CN103570651A - Preparation method of Ramelteon intermediate - Google Patents
Preparation method of Ramelteon intermediate Download PDFInfo
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- CN103570651A CN103570651A CN201210266571.0A CN201210266571A CN103570651A CN 103570651 A CN103570651 A CN 103570651A CN 201210266571 A CN201210266571 A CN 201210266571A CN 103570651 A CN103570651 A CN 103570651A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
Abstract
The invention relates to a preparation method of a Ramelteon intermediate. The Ramelteon intermediate is prepared by taking 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one as a raw material, and then subjecting the raw material to a series of simple reactions so as to obtain the Ramelteon intermediate. The preparation method of the Ramelteon intermediate has the advantages of high yield, high product purity, simple operation, low cost, and suitability for mass production.
Description
Invention field
The present invention relates to the preparation method of ramelteon intermediate, the concrete method for preparation 2-(1,6,7,8-tetrahydrochysene-2H-indeno [5,4-b] furans-8-yl) acetic acid.
Background technology
Ramelteon, chemistry (S)-N-[2-(1,6,7,8-tetrahydrochysene-2H-indeno [5,4-b] furans-8-yl) ethyl by name] propionic acid amide, structural formula is:
Ramelteon is researched and developed by Japanese Wu Tian company, is a kind of potent, high selectivity melatonin receptor agonist, and it acts on the black sharp MT that takes off on suprachiasmatic nucleus (being also called as circadian clock)
1and MT
2acceptor.Ramelteon is to MT
1the avidity of acceptor, selectivity and effect are larger than melatonin, and MT
1acceptor is considered to again an integral part of sleep quality management.Different from benzodiazepine medicine, ramelteon can not reduce human body rapid eye movement (REM) sleep, is first without abuse and dependent insomnia prescribed treatment medicine.
2-(1,6,7,8-tetrahydrochysene-2H-indeno [5,4-b] furans-8-yl) acetic acid is the important intermediate of preparing ramelteon, by this intermediate, can synthesize high yield, high purity, the ramelteon that foreign matter content is low, and reactions steps is simple, easily realize, in existing pertinent literature WO2008151170A2, WO2009056993, CN101654445A, CN101824012A, disclose by 2-(1,6,7,8-tetrahydrochysene-2H-indeno [5,4-b] furans-8-yl) acetic acid is prepared the reaction process of ramelteon.
Open with 1,2 in CN101654445A, 6,7-tetrahydrochysene-8H-indeno-[5,4-b] furans-8-ketone is starting raw material, by Wittig-Horner or Wittig condensation, obtains (1,6,7,8-tetrahydrochysene-8H-indeno-[5,4-b] furans-8-subunit) acetonitrile, through reduction, hydrolysis, obtain 2-(1,6,7 again, 8-tetrahydrochysene-2H-indeno [5,4-b] furans-8-yl) acetic acid.The method adopts in the step of Wittig-Horner or Wittig reaction, need under sodium hydride effect, react, and wherein sodium hydride has extremely strong reductibility, is heated or contacts and emit heat and hydrogen with moisture, acids, causes burning and blast; Also kickback be can there is with oxygenant, burning or blast caused; Irritant to eye and respiratory system, skin directly contact causes and burns, and initiation potential very easily, is not suitable for large-scale industrialization and produces aborning.
2-(1 is disclosed in CN101824012A, 6,7,8-tetrahydrochysene-2H-indeno [5,4-b] furans-8-yl) acetic acid, a. the 4-aldehyde radical benzofuran compound of take is starting raw material, under organic solvent and alkaline condition with acetylacetic ester (straight chained alkyl or branched-chain alkyl that wherein R5 is C1-8) after Knoevenagel condensation, Michael addition reaction, generate intermediate (7); B. then through basic hydrolysis, acid neutralization, obtain 3-(cumarone-4-yl) pentanedioic acid; C. by 3-(cumarone-4-yl) pentanedioic acid catalytic hydrogenation obtains 3-(2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid; D. by 3-(cumarone-4-yl) pentanedioic acid through acidylate cyclization, generates 2-(6-oxygen-1,6,7,8-tetrahydrochysene-2H-indeno [5,4-b] furans-8-yl) acetic acid in solvent-free or organic solvent; E.2-(6-oxygen-1,6,7,8-tetrahydrochysene-2H-indeno [5,4-b] furans-8-yl) acetic acid obtains 2-(1,6,7,8-tetrahydrochysene-2H-indeno [5,4-b] furans-8-yl) acetic acid through catalytic hydrogenation.This reaction scheme is prepared intermediate (7) process and is easily produced by product, Knoevenagel condensation reaction gained by product and intermediate (7) separation and purification occurs difficult, and reaction conditions is wayward, and productive rate is low.And this reaction scheme reactions steps is complicated, complex operation, is not suitable for large-scale industrialization and produces.
Summary of the invention
The inventor sends a kind of method of preparing ramelteon intermediate by a large amount of experiment openings, and this intermediate is 2-(1,6,7,8-tetrahydrochysene-2H-indeno [5,4-b] furans-8-yl) acetic acid (intermediate III).The present invention is with 4,5-bis-bromo-1,2,6,7-tetrahydrochysene-8H-indeno-[5,4-b] furans-8-ketone is raw material, by three different reaction schemes, makes ramelteon intermediate, wherein each reactions steps has clear and definite, ripe reaction mechanism, side reaction is few, and dopant species and content are subject to strict control, and productive rate is high, reactions steps is simple to operate, is applicable to large-scale industrialization and produces.
Concrete technical scheme of the present invention is as follows:
Prepare ramelteon intermediate III method one, comprise the following steps:
A. chemical compounds I under alkali effect with phosphorous acetic acid reagent react, generate compound ii, wherein phosphorous acetic acid reagent is a kind of in 2-(diethoxy phosphonate group) acetic acid or triphenylacetic acid quaternary alkylphosphonium salt;
B. compound ii, under reductive agent effect, obtains intermediate III, and wherein reductive agent is a kind of in Pd-C/H2, Raney Ni/H2, lithium aluminium hydride or zinc/hydrochloric acid.
In described step a, comprise the following steps:
(1) under temperature 0-5 ℃ condition, alkali and phosphorus reagent are added in organic solvent, rise to stirring at room, obtain reaction soln;
(2) chemical compounds I is dissolved in to reaction soln, is warmed up to 90-100 ℃ and reacts, obtain compound ii.
Alkali in described step a is a kind of in sodium hydride, potassium tert.-butoxide, hexamethyldisilazane lithium, hmds base sodium, hmds base potassium, n-Butyl Lithium.
Step in the inventive method one is simple, with 4,5-bis-bromo-1,2,6,7-tetrahydrochysene-8H-indeno-[5,4-b] furans-8-ketone is raw material, only by Wittig-Horner and reduction reaction, obtains intermediate III, reaction mechanism is ripe, and by product is few, and productive rate is high, is applicable to large-scale industrialization and produces.
Prepare ramelteon intermediate III method two, comprise the following steps:
C. chemical compounds I is reacted under catalyst action with propane dinitrile, generate compound ii A;
D. compound ii A generates compound ii B under the effect of acid or alkali;
E. compound ii B reacts with reductive agent and obtains intermediate III.
Catalyzer in described step c is a kind of in pyridine, piperidines, diethylamine, sodium carbonate, ethanamide/acetic acid.
In described step c, the mol ratio of chemical compounds I and propane dinitrile is 1:1-3.
Acid in described steps d is one or more in acetic acid, hydrochloric acid, phosphoric acid, phenylformic acid, oxalic acid; Alkali is a kind of in sodium hydroxide, potassium hydroxide.
In described step e, reductive agent is a kind of in Pd-C/H2, Raney Ni/H2, lithium aluminium hydride, zinc/hydrochloric acid.
Prepare ramelteon intermediate III method three, comprise the following steps:
F. by chemical compounds I under reductive agent effect, generate compound ii C, wherein reductive agent is a kind of in Pd-C/H2, Raney Ni/H2, lithium aluminium hydride or zinc/hydrochloric acid;
G. compound ii C reacts under catalyst action with propane dinitrile, generates compound ii D;
H. compound ii D first generates compound ii E through reductive agent effect, then under the condition of acid or alkali, generates intermediate III or compound ii D first generates compound ii F through acid or alkali effect, then react generation intermediate III with reductive agent.
