CN106749131A - Racemization prepares ramelteon intermediate method - Google Patents
Racemization prepares ramelteon intermediate method Download PDFInfo
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- CN106749131A CN106749131A CN201510808679.1A CN201510808679A CN106749131A CN 106749131 A CN106749131 A CN 106749131A CN 201510808679 A CN201510808679 A CN 201510808679A CN 106749131 A CN106749131 A CN 106749131A
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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 discloses the racemization method of one kind (R) -2- (1,6,7,8- tetrahydrochysene -2H- indeno (5,4-b) furans -8- bases) acetic acid (R types-I), comprise the following steps：
Description
Technical field
The invention belongs to chemical pharmacy field, specifically related to pass through (R) -2- (1,6,7,8- tetrahydrochysene -2H- indeno (5,4-b) furans -8- bases) acetic acid (being abbreviated as R types-I) racemization prepares ramelteon intermediate.
Background technology
Ramelteon (English name：Ramelteon it is) that, by the melatonin receptor activator of Japanese Wu Tian companies exploitation, energy selectively acting can be used to treat the insomnia being characterized with difficulty falling asleep in MT1 and MT2 acceptors.Slow wave sleep (SWS) and REM sleep (REW) can be increased, so as to reduce insomnia.In addition, this product is for GABA acceptors, dopamine receptor, acetylcholinergic receptor, opiate receptor etc. almost without affinity, there is the entirely different mechanism of action with traditional hypnotic sedative agent, and help to adjust sleep cycle, improve the health care of sleep quality and be first hypnotic sedative agent for not being put into special control without substantially additive.Ramelteon it is chemical entitled：(S)-N- [2- (1,6,7,8- tetrahydrochysene -2H- indeno [5,4-b] furans -8- bases) ethyl] propionamide, its structural formula is as follows：
In the building-up process of ramelteon, the key for being configured to synthetic route of benzyl position chiral carbon.At present, in the synthesis of ramelteon, the method for building benzyl position chiral carbon includes：
Route one：(bibliography：J.Med.Chem.,2002,45(19):4222-4239)
In route one：Compound 1 obtains chipal compounds 2 through asymmetric reduction, and compound 2 obtains end-product ramelteon 9 by bromo, phenolic ether hydrolysis demethylation, allyl group alkylated, Claisen rearrangements, ozonisation, reduction, debrominate, Mesylation and substitution cyclization again.
In the route, the structure of benzyl position chiral carbon is, in first step reaction, to be realized by the asymmetric hydrogenation of double bond, and due to having used the chiral catalyst of costliness, cost is greatly increased, and does not meet the requirement of industrialized production.
Route two：(bibliography：Chinese Chemical Letters, 2011 (22):264-267)
Route two include compound 10 first pass through with (S) -4- Bian Ji oxazole -2- ketone occur substitution reaction obtain compound 11; 11 build target benzyl position chiral carbon generation compound 12 with allyl chloride reaction again; 12 obtain compound 13 through reduction reaction again; 13 are substituted; closed loop obtains compound 16,16 and obtains compound 18,18 and obtain compound 19 with hydrazine reaction again with phthalimide reaction after carrying out reduction after oxidation; by by the amino of compound 19 it is propionating after, obtain compound 2.With reference to the method for route one, can be synthesized by compound 2 and obtain end-product ramelteon 9.
Agents useful for same is more cheap and easy to get in route two, but complex steps, is unfavorable for industrial amplification.And the structure of the benzyl position chirality of ramelteon is, by introducing chiral oxazolidone auxiliary group in compound 10, so as under the influence of the auxiliary group, carry out asymmetric Isosorbide-5-Nitrae-addition, to construct the benzyl of the ramelteon of chirality.
In addition, additionally providing the method for route three in international monopoly WO2008151170 to build the chirality of the benzyl position of ramelteon：
The route three is that benzyl position chiral carbon is built by splitting the racemic modification as shown in raceme-I, obtain crucial chiral intermediate (S) -2 [1,6,7,8- tetrahydrochysene -2H- indeno (5,4-b) furans -8- bases] acetic acid (S types-I), compound S type-I are through amidatioon, reduction is obtained compound 24,24 and obtains end-product ramelteon 9 with propionyl chloride reaction again.The agents useful for same of route three is cheap and easy to get, simple to operate, is the method that current industrial production is generally used.However, resolution of racemic body there is also very big deficiency obtaining the method for single configuration product, that is, the yield for obtaining the product (i.e. S types-I) of target configuration is about 40%, and yield is very low.Because resolution of racemic body must just produce the waste of 50% enantiomter, therefore the yield for splitting in theory to be impossible to more than 50% in theory.
In sum, the existing method for building ramelteon intermediate benzyl position chiral carbon has various, however, these methods all have such or such various shortcomings, such as route one and route two is respectively present defects such as agents useful for same costliness, complex steps etc..Route three is more commonly used in the industrial production, but resolution of racemic body has a very big deficiency obtaining the method for single configuration product in itself, i.e., in the product for obtaining target configuration simultaneously, inevitable loss falls that a part of product of non-targeted configuration accessory substance；So as to also cause resolution reaction yield low.In addition, title intermediate (S) -2 [1,6,7,8- tetrahydrochysene -2H- indenos (5,4-b) furans -8- bases] acetic acid the market price it is higher, therefore re-use split mother liquor in non-targeted configuration accessory substance, convert target configuration turn into solution the route industrialized production key.
The content of the invention
The technical problems to be solved by the invention are in order in overcoming the method for existing structure ramelteon intermediate benzyl position chiral carbon, expensive reagent need to be used, cost is very high, or yield is relatively low, be not suitable for the defects such as industrialized production, there is provided a kind of by (R) -2- (1,6,7,8- tetrahydrochysene -2H- indenos (5,4-b) furans -8- bases) acetic acid (being abbreviated as R types-I) racemization method, realize cycling and reutilization, cause the relatively low deficiency of yield to make up resolution reaction.Present method avoids using expensive catalyst, low cost, reactions steps are few, high income, reduce three waste discharge, compensate for the deficiency of route three, are more suitable for industrialized production.
Therefore, the invention provides the racemization method of R types-I, comprising the following steps：
1), in organic solvent, in the presence of radical initiator and catalyst, the oxidized dehydrogenation reactions of R types-I are converted into compound ii；
2), in organic solvent, compound II is reacted by hydro-reduction obtain raceme-I in the presence of a hydrogenation catalyst.
Part the following is present invention reaction is preferable to carry out condition or implementation method.
In step 1) in, the organic solvent used by the oxidative dehydrogenation is conventional acid, such as：The arbitrary proportion mixed system that one or more of acetic acid, hydrochloric acid etc., or acid and other common solvents such as acetonitrile, methyl alcohol, ethanol, pyridine etc..Acetic acid specifically preferred according to the invention makees solvent.The consumption of organic solvