CN105418576A - Pseudo-ephedrine derivative and antiallergic application thereof - Google Patents

Pseudo-ephedrine derivative and antiallergic application thereof Download PDF

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CN105418576A
CN105418576A CN201510782844.0A CN201510782844A CN105418576A CN 105418576 A CN105418576 A CN 105418576A CN 201510782844 A CN201510782844 A CN 201510782844A CN 105418576 A CN105418576 A CN 105418576A
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isochroman
ketone
methylamino
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ethylamino
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CN105418576B (en
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黄林海
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Tianchang Yifan Pharmaceutical Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
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Abstract

The invention discloses a pseudo-ephedrine derivative, and belongs to the field of organic synthesis. The invention discloses the pseudo-ephedrine derivative shown in the structural general structure I or salt or ether or prodrug which is acceptable in pharmacy, a preparation method of the pseudo-ephedrine derivative and application of a compound containing one or more pseudo-ephedrine derivatives in treatment and prevention of an antiallergic drug.

Description

A kind of pseudoephedrine analog derivative and antianaphylaxis application thereof
Technical field
The present invention relates to a kind of organism, particularly a kind of pseudoephedrine analog derivative and preparation method thereof and application.
Background technology
Irritated is after in immunity system contact environment, part affects the little anaphylactogen factor to common people, the a series of allergy phenomenons caused, comprise allergic rhinitis, food anaphylaxis, urticaria, atopic dermatitis, asthma and the anaphylaxis of whole body type etc.; Symptom may have blood-shot eye illness, cause scratch where it itches fash, runny nose, expiratory dyspnea and swelling etc.
Allergy is quite common symptom.Country under development, the people of about 20% perplex by allergic rhinitis, the people of about 6% had the experience of a food anaphylaxis at least, had the people of 20% nearly, at least experienced an atopic dermatitis among all one's life.According to the difference of country, have the people of 1% to 18% to have the symptom of asthma, the people of 0.05% to 2% can experience systemic allergic.Therefore the ratio of many hypersensitive diseases has the trend of rising, researches and develops new and effective Claritin significant.
Summary of the invention
Goal of the invention of the present invention is: for above-mentioned Problems existing, provides a kind of pseudoephedrine analog derivative and preparation method thereof, and the application of this compounds in the antianaphylactic medicine of preparation.
The technical solution used in the present invention is as follows:
A kind of pseudoephedrine analog derivative of the present invention, or its pharmacy acceptable salt, ester or prodrug, general structure I is as follows:
Wherein,
Ar is the hexa-atomic fragrant heterocycle of various structures; X 1, X 2, X 3, X 4be O, S, N, NH or CH independently of one another;
Heterocycle Ar is optionally by (C 1-4) alkyl, (C 3-7) cycloalkyl, (C 3-7) cycloalkyl-(C 1-3) alkyl replacement, wherein said alkyl, cycloalkyl or cycloalkylalkyl can be monosubstituted by-OH.
R 1, R 2be H, (C independently of one another 1-4) alkyl, halogen, CF 3, NO 2, (C 1-8) alkoxyl group
A kind of pseudoephedrine analog derivative of the present invention is following compounds:
A kind of pseudoephedrine analog derivative of the present invention is one of following compounds:
Two ((the S)-2-(methylamino) propyl group of 1,6-) isochroman-3-ketone,
Two ((the S)-2-(methylamino) butyl of 1,6-) isochroman-3-ketone,
Two ((the S)-2-(ethylamino) butyl of 1,6-) isochroman-3-ketone,
Two ((the S)-2-(ethylamino) propyl group of 1,6-) isochroman-3-ketone,
1-((S)-2-(tert-butylamino) propyl group)-6-((R)-2-(ethylamino)-3,3-dimethylbutyls) isochroman-3-ketone,
Two ((the R)-3-methyl-2-(methylamino) butyl of 1,6-) isochroman-3-ketone,
1,6-two ((R)-3,3,3-tri-fluoro-2-(methylamino) propyl group) isochroman-3-ketone,
Two ((S)-2-(methylamino-)-2-nitro-ethyl of 1,6-) isochroman-3-ketone,
Two (the bromo-2-(ethylamino of (S)-2-) ethyl of 1,6-) isochroman-3-ketone,
Two (the chloro-2-(methylamino of (S)-2-) ethyl of 1,6-) isochroman-3-ketone.
