CN103570651B - A kind of method preparing ramelteon intermediate - Google Patents
A kind of method preparing ramelteon intermediate Download PDFInfo
- Publication number
- CN103570651B CN103570651B CN201210266571.0A CN201210266571A CN103570651B CN 103570651 B CN103570651 B CN 103570651B CN 201210266571 A CN201210266571 A CN 201210266571A CN 103570651 B CN103570651 B CN 103570651B
- Authority
- CN
- China
- Prior art keywords
- compound
- acid
- acetic acid
- reductive agent
- alkali
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of method preparing ramelteon intermediate, the method for raw material, finally obtains ramelteon intermediate through a series of simple reaction process with bromo-1,2,6,7-tetrahydrochysene-8H-indeno [5, the 4-b] furans-8-ketone of 4,5-bis-.The ramelteon intermediate productive rate that present method obtains is high, and purity is high, simple to operate, and cost is low, is applicable to industrialization scale operation.
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-base) acetic acid.
Background technology
Ramelteon, chemistry (S)-N-[2-(1,6,7,8-tetrahydrochysene-2H-indeno [5,4-b] furans-8-base) ethyl] propionic acid amide by name, 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, and suprachiasmatic nucleus (being also called as circadian clock) takes off black sharp MT
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-base) acetic acid is the important intermediate preparing ramelteon, high yield can be synthesized by this intermediate, high purity, the ramelteon that foreign matter content is low, and reactions steps is simple, easy realization, disclose in existing pertinent literature WO2008151170A2, WO2009056993, CN101654445A, CN101824012A by 2-(1,6,7,8-tetrahydrochysene-2H-indeno [5,4-b] furans-8-base) acetic acid prepares the reaction process of ramelteon.
Open with 1 in CN101654445A, 2,6,7-tetrahydrochysene-8H-indeno-[5,4-b] furans-8-ketone is starting raw material, obtains (1 by Wittig-Horner or Wittig condensation, 6,7,8-tetrahydrochysene-8H-indeno-[5,4-b] furans-8-subunit) acetonitrile, 2-(1,6,7 is obtained again through reduction, hydrolysis, 8-tetrahydrochysene-2H-indeno [5,4-b] furans-8-base) acetic acid.The method adopts in the step of Wittig-Horner or Wittig reaction, and need to react under sodium hydride effect, wherein sodium hydride has extremely strong reductibility, is heated or contacts with moisture, acids and namely release heat and hydrogen, causes burning and blast; Also can there is kickback with oxygenant, cause burning or blast; To eye and respiratory system irritant, direct skin contact causes burns, aborning very easily initiation potential, is not suitable for industrialization scale operation.
2-(1 is disclosed in CN101824012A, 6,7,8-tetrahydrochysene-2H-indeno [5,4-b] furans-8-base) acetic acid, a. with 4-aldehyde radical benzofuran compound for starting raw material, under organic solvent and alkaline condition with acetylacetic ester (wherein R5 is straight chained alkyl or the branched-chain alkyl of C1-8) after Knoevenagel condensation, Michael addition reaction, generate intermediate (7); B. then 3-(cumarone-4-base is obtained through basic hydrolysis, acid neutralization) pentanedioic acid; C. by 3-(cumarone-4-base) pentanedioic acid catalytic hydrogenation obtains 3-(2,3-Dihydrobenzofuranes-4-base) pentanedioic acid; D. by 3-(cumarone-4-base) pentanedioic acid through acidylate cyclization, generates 2-(6-oxygen-1,6,7,8-tetrahydrochysene-2H-indeno [5,4-b] furans-8-base) acetic acid in solvent-free or organic solvent; E.2-(6-oxygen-1,6,7,8-tetrahydrochysene-2H-indeno [5,4-b] furans-8-base) acetic acid obtains 2-(1,6,7,8-tetrahydrochysene-2H-indeno [5,4-b] furans-8-base) acetic acid through catalytic hydrogenation.This reaction scheme is prepared intermediate (7) process and is easily produced by product, and Knoevenagel condensation reaction gained by product and intermediate (7) separation and purification difficulty occur, and reaction conditions is wayward, and productive rate is low.And this reaction scheme reactions steps is complicated, and complex operation, is not suitable for industrialization scale operation.
Summary of the invention
The present inventor sends a kind of method 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-base) acetic acid (intermediate III).The present invention with 4,5-bis-bromo-1,2,6,7-tetrahydrochysene-8H-indeno-[5,4-b] furans-8-ketone is raw material, obtains ramelteon intermediate by three different reaction schemes, 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 industrialization scale operation.
Concrete technical scheme of the present invention is as follows:
Preparation ramelteon intermediate III method one, 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 the one in 2-(diethoxy phosphonate group) acetic acid or triphenylacetic acid quaternary alkylphosphonium salt;
B. compound ii is under reductive agent effect, obtains intermediate III, and wherein reductive agent is the one in Pd-C/H2, RaneyNi/H2, lithium aluminium hydride or zinc/hydrochloric acid.
Comprise the following steps in described step a:
(1) under temperature 0-5 DEG C of condition, alkali and phosphorus reagent are added in organic solvent, rises to stirring at room temperature, obtain reaction soln;
(2) chemical compounds I is dissolved in reaction soln, is warmed up to 90-100 DEG C and reacts, obtain compound ii.
Alkali in described step a is the one 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, and 2,6,7-tetrahydrochysene-8H-indeno-[5,4-b] furans-8-ketone is raw material, obtains intermediate III by means of only Wittig-Horner and reduction reaction, reaction mechanism is ripe, and by product is few, and productive rate is high, is applicable to industrialization scale operation.
Preparation ramelteon intermediate III method two, comprises the following steps:
C. chemical compounds I and propane dinitrile are reacted under catalyst action, generate compound ii A;
D. compound ii A acid or alkali effect under generate compound ii B;
E. compound ii B and reductive agent are obtained by reacting intermediate III.
Catalyzer in described step c is the one 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 the one in sodium hydroxide, potassium hydroxide.
In described step e, reductive agent is the one in Pd-C/H2, RaneyNi/H2, lithium aluminium hydride, zinc/hydrochloric acid.
Preparation ramelteon intermediate III method three, comprises the following steps:
F. by chemical compounds I under reductive agent effect, generate compound ii C, wherein reductive agent is the one in Pd-C/H2, RaneyNi/H2, lithium aluminium hydride or zinc/hydrochloric acid;
G. compound ii C and propane dinitrile react under catalyst action, generate 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 reacts with reductive agent and generate intermediate III.
Catalyzer in described step g is the one 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 the one in Pd-C/H2, RaneyNi/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 the one 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 utilizing Knoevenagel that chemical compounds I or compound ii C and propane dinitrile react, this reaction conditions is gentle, do not need the reaction conditions that High Temperature High Pressure etc. is restive, react under the catalyst action of the stable in properties such as pyridine, piperidines, aftertreatment is simple, is applicable to industrialization scale operation.
Available this area of starting material compound I of the present invention common technique obtains, including, but not limited to method disclosed in Publication about Document: WO2008151170, WO2012035303, WO2010041271.
Embodiment
Embodiment 1(method one)
Under temperature 0-5 DEG C of condition, NaH and 22.5g2-(diethoxy phosphonate group) acetic acid of 3.4g60% is dissolved in 300mL toluene, rises to stirring at room temperature and make dissolving, add 19.0g chemical compounds I, be warmed up to 90-100 DEG C of stirring, high performance liquid chromatography detection reaction is complete, is cooled by reaction solution and is added to the water, and stirs, organic phase is separated, drying, obtains 19.2g compound ii, productive rate: 89.7%.
1.8g10%Pd/C and 18.5g compound ii is dissolved in 200mL ethanol, passes 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 DEG C of 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 temperature and make dissolving, add 16.6g chemical compounds I, be warmed up to 90-100 DEG C of stirring, high performance liquid chromatography detection reaction is complete, is cooled by reaction solution and is added to the water, and stirs, with dichloromethane extraction, drying, obtains 16.51g compound ii, productive rate: 88.3%.
0.5gRaneyNi and 16.0g compound ii is dissolved in 180mL methyl alcohol, passes 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 DEG C of condition, 21.7g hexamethyldisilazane lithium and 31.7g2-(diethoxy phosphonate group) acetic acid are dissolved in 450mLN, in dinethylformamide, rise to stirring at room temperature and make dissolving, add 20g chemical compounds I, be warmed up to 90-100 DEG C of stirring, high performance liquid chromatography detection reaction is complete, reaction solution is cooled and is 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 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 with water and salt water washing, anhydrous magnesium sulfate drying, filters, decompression desolventizes, finally obtain 15.66g compound ii A, productive rate: 91.2%, directly can carry out next step reaction without the need to aftertreatment.
Be dissolved in the mixing solutions of 100mL hydrochloric acid and 50mL acetic acid by 15g compound ii A, stir, TLC detection reaction is complete, removes solvent under reduced pressure, uses ethanol-water mixed solvent recrystallization, obtain 12.85g compound ii B, productive rate: 87.1%.
Be dissolved in 120mL acetic acid by 12g compound ii B and 1.2g10%Pd/C, pass into hydrogen, stir, high performance liquid chromatography detection reaction is complete, filters, underpressure distillation, dry, obtains 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 with 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%, directly can carry out next step reaction without the need to aftertreatment.
Be dissolved in 180mL oxalic acid by 14.56g compound ii A, stir, TLC detection reaction is complete, removes solvent under reduced pressure, uses ethanol-water mixed solvent recrystallization, obtain 12.36g compound ii B, productive rate: 86.3%.
Be dissolved in 150mL ethanol by 11.7g compound ii B and 0.35gRaneyNi, pass into hydrogen, stir, high performance liquid chromatography detection reaction is complete, filters, underpressure distillation, dry, obtains 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 with water and salt water washing, anhydrous sodium sulfate drying, filters, decompression desolventizes, finally obtain 14.86g compound ii A, productive rate: 89.5%, directly can carry out next step reaction without the need to aftertreatment.
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 10% hydrochloric acid regulates pH5-7, by extracted with diethyl ether, organic layer is washed, Calcium Chloride Powder Anhydrous is dry, filters, removes solvent under reduced pressure, obtain 11.9g compound ii B, productive rate: 86.4%.
Be dissolved in 90mL acetic acid by 11g compound ii B and 5.0g lithium aluminium hydride, high performance liquid chromatography detection reaction is complete, filters, underpressure distillation, dry, obtains 5.62g intermediate III, productive rate: 87.7%.
Embodiment 7(method three)
15g chemical compounds I and 1.6g10%Pd/C are dissolved in 200mL 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, 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 with water and salt water washing, anhydrous magnesium sulfate drying, filters, decompression desolventizes, finally obtain 7.1g compound ii D, productive rate: 89.8%, directly can carry out next step reaction without the need to aftertreatment.
Be dissolved in 60mL acetic acid by 6.5g compound ii D and 0.7g10%Pd/C, pass into hydrogen, high performance liquid chromatography detection reaction is complete, filters, underpressure distillation, dry, obtains 5.8g compound ii E, productive rate: 88.4%.
Be dissolved in 60ml phenylformic acid by 5g compound ii E, stir, TLC detection reaction is complete, removes solvent under reduced pressure, uses ethanol-water mixed solvent recrystallization, obtain 4.3g intermediate III, productive rate: 88.3%.
Embodiment 8(method three)
Be dissolved in 230mL hydrochloric acid by 17g chemical compounds I and 11.65g zinc, GC-MS detection reaction is complete, and filter, filtrate being spin-dried for is dissolved in methylene dichloride, wash with water once, anhydrous magnesium sulfate drying, be 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 with water and salt water washing, anhydrous magnesium sulfate drying, filters, decompression desolventizes, finally obtain 8.0g compound ii D, productive rate: 89.6%, directly can carry out next step reaction without the need to process.