Catalyzer in described step g is a kind of in pyridine, piperidines, diethylamine, sodium carbonate, ethanamide/acetic acid.
In described step g, the mol ratio of compound ii C and propane dinitrile is 1:1-3.
Reductive agent in described step h is a kind of in Pd-C/H2, Raney Ni/H2, lithium aluminium hydride, zinc/hydrochloric acid, sodium borohydride, POTASSIUM BOROHYDRIDE.
Acid in described step h is one or more in acetic acid, hydrochloric acid, phosphoric acid, phenylformic acid, oxalic acid; Alkali is a kind of in sodium hydroxide, potassium hydroxide.
Step in the inventive method two and method three is simple, mild condition, and yield is better, and by product is few, and product purity is high.It is the reaction mechanism of utilizing Knoevenagel that chemical compounds I or compound ii C react with propane dinitrile, this reaction conditions is gentle, do not need the restive reaction conditionss such as High Temperature High Pressure, under the catalyst action of the stable in properties such as pyridine, piperidines, react, aftertreatment is simple, is applicable to large-scale industrialization and produces.
Starting material compound I of the present invention can make by this area common technique, including, but not limited to disclosed method: WO2008151170, WO2012035303, WO2010041271 in Publication about Document.
Embodiment
embodiment 1(method one)
Under temperature 0-5 ℃ condition, the NaH of 3.4g 60% and 22.5g 2-(diethoxy phosphonate group) acetic acid are dissolved in 300mL toluene, rise to stirring at room and make to dissolve, add 19.0g chemical compounds I, be warmed up to 90-100 ℃ of stirring, high performance liquid chromatography detection reaction is complete, and reaction solution is cooling and be added to the water, and stirs, organic phase is separated, dry, obtain 19.2g compound ii, productive rate: 89.7%.
1.8 g 10% Pd/C and 18.5g compound ii are dissolved in to 200 mL ethanol, pass into hydrogen, TLC detection reaction is complete, filters, and filtrate concentrates to obtain 9.58g intermediate III, productive rate: 88.9%.
embodiment 2(method one)
Under temperature 0-5 ℃ condition, 8.9g potassium tert.-butoxide and 21g triphenylacetic acid quaternary alkylphosphonium salt are dissolved in 280mL dimethyl sulfoxide (DMSO), rise to stirring at room and make to dissolve, add 16.6g chemical compounds I, be warmed up to 90-100 ℃ of stirring, high performance liquid chromatography detection reaction is complete, and reaction solution is cooling and be added to the water, and stirs, with dichloromethane extraction, dry, obtain 16.51g compound ii, productive rate: 88.3%.
0.5g Raney Ni and 16.0g compound ii are dissolved in to 180mL methyl alcohol, pass into hydrogen, TLC detection reaction is complete, filters, and filtrate concentrates to obtain 8.2g intermediate III, productive rate: 87.9%.
embodiment 3(method one)
Under temperature 0-5 ℃ condition, 21.7g hexamethyldisilazane lithium and 31.7g 2-(diethoxy phosphonate group) acetic acid are dissolved in 450mL DMF, rising to stirring at room makes to dissolve, add 20g chemical compounds I, be warmed up to 90-100 ℃ of stirring, high performance liquid chromatography detection reaction is complete, reaction solution is cooling and be added to the water, stir, be extracted with ethyl acetate, dry, obtain 19.96g compound ii, productive rate: 88.6%.
6.23g lithium aluminium hydride and 18.4g compound ii are dissolved in to 220mL tetrahydrofuran (THF), and TLC detection reaction is complete, filters, and filtrate concentrates to obtain 9.45g intermediate III, and productive rate is: 88.1%.
embodiment 4(method two)
By 15.0g chemical compounds I, 5.64g propane dinitrile, 2.26g ammonium acetate and 4.5mL acetic acid are dissolved in 115mL toluene and react, and TLC detection reaction is complete, liquid phase is poured out, and water and salt water washing, anhydrous magnesium sulfate drying, filters, decompression desolventizes, finally obtain 15.66g compound ii A, productive rate: 91.2%, without aftertreatment, can directly carry out next step reaction.
