamine derivatives, it is characterized in that: in steps A, described organic solvent is one of methylene dichloride, trichloromethane, benzene, toluene.
3. the chemical synthesis process of (1R, the 2S) described in the claim 1-2-aryl rings propanamine derivatives, it is characterized in that: in steps A, used catalyzer is 1-ethyl (3-dimethylamino-propyl) carbodiimide or dicyclohexylcarbodiimide.
4. the chemical synthesis process of (1R, the 2S) described in the claim 1-2-aryl rings propanamine derivatives, it is characterized in that: in step B, selected strong polar aprotic solvent is one of DMF, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO).
5. the chemical synthesis process of (1R, the 2S) described in the claim 1-2-aryl rings propanamine derivatives, it is characterized in that: selected alkali is sodium hydride or potassium hydride KH in the reaction of step B.
6. the chemical synthesis process of (1R, the 2S) described in the claim 1-2-aryl rings propanamine derivatives, it is characterized in that: in the hydrolysis reaction of step C, used solvent is the mixed solvent of water-methanol or water-ethanol.
7. the chemical synthesis process of (1R, the 2S) described in the claim 1-2-aryl rings propanamine derivatives is characterized in that: take off that used acid is hydrochloric acid or trifluoroacetic acid in the reaction of Boc free amine group in step D.
8. the chemical synthesis process of (1R, the 2S) described in the claim 1-2-aryl rings propanamine derivatives is characterized in that: be methyl alcohol or ethanol at the alcohol described in the step e.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104119235A (en) * | 2014-07-30 | 2014-10-29 | 天津市斯芬克司药物研发有限公司 | Cyclopropylmethylamine compound and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2018020366A1 (en) * | 2016-07-26 | 2018-02-01 | Glaxosmithkline Intellectual Property (No.2) Limited | Crystalline (r)-mandelate salt of (1r,2s)-2-phenylcyclopropylamine |
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