The preparation method of a kind of pseudoephedrine analog derivative of the present invention, step is as follows:
Reagent and condition: sodium ethylate, DMF, reflux;
Wherein Ar, X 1, X 2, X 3, X 4, R 1and R 2the logical upper general formula I of definition described in.
A kind of pseudoephedrine analog derivative of the present invention, the preparation method of general formula I a compound is as follows:
Reagent and condition: (Ia-i) Periodic acid, chromium trioxide, glucose isomerase, acetonitrile, room temperature; (Ia-ii) sodium hydride, ethanol, α-amylase, room temperature; (Ia-iii) sodium borohydride, DMF, reflux; (Ia-iv) sodium ethylate, DMF, reflux;
Wherein R 1and R 2the logical upper general formula I of definition described in.
A kind of anti-allergy agent compositions, comprises compound described in claim 1-3 any one claim or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers or vehicle.
The application of a kind of pseudoephedrine analog derivative of the present invention in the antianaphylactic medicine of preparation.
Experiment shows, the compounds of this invention has antianaphylactic biological activity, can be applied in Claritin.The compounds of this invention both can itself also can the form of its pharmacy acceptable salt or solvate use.The pharmacy acceptable salt of compound of Formula I comprises the conventional salt formed with pharmaceutically acceptable mineral acid or organic acid or mineral alkali or organic bases.The example of acid salt be applicable to comprises with hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, Hydrogen bromide, perchloric acid, fumaric acid, acetic acid, propionic acid, succsinic acid, oxyacetic acid, formic acid, lactic acid, toxilic acid, tartrate, citric acid, flutters the salt that acid, propanedioic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, fumaric acid, toluenesulphonic acids, methylsulfonic acid, naphthalene-2-sulfonic acid, Phenylsulfonic acid, hydroxy-benzoic acid, hydroiodic acid HI, oxysuccinic acid etc. formed.The ion of suitable base addition salt comprises and sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N, N '-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, quadrol, N-methyl glucoside by and the salt that formed such as PROCAINE HCL, PHARMA GRADE.When relating to the compounds of this invention herein, comprise compound of Formula I and pharmacy acceptable salt thereof or solvate.
The compounds of this invention general formula I can become pharmaceutical composition with Conventional pharmaceutical carriers or vehicle group.Change pharmaceutical composition by oral or unusual road administration.Pharmaceutical composition of the present invention can be prepared into various formulation by this area ordinary method, includes but not limited to tablet, capsule, solution, suspension, granule or injection etc., oral administration or very road administration.
Compound of the present invention carries out new structural modification and furthers investigate also contributing to developing the Claritin made new advances.
Embodiment
In order to make the object of invention, technical scheme and advantage clearly understand, below in conjunction with embodiment, the present invention is further elaborated.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
Embodiment 1
Two ((the S)-2-(methylamino) propyl group of 1,6-) isochroman-3-ketone (Ia-1, R 1=R 2=CH 3)
Taking the 2-(5-chloro-2-methyl phenyl of 1.71g) second-1-alcohol is placed in 150mL there-necked flask, measure 20mL acetonitrile, stirring and dissolving at ambient temperature, add 0.4g glucose isomerase, 0.2g chromium trioxide, at room temperature continues to stir 10min, takes 2.28g Periodic acid and be dissolved in 10mL acetonitrile, progressively slowly drop to reaction system, under room temperature, continue reaction 36h.After Ia-1 reacts completely, stopped reaction, concentrating under reduced pressure solvent, by column chromatography, developping agent is acetone: ether=1:5, obtains Ia-2,1.32g(yield 66.3%).