Be dissolved in 80mL ethyl acetate by 7.5g compound ii D and 0.7g10%Pd/C, pass into hydrogen, high performance liquid chromatography detection reaction is complete, filters, underpressure distillation, dry, obtains 6.64g compound ii E, productive rate: 87.7%.
Be dissolved in the mixing solutions of 20mL phosphoric acid and 60mL hydrochloric acid by 6g compound ii E, stir, TLC detection reaction is complete, removes solvent under reduced pressure, uses ethanol-water mixed solvent recrystallization, obtain 5.1g intermediate III, productive rate: 87.3%.
Embodiment 9(method three)
16g chemical compounds I and 1.6g10%Pd/C are dissolved in 180mL 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, 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 with water and salt water washing, anhydrous magnesium sulfate drying, filters, decompression desolventizes, finally obtain 7.44g compound ii D, productive rate: 89.7%, directly can carry out next step reaction without the need to aftertreatment.
Be dissolved in the mixing solutions of 20mL acetic acid and 50mL hydrochloric acid by 6.5g compound ii D, stir, TLC detection reaction is complete, removes solvent under reduced pressure, uses ethanol-water mixed solvent recrystallization, obtain 5.6g compound ii F, productive rate: 88.6%.
Be dissolved in 60mL acetic acid by 5g compound ii F and 0.3gRaneyNi, pass into hydrogen, high performance liquid chromatography detection reaction is complete, filters, underpressure distillation, dry, obtains 4.45g intermediate III, productive rate: 88.1%.
Embodiment 10(method three)
13g chemical compounds I and 0.46gRaneyNi are dissolved in 150mL 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 85mLN, react in dinethylformamide, TLC detection reaction is complete, adds water, extraction into ethyl acetate, anhydrous magnesium sulfate drying, filter, decompression desolventizes, and finally obtains 5.7g compound ii D, productive rate: 89.3%, directly can carry out next step reaction without the need to aftertreatment.
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 10% hydrochloric acid regulates pH5-7, is extracted with ethyl acetate, organic layer is washed, Calcium Chloride Powder Anhydrous is dry, filters, removes solvent under reduced pressure, obtain 4.2g compound ii F, productive rate: 86.4%.
Be dissolved in 50mL methyl alcohol by 3.5g compound ii F and 1.2g sodium borohydride, high performance liquid chromatography detection reaction is complete, filters, underpressure distillation, dry, obtains 3.05g intermediate III, productive rate: 86.4%.
Claims (10)
1. prepare a method for ramelteon intermediate III, it is characterized in that, 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 the one in 2-(diethoxy phosphonate group) acetic acid or triphenylacetic acid quaternary alkylphosphonium salt, and alkali is the one in sodium hydride, potassium tert.-butoxide, hexamethyldisilazane lithium, hmds base sodium, hmds base potassium, n-Butyl Lithium;
B. compound ii is under reductive agent effect, obtains intermediate III, and wherein reductive agent is the one in Pd-C/H2, RaneyNi/H2, lithium aluminium hydride or zinc/hydrochloric acid.
2. method according to claim 1, is characterized in that, comprises the following steps in described step a:
(1) under temperature 0-5 DEG C of condition, alkali and phosphorous acetic acid reagent are added in organic solvent, rises to stirring at room temperature, obtain reaction soln;
(2) chemical compounds I is dissolved in reaction soln, is warmed up to 90-100 DEG C and reacts, obtain compound ii.
3. prepare a method for ramelteon intermediate III, it is characterized in that, comprise the following steps:
C. chemical compounds I and propane dinitrile react under catalyst action, generate compound ii A;
D. compound ii A acid or alkali effect under generate compound ii B;
E. compound ii B and reductive agent are obtained by reacting intermediate III, and wherein reductive agent is the one in Pd-C/H2, RaneyNi/H2, lithium aluminium hydride, zinc/hydrochloric acid.