15g compound ii A is dissolved in the mixing solutions of 100mL hydrochloric acid and 50mL acetic acid, stirs, TLC detection reaction is complete, removes solvent under reduced pressure, uses ethanol-water mixed solvent recrystallization, obtains 12.85g compound ii B, productive rate: 87.1%.
12g compound ii B and 1.2g 10% Pd/C are dissolved in 120mL acetic acid, pass into hydrogen, stir, high performance liquid chromatography detection reaction is complete, filter, and underpressure distillation, dry, obtain 6.16g intermediate III, productive rate: 88.1%.
embodiment 5(method two)
By 16.6g chemical compounds I, 3.3g propane dinitrile, 3.16g pyridine is dissolved in 130mL ethyl acetate and reacts, and TLC detection reaction is complete, liquid phase is poured out, and water and salt water washing, Calcium Chloride Powder Anhydrous is dry, filters, decompression desolventizes, finally obtain 16.91g compound ii A, productive rate: 89.0%, without aftertreatment, can directly carry out next step reaction.
14.56g compound ii A is dissolved in 180mL oxalic acid, stirs, TLC detection reaction is complete, removes solvent under reduced pressure, uses ethanol-water mixed solvent recrystallization, obtains 12.36g compound ii B, productive rate: 86.3%.
11.7g compound ii B and 0.35g Raney Ni are dissolved in 150mL ethanol, pass into hydrogen, stir, high performance liquid chromatography detection reaction is complete, filter, and underpressure distillation, dry, obtain 5.98g intermediate III, productive rate: 87.7%.
embodiment 6(method two)
By 14.5g chemical compounds I, 8.58g propane dinitrile, 3.10g diethylamine is dissolved in 100mL methylene dichloride and reacts, and TLC detection reaction is complete, liquid phase is poured out, and water and salt water washing, anhydrous sodium sulfate drying, filters, decompression desolventizes, finally obtain 14.86g compound ii A, productive rate: 89.5%, without aftertreatment, can directly carry out next step reaction.
14.0g compound ii A and 2.95g sodium hydroxide are dissolved in 40mL ethanol and 60mL deionized water, stir, TLC detection reaction is complete, remove ethanol under reduced pressure, by extracted with diethyl ether, water layer regulates pH5-7 with 10% hydrochloric acid, by extracted with diethyl ether, organic layer is washed, Calcium Chloride Powder Anhydrous is dry, filters, and removes solvent under reduced pressure, obtain 11.9g compound ii B, productive rate: 86.4%.
11g compound ii B and 5.0g lithium aluminium hydride are dissolved in 90mL acetic acid, and high performance liquid chromatography detection reaction is complete, filter, and underpressure distillation, dry, obtain 5.62g intermediate III, productive rate: 87.7%.
embodiment 7(method three)
15g chemical compounds I and 1.6g 10% Pd/C are dissolved in 200 mL acetic acid, pass into hydrogen, GC-MS detection reaction is complete, filters, filtrate being spin-dried for is dissolved in ethyl acetate, washes with water once, and anhydrous magnesium sulfate drying, is spin-dried for, with ethyl alcohol recrystallization, obtain 6.68g compound ii C, productive rate: 85.0%.
By 6.2g compound ii C, 4.74g propane dinitrile, 2.2g ammonium acetate and 4mL acetic acid are dissolved in 70mL toluene and react, and TLC detection reaction is complete, liquid phase is poured out, and water and salt water washing, anhydrous magnesium sulfate drying, filters, decompression desolventizes, finally obtain 7.1g compound ii D, productive rate: 89.8%, without aftertreatment, can directly carry out next step reaction.
6.5g compound ii D and 0.7g 10% Pd/C are dissolved in 60mL acetic acid, pass into hydrogen, high performance liquid chromatography detection reaction is complete, filter, and underpressure distillation, dry, obtain 5.8g compound ii E, productive rate: 88.4%.
5g compound ii E is dissolved in 60ml phenylformic acid, stirs, TLC detection reaction is complete, removes solvent under reduced pressure, uses ethanol-water mixed solvent recrystallization, obtains 4.3g intermediate III, productive rate: 88.3%.
embodiment 8(method three)
17g chemical compounds I and 11.65g zinc are dissolved in 230 mL hydrochloric acid, and GC-MS detection reaction is complete, filters, and filtrate being spin-dried for is dissolved in methylene dichloride, wash with water once, anhydrous magnesium sulfate drying, is spin-dried for, with ethyl alcohol recrystallization, obtain 7.54g compound ii C, productive rate: 84.6%.