Taking the chloro-2-Fonnylphenyl of 2-(5-of 1.99g) acetic acid (Ia-2) is placed in 150mL round-bottomed flask; measure 20mL ethanol; stirring and dissolving at ambient temperature; add the N-dimethyl propylene-2-amine of 1.83g; add the α-amylase of 0.5g, at room temperature continue to stir 10min, take 0.48g sodium hydride; after stirred at ambient temperature 18h, reflux 10h.After Ia-2 reacts completely, stopped reaction, is cooled to rapidly 0 DEG C under condition of ice bath, produces white precipitate, filters, washing with alcohol, dry, obtains Ia-3,1.48g(productive rate 48.3%).
Take the 2-(2-((S of 3.07g)-3-(methylamino) butyryl radicals)-5-((S)-2-(methylamino) propyl group) phenyl) acetic acid (Ia-3); be placed in 150mL round-bottomed flask; measure the DMF of 15mL; stirring and dissolving at ambient temperature, takes 0.57g sodium borohydride, is dissolved in 5mLDMF; slowly be added drop-wise in round-bottomed flask under the condition of ice bath; continue to stir 30min under ice bath, clear-cutting forestland to room temperature, heating reflux reaction 5h.After Ia-3 reacts completely, stopped reaction, by column chromatography, developping agent is methyl alcohol: methylene dichloride=1:4, obtains Ia-4,0.64g(yield 20.7%).
Take the 2-(2-((3S of 3.08g)-1-hydroxyl-3-(methylamino) butyl)-5-((S)-2-(methylamino) propyl group) phenyl) acetic acid (Ia-4), be placed in 150mL round-bottomed flask, measure the DMF of 15mL, stirring and dissolving at ambient temperature, takes 1.02g sodium ethylate, is dissolved in 5mLDMF, slowly be added drop-wise in round-bottomed flask under the condition of ice bath, continue to stir 30min under ice bath, clear-cutting forestland to room temperature, heating reflux reaction 18h.After Ia-4 reacts completely, stopped reaction, by column chromatography, developping agent is ethanol: ethyl acetate=1:10, obtains Ia-5,0.68g(yield 23.4%).White solid, mp:215 ~ 221 DEG C, MSm/z:291.31(M+H), 313.32(M+Na); 1h-NMR(DMSO-d 6, ppm) δ: 7.42 ~ 7.08(m, 3H), 5.85(d, 1H), 3.52 ~ 3.32(m, 4H), 3.26(m, 2H) and, 3.11(m, 1H), 2.79 ~ 2.54(m, 4H), 1.92(s, 2H), 1.11 ~ 1.06(m, 2H); 13c-NMR(DMSO-d 6, ppm) and δ: 168.6,137.5,136.4,132.8,130.5,128.6,136.7,66.3,59.2,52.0,44.7,42.4,36.9,33.7,21.2,20.8.
Embodiment 2
Two ((the S)-2-(methylamino) butyl of 1,6-) isochroman-3-ketone (R 1=CH 3, R 2=CH 2cH 3)
Preparation method is as embodiment 1, and difference uses N-methyl fourth-2-amine.White solid, mp:216 ~ 220 DEG C, MSm/z:341.46(M+Na); 1h-NMR(DMSO-d 6, ppm) δ: 7.42 ~ 7.09(m, 3H), 6.85(m, 1H), 3.52 ~ 3.49(d, 2H), 3.12 ~ 3.06(m, 4H), 2.93 ~ 2.54(m, 4H), 1.92 ~ 1.48(m, 2H), 0.87(t, 2H); 13c-NMR(DMSO-d 6, ppm) and δ: 167.4,138.1,137.3,135.4,132.5,130.9,125.3,68.9,67.9,66.4,58.4,42.2,39.9,36.9,34.0,27.8,10.7.
Embodiment 3
Two ((the S)-2-(ethylamino) butyl of 1,6-) isochroman-3-ketone (R 1=R 2=CH 2cH 3)
Preparation method is as embodiment 1, and difference uses N-diethyl butyl-2-amine.White solid, mp:201 ~ 215 DEG C, MSm/z:347.09(M+H), 369.26(M+Na); 1h-NMR(DMSO-d 6, ppm) and δ: 7.37 ~ 7.18 (m, 3H), 5.72(m, 1H), 3.52 ~ 3.38(m, 4H), 2.91 (d, 1H), 2.79 (d, 1H), 2.59 ~ 2.54 (m, 3H), 2.13 (m, 1H), 1.97 ~ 1.53 (m, 4H), 1.11 (s, 2H), 0.84 (t, 2H); 13c-NMR(DMSO-d 6, ppm) and δ: 169.4,138.1,136.7,135.4,130.5,128.7,126.9,66.6,62.4,55.9,42.2,40.1,36.9,28.6,27.4,15.9,10.3.