4. method according to claim 3, is characterized in that, in described step c, catalyzer is the one in pyridine, piperidines, diethylamine, sodium carbonate, ammonium acetate/acetic acid.
5. method according to claim 3, is characterized in that, in described step c, the mol ratio of chemical compounds I and propane dinitrile is 1:1-3.
6. method according to claim 3, 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 the one in sodium hydroxide, potassium hydroxide.
7. prepare a method for ramelteon intermediate III, it is characterized in that, comprise the following steps:
F. by chemical compounds I under reductive agent effect, generate compound ii C, wherein reductive agent is the one in Pd-C/H2, RaneyNi/H2, lithium aluminium hydride or zinc/hydrochloric acid;
G. compound ii C and propane dinitrile react under catalyst action, generate compound ii D;
H. compound ii D first generates compound ii E through reductive agent effect, under the condition of acid or alkali, generate intermediate III or compound ii D again and first generate compound ii F through acid or alkali effect, react with reductive agent and generate intermediate III, its reductive agent is the one in Pd-C/H2, RaneyNi/H2, lithium aluminium hydride, zinc/hydrochloric acid, sodium borohydride, POTASSIUM BOROHYDRIDE;
。
8. method according to claim 7, is characterized in that, the catalyzer in described step g is the one in pyridine, piperidines, diethylamine, sodium carbonate, ammonium acetate/acetic acid.
9. method according to claim 7, is characterized in that, in described step g, the mol ratio of compound ii C and propane dinitrile is 1:1-3.
10. method according to claim 7, 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 the one in sodium hydroxide, potassium hydroxide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210266571.0A CN103570651B (en) | 2012-07-30 | 2012-07-30 | A kind of method preparing ramelteon intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210266571.0A CN103570651B (en) | 2012-07-30 | 2012-07-30 | A kind of method preparing ramelteon intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103570651A CN103570651A (en) | 2014-02-12 |
| CN103570651B true CN103570651B (en) | 2016-04-27 |
Family
ID=50043438
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210266571.0A Active CN103570651B (en) | 2012-07-30 | 2012-07-30 | A kind of method preparing ramelteon intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103570651B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105622557B (en) * | 2014-11-05 | 2018-12-04 | 上海医药工业研究院 | Ramelteon intermediate and preparation method thereof |
| CN106749131B (en) * | 2015-11-20 | 2019-03-08 | 上海医药工业研究院 | Racemization prepares ramelteon intermediate method |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008151170A2 (en) * | 2007-05-31 | 2008-12-11 | Teva Pharmaceutical Industries Ltd. | Process for the synthesis of ramelteon and its intermediates |
| CN101654445A (en) * | 2008-08-22 | 2010-02-24 | 四川大学 | Compound for preparing ramelteon, preparation method thereof and application thereof |
| WO2010045565A1 (en) * | 2008-10-16 | 2010-04-22 | Teva Pharmaceutical Industries Ltd. | Process for the synthesis of ramelteon and its intermediates |
| CN101824012A (en) * | 2009-03-02 | 2010-09-08 | 四川大学 | 2-(1,6,7,8-tetrahydrogen-2H-indeno-[5,4-b] furan-8-group) acetonitrile, preparation method and applciation |
| CN102070576A (en) * | 2011-01-12 | 2011-05-25 | 四川大学 | 1-indanone-3-acetic acid compound as well as preparation method and application of 1-indanone-3-acetic acid compound |
| CN102358733A (en) * | 2011-09-01 | 2012-02-22 | 四川大学 | 2-(1-oxy-1H-indene-3-radical) acetic acid compound and preparation method and application thereof |
-
2012
- 2012-07-30 CN CN201210266571.0A patent/CN103570651B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008151170A2 (en) * | 2007-05-31 | 2008-12-11 | Teva Pharmaceutical Industries Ltd. | Process for the synthesis of ramelteon and its intermediates |
| CN101654445A (en) * | 2008-08-22 | 2010-02-24 | 四川大学 | Compound for preparing ramelteon, preparation method thereof and application thereof |
| WO2010045565A1 (en) * | 2008-10-16 | 2010-04-22 | Teva Pharmaceutical Industries Ltd. | Process for the synthesis of ramelteon and its intermediates |
| CN101824012A (en) * | 2009-03-02 | 2010-09-08 | 四川大学 | 2-(1,6,7,8-tetrahydrogen-2H-indeno-[5,4-b] furan-8-group) acetonitrile, preparation method and applciation |
| CN102070576A (en) * | 2011-01-12 | 2011-05-25 | 四川大学 | 1-indanone-3-acetic acid compound as well as preparation method and application of 1-indanone-3-acetic acid compound |
| CN102358733A (en) * | 2011-09-01 | 2012-02-22 | 四川大学 | 2-(1-oxy-1H-indene-3-radical) acetic acid compound and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103570651A (en) | 2014-02-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101792400B (en) | Synthetic method for agomelatine | |
| CN102276559B (en) | Method for synthesizing 3-hydroxymethyl tetrahydrofuran | |
| CN104496979A (en) | Method for preparing oxazolidinone compound and intermediate thereof | |
| CN104130258B (en) | The method for transformation of a kind of dimer | |
| CN105777835A (en) | Method for preparing chenodeoxycholic acid analogue | |
| CN103467525B (en) | Hydrogen peroxide oxidation method prepares the method for six (4-carboxy-phenoxy)-ring three phosphonitrile | |
| CN103570651B (en) | A kind of method preparing ramelteon intermediate | |
| CN102731605B (en) | A kind of purification process of Abiraterone acetate | |
| CN101838212B (en) | Method for synthesizing L-carnitine by using (R)-(-)-3-chlorine-1,2-propylene glycol as chiral initiative raw material | |
| CN101845070B (en) | Synthesis method of antineoplastic medicine capecitabine | |
| CN102491953A (en) | Method for synthesizing florfenicol midbody RT0131 | |
| CN108794319B (en) | Preparation method of ibuprofen impurity A | |
| CN103980120A (en) | Synthesis method of D,L-danshensu isopropyl ester | |
| CN101786949B (en) | Method for preparing 4-ethyl octanoic acid through microwave heating | |
| CN103787968B (en) | The preparation method of compound | |
| Cunha et al. | Microwave-assisted convenient syntheses of 2-indolizine derivatives from Morita-Baylis-Hillman adducts: new in silico potential ion channel modulators | |
| CN101973897B (en) | Synthesis method of valdoxan intermediate 2-(7-methoxy-1-naphthyl)ethylamine | |
| CN105745191A (en) | Method for preparing silodosin and intermediate thereof | |
| CN103172497A (en) | Industrialized production process of new medicament benvitimod for treating psoriasis | |
| CN102127061B (en) | One prepares improving one's methods of fluoro-3, the 4-dihydro-2 H-1-benzopyran-2-epoxy ethanes of 6- | |
| CN103570558A (en) | Synthesis method of 2-methyl-3-trifluoromethyl phenylamine | |
| CN107954872B (en) | Method for synthesizing malonate type compound | |
| CN102532149B (en) | Asymmetric synthesis method for galanthamine and lycoramine | |
| CN105541910A (en) | Diethyl p-toluenesulfonyloxy methylphosphonate synthesis method | |
| CA2750125A1 (en) | Methods for preparing s1p receptor agonists and antagonists |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 101113 Beijing Guangyuan Tongzhou District Industrial Development Zone in Tongzhou Street No. 8 Patentee after: Beijing Fuyuan Pharmaceutical Co., Ltd. Address before: 101113 Beijing Guangyuan Tongzhou District Industrial Development Zone in Tongzhou Street No. 8 Patentee before: Beijing Winsunny Pharmaceutical Co., Ltd. |