By 7.0g compound ii C, 2.64g propane dinitrile, 3.42g piperidines is dissolved in 100mL methylene dichloride and reacts, and TLC detection reaction is complete, liquid phase is poured out, and water and salt water washing, anhydrous magnesium sulfate drying, filters, decompression desolventizes, finally obtain 8.0g compound ii D, productive rate: 89.6%, without processing, can directly carry out next step reaction.
7.5g compound ii D and 0.7g 10% Pd/C are dissolved in 80mL ethyl acetate, pass into hydrogen, high performance liquid chromatography detection reaction is complete, filter, and underpressure distillation, dry, obtain 6.64g compound ii E, productive rate: 87.7%.
6g compound ii E is dissolved in the mixing solutions of 20mL phosphoric acid and 60mL hydrochloric acid, stirs, TLC detection reaction is complete, removes solvent under reduced pressure, uses ethanol-water mixed solvent recrystallization, obtains 5.1g intermediate III, productive rate: 87.3%.
embodiment 9(method three)
16g chemical compounds I and 1.6g 10% Pd/C are dissolved in 180 mL acetic acid, pass into hydrogen, GC-MS detection reaction is complete, filters, filtrate being spin-dried for is dissolved in ether, washes with water once, and anhydrous sodium sulfate drying, is spin-dried for, with ethyl alcohol recrystallization, obtain 7.14g compound ii C, productive rate: 85.1%.
By 6.5g compound ii C, 4.93g propane dinitrile, 2.6g ammonium acetate and 5mL acetic acid are dissolved in 100mL toluene and react, and TLC detection reaction is complete, liquid phase is poured out, and water and salt water washing, anhydrous magnesium sulfate drying, filters, decompression desolventizes, finally obtain 7.44g compound ii D, productive rate: 89.7%, without aftertreatment, can directly carry out next step reaction.
6.5g compound ii D is dissolved in the mixing solutions of 20mL acetic acid and 50mL hydrochloric acid, stirs, TLC detection reaction is complete, removes solvent under reduced pressure, uses ethanol-water mixed solvent recrystallization, obtains 5.6g compound ii F, productive rate: 88.6%.
5g compound ii F and 0.3g Raney Ni are dissolved in 60mL acetic acid, pass into hydrogen, high performance liquid chromatography detection reaction is complete, filter, and underpressure distillation, dry, obtain 4.45g intermediate III, productive rate: 88.1%.
embodiment 10(method three)
13g chemical compounds I and 0.46g Raney Ni are dissolved in 150 mL acetic acid, pass into hydrogen, GC-MS detection reaction is complete, filters, filtrate being spin-dried for is dissolved in ethyl acetate, washes with water once, and Calcium Chloride Powder Anhydrous is dry, is spin-dried for, with ethyl alcohol recrystallization, obtain 5.74g compound ii C, productive rate: 84.3%.
By 5.0g compound ii C, 5.74g propane dinitrile, 3.65g sodium carbonate is dissolved in 85mL N, in dinethylformamide, react, TLC detection reaction is complete, adds water, ethyl acetate extraction, anhydrous magnesium sulfate drying, filter, decompression desolventizes, and finally obtains 5.7g compound ii D, productive rate: 89.3%, without aftertreatment, can directly carry out next step reaction.
5.0g compound ii D and 2.0g potassium hydroxide are dissolved in 30mL ethanol and 60mL deionized water, stir, TLC detection reaction is complete, remove ethanol under reduced pressure, be extracted with ethyl acetate, water layer regulates pH5-7 with 10% hydrochloric acid, is extracted with ethyl acetate, organic layer is washed, Calcium Chloride Powder Anhydrous is dry, filters, and removes solvent under reduced pressure, obtain 4.2g compound ii F, productive rate: 86.4%.
3.5g compound ii F and 1.2g sodium borohydride are dissolved in 50mL methyl alcohol, and high performance liquid chromatography detection reaction is complete, filter, and underpressure distillation, dry, obtain 3.05g intermediate III, productive rate: 86.4%.