Embodiment 4
Two ((the S)-2-(ethylamino) propyl group of 1,6-) isochroman-3-ketone (R 1=CH 2cH 3, R 2=CH 3)
Preparation method is as embodiment 1, and difference uses N-diethyl propyl group-2-amine.White solid, mp:226 ~ 241 DEG C, MSm/z:319.39(M+H); 1h-NMR(DMSO-d 6, ppm) and δ: 7.61 ~ 7.20 (m, 3H), 6.41(m, 1H), 3.56 ~ 3.11(m, 5H), 2.79 ~ 2.54(m, 5H), 1.92 ~ 1.11(m, 6H); 13c-NMR(DMSO-d 6, ppm) and δ: 169.5,167.9,138.2,134.6,131.2,127.6,126.9,67.5,56.7,49.2,45.0,43.5,42.6,36.1,22.9,15.4.
Embodiment 5
1-((S)-2-(tert-butylamino) propyl group)-6-((R)-2-(ethylamino)-3,3-dimethylbutyls) isochroman-3-ketone (R 1=CH 3, R 2=sec.-propyl)
Preparation method is as embodiment 1, and difference uses N-sec.-propyl-2-methyl-prop-2-amine.White solid, mp:267 ~ 281 DEG C, MSm/z:411.07(M+Na); 1h-NMR(DMSO-d 6, ppm) and δ: 7.52 ~ 7.09 (m, 3H), 5.64(d, 1H), 3.47 ~ 3.21(m, 2H), 2.71(m, 2H) and, 2.64(s, 1H), 2.57 ~ 2.31(m, 2H), 1.92(m, 2H), 1.22 ~ 1.06(m, 5H), 0.89(t, 3H); 13c-NMR(DMSO-d 6, ppm) and δ: 172.5,150.9,148.2,141.6,132.7,128.9,127.1,75.9,64.1,60.2,43.7,42.5,39.7,37.4,36.2,30.5,27.3,22.4,16.1.
Embodiment 6
Two ((the R)-3-methyl-2-(methylamino) butyl of 1,6-) isochroman-3-ketone (R 1=sec.-propyl, R 2=CH 3)
Preparation method is as embodiment 1, and difference uses N-3-dimethyl butyrate-2-amine.White solid, mp:261 ~ 273 DEG C, MSm/z:347.09(M+H), 369.26(M+Na); 1h-NMR(DMSO-d 6, ppm) and δ: 7.45 ~ 7.16 (m, 3H), 5.82(m, 1H), 3.62 ~ 3.40(m, 4H), 2.93 (d, 1H), 2.71 (d, 1H), 2.63 ~ 2.52 (m, 3H), 2.21 (m, 1H), 1.97 ~ 1.54 (m, 4H), 1.30 (s, 2H), 0.87 (t, 2H); 13c-NMR(DMSO-d 6, ppm) and δ: 168.4,138.7,136.4,135.9,131.5,129.6,127.8,67.1,64.9,57.9,43.2,41.6,37.9,29.3,28.0,16.9,10.3.
Embodiment 7
1,6-two ((R)-3,3,3-tri-fluoro-2-(methylamino) propyl group) isochroman-3-ketone (R 1=trifluoromethyl, R 2=CH 3)
Preparation method is as embodiment 1, and difference is use 1,1,1-trifluoro-N-methyl third-2-amine.White solid, mp:317 ~ 326 DEG C, MSm/z:421.42(M+Na); 1h-NMR(DMSO-d 6, ppm) and δ: 7.73 ~ 7.64 (m, 3H), 5.84(m, 1H), 5.11(d, 1H) and, 4.61(m, 1H), 3.59 ~ 3.34(m, 6H), 2.74 ~ 2.28(m, 4H); 13c-NMR(DMSO-d 6, ppm) and δ: 172.6,147.3,137.9,134.2,132.6,129.1,128.3,127.5,124.8,72.6,68.6,65.8,37.8,33.7,24.3,22.0.
Embodiment 8
Two ((S)-2-(methylamino-)-2-nitro-ethyl of 1,6-) isochroman-3-ketone (R 1=NO 2, R 2=CH 3)
Preparation method is as embodiment 1, and difference uses N-methyl isophthalic acid-second nitro-1-amine.White solid, mp:284 ~ 295 DEG C, MSm/z:353.16(M+H), 374.26(M+Na); 1h-NMR(DMSO-d 6, ppm) and δ: 7.36 ~ 7.09 (m, 3H), 5.46 ~ 5.32(t, 2H), 4.84(d, 1H), 3.52 ~ 3.38(m, 3H), 3.17 ~ 3.10(m, 7H), 2.56(d, 2H); 13c-NMR(DMSO-d 6, ppm) and δ: 175.4,160.4,139.2,137.6,132.6,128.1,126.7,108.9,100.4,63.4,38.5,36.9,35.1,31.6.
Embodiment 9
Two (the bromo-2-(ethylamino of (S)-2-) ethyl of 1,6-) isochroman-3-ketone (R 1=Br, R 2=CH 2cH 3)
Preparation method is as embodiment 1, and difference uses the bromo-N-diethyl of 1--1-amine.White solid, mp:326 ~ 331 DEG C, MSm/z:449.01(M+H), 471.38(M+Na); 1h-NMR(DMSO-d 6, ppm) and δ: 7.48 ~ 7.26 (m, 3H), 6.71(d, 1H), 5.31(m, 1H) and, 4.16(s, 1H), 3.47 ~ 3.00(m, 6H), 2.59 ~ 2.44(t, 3H), 1.54(s, 2H); 13c-NMR(DMSO-d 6, ppm) and δ: 173.8,137.6,136.9,134.1,130.8,129.4,128.6,67.1,66.4,58.4,48.3,46.0,42.9,36.7,14.8.
Embodiment 10
Two (the chloro-2-(methylamino of (S)-2-) ethyl of 1,6-) isochroman-3-ketone (R 1=Cl, R 2=CH 3)
Preparation method is as embodiment 1, and difference uses the chloro-N-dimethyl of 1--1-amine.White solid, mp:313 ~ 328 DEG C, MSm/z:354.18(M+Na); 1h-NMR(DMSO-d 6, ppm) and δ: 7.48 ~ 7.19 (m, 3H), 5.83(m, 1H), 4.99 ~ 4.62(t, 2H), 3.57 ~ 3.17(m, 4H), 3.24(s, 2H) and, 3.04(s, 1H), 2.79(m, 1H) and, 2.22(d, 2H); 13c-NMR(DMSO-d 6, ppm) and δ: 170.6,137.1,133.7,132.6,130.8,128.6,126.3,81.1,72.6,64.8,45.8,37.5,31.1.
Embodiment 11
Experiment content: measure antiallergic activity experiment
Test material:
1. experiment mice: Kunming mouse, body weight 18 ~ 22g, male and female half and half, have Sichuan University's Experimental Animal Center to provide, animal rank: one-level.
Testing method:
Compound causes the impact of mouse capillary permeability to histamine
Experimental technique: often organize mouse 10, each group of single oral gives by reagent 8mg/kg/10ml, the oral Loratadine of positive drug group, blank group gives isopyknic solvent 0.2%CMC-Na, 1h after administration, after mouse tail vein injection 1% Evans Blue 10ml/kg, intradermal injection immediately 0.1% histamine phosphate 0.1ml/ only, form a cuticle mound, after 30min, mouse takes off cervical vertebra execution, peel belly indigo plant dye skin, shred with operating scissors and be placed in test tube, 24h is soaked with acetone-physiological saline 2ml (7: 3), the centrifugal 10min of 2000r/min, get its supernatant liquor in 610nm place colorimetric, record OD value, and by the typical curve of Evans Blue, calculate concentration.Biological assessment the results are shown in table 1
Table 1
The impact of the impact of the wealthy swelling rate of compound p-Xylol induced mice ear
Get qualified mouse 132, be divided into 22 groups at random by body weight, often organize 6, male and female half and half.Get compound 1-10 positive control Ibuprofen BP/EP group and model control group.The dosage of compound is 4mg/kg, and Ibuprofen BP/EP group dosage is 30mg/kg, and model group gives isometric 0.5%CMC-Na.Administration volume is 0.4ml/20g, and every day is administered once, continuous 5 days.After last administration 0.5 hour, in auris dextra wide pros and cons uniform application dimethylbenzene, every mouse 0.1ml.Put to death animal after one hour, cut two ears (left ear in contrast) along auricle baseline, sweep away two ears with the punch tool of diameter 9mm at same position and weigh (g), and obtain swelling and inhibitory rate of intumesce (%).Biological assessment the results are shown in table 2
Swelling=auris dextra sheet weight (g)-left auricle weight (g)
Inhibitory rate of intumesce (%)=(model swelling mean value-administration swelling mean value)/model group swelling rate × 100%
Table 2
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any amendments done within the spirit and principles in the present invention, equivalent replacement and improvement etc., all should be included within protection scope of the present invention.

Claims (4)

1. a pseudoephedrine analog derivative, or its pharmacy acceptable salt, ester or prodrug, is characterized in that, general structure I is as follows:
Wherein,
Ar is the hexa-atomic fragrant heterocycle of various structures; X 1, X 2, X 3, X 4be O, S, N, NH or CH independently of one another;
Heterocycle Ar is optionally by (C 1-4) alkyl, (C 3-7) cycloalkyl, (C 3-7) cycloalkyl-(C 1-3) alkyl replacement, wherein said alkyl, cycloalkyl or cycloalkylalkyl can be monosubstituted by-OH.
2.R 1, R 2be H, (C independently of one another 1-4) alkyl, halogen, CF 3, NO 2, (C 1-8) alkoxyl group
As claims requires the compound as described in 1, it is characterized in that, be following compounds:
Compound as claimed in claim 1 or 2, is characterized in that, is one of following compounds:
Two ((the S)-2-(methylamino) propyl group of 1,6-) isochroman-3-ketone,
Two ((the S)-2-(methylamino) butyl of 1,6-) isochroman-3-ketone,
Two ((the S)-2-(ethylamino) butyl of 1,6-) isochroman-3-ketone,
Two ((the S)-2-(ethylamino) propyl group of 1,6-) isochroman-3-ketone,
1-((S)-2-(tert-butylamino) propyl group)-6-((R)-2-(ethylamino)-3,3-dimethylbutyls) isochroman-3-ketone,
Two ((the R)-3-methyl-2-(methylamino) butyl of 1,6-) isochroman-3-ketone,
1,6-two ((R)-3,3,3-tri-fluoro-2-(methylamino) propyl group) isochroman-3-ketone,
Two ((S)-2-(methylamino-)-2-nitro-ethyl of 1,6-) isochroman-3-ketone,
Two (the bromo-2-(ethylamino of (S)-2-) ethyl of 1,6-) isochroman-3-ketone,
Two (the chloro-2-(methylamino of (S)-2-) ethyl of 1,6-) isochroman-3-ketone.
3. an anti-allergy agent compositions, comprises compound described in claim 1-3 any one claim or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers or vehicle.
4. the application of compound described in claim 1-3 any one in the antianaphylactic medicine of preparation.
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吴桂荣 等: "伪麻黄碱水杨酸盐的药用研究(Ⅱ)—解热、对心率和血压及组胺所致刺激反应的影响", 《药学进展》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105399719A (en) * 2015-11-20 2016-03-16 黄林海 Pseudoephedrine derivant and application of pseudoephedrine derivant to gastrointestinal ulcer resistance
CN105461676A (en) * 2015-11-20 2016-04-06 黄林海 Pseudoephedrine derivative and preparation method and application thereof
CN105399719B (en) * 2015-11-20 2017-12-15 王本军 A kind of pseudoephedrine analog derivative and preparation method and application

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