Claims (13)
1. a method of preparing ramelteon intermediate III, is characterized in that, comprises the following steps:
A. chemical compounds I under alkali effect with phosphorous acetic acid reagent react, generate compound ii, wherein phosphorous acetic acid reagent is a kind of in 2-(diethoxy phosphonate group) acetic acid or triphenylacetic acid quaternary alkylphosphonium salt;
B. compound ii, under reductive agent effect, obtains intermediate III, and wherein reductive agent is a kind of in Pd-C/H2, Raney Ni/H2, lithium aluminium hydride or zinc/hydrochloric acid.
2. method according to claim 1, is characterized in that, in described step a, comprises the following steps:
(1) under temperature 0-5 ℃ condition, alkali and phosphorous acetic acid reagent are added in organic solvent, rise to stirring at room, obtain reaction soln;
(2) chemical compounds I is dissolved in to reaction soln, is warmed up to 90-100 ℃ and reacts, obtain compound ii.
3. method according to claim 1, is characterized in that, described alkali is a kind of in sodium hydride, potassium tert.-butoxide, hexamethyldisilazane lithium, hmds base sodium, hmds base potassium, n-Butyl Lithium.
4. a method of preparing ramelteon intermediate III, is characterized in that, comprises the following steps:
C. chemical compounds I reacts under catalyst action with propane dinitrile, generates compound ii A;
D. compound ii A generates compound ii B under the effect of acid or alkali;
E. compound ii B reacts with reductive agent and obtains intermediate III.
5. method according to claim 4, is characterized in that, in described step c, catalyzer is a kind of in pyridine, piperidines, diethylamine, sodium carbonate, ethanamide/acetic acid.
6. method according to claim 4, is characterized in that, in described step c, the mol ratio of chemical compounds I and propane dinitrile is 1:1-3.
7. method according to claim 4, is characterized in that, in described steps d, acid is one or more in acetic acid, hydrochloric acid, phosphoric acid, phenylformic acid, oxalic acid; Alkali is a kind of in sodium hydroxide, potassium hydroxide.
8. method according to claim 4, is characterized in that, in described step e, reductive agent is a kind of in Pd-C/H2, Raney Ni/H2, lithium aluminium hydride, zinc/hydrochloric acid.
9. a method of preparing ramelteon intermediate III, is characterized in that, comprises the following steps:
F. by chemical compounds I under reductive agent effect, generate compound ii C, wherein reductive agent is a kind of in Pd-C/H2, Raney Ni/H2, lithium aluminium hydride or zinc/hydrochloric acid;
G. compound ii C reacts under catalyst action with propane dinitrile, generates compound ii D;
H. compound ii D first generates compound ii E through reductive agent effect, then under the condition of acid or alkali, generates intermediate III or compound ii D first generates compound ii F through acid or alkali effect, then react generation intermediate III with reductive agent;
10. method according to claim 9, is characterized in that, the catalyzer in described step g is a kind of in pyridine, piperidines, diethylamine, sodium carbonate, ethanamide/acetic acid.
11. methods according to claim 9, is characterized in that, in described step g, the mol ratio of compound ii C and propane dinitrile is 1:1-3.
12. methods according to claim 9, is characterized in that, the reductive agent in described step h is a kind of in Pd-C/H2, Raney Ni/H2, lithium aluminium hydride, zinc/hydrochloric acid, sodium borohydride, POTASSIUM BOROHYDRIDE.
13. methods according to claim 9, is characterized in that, the acid in described step h is one or more in acetic acid, hydrochloric acid, phosphoric acid, phenylformic acid, oxalic acid; Alkali is a kind of in sodium hydroxide, potassium hydroxide.
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| CN105622557A (en) * | 2014-11-05 | 2016-06-01 | 上海医药工业研究院 | Ramelteon intermediate and preparation method thereof |
| CN105622557B (en) * | 2014-11-05 | 2018-12-04 | 上海医药工业研究院 | Ramelteon intermediate and preparation method thereof |
| CN106749131A (en) * | 2015-11-20 | 2017-05-31 | 上海医药工业研究院 | Racemization prepares ramelteon intermediate method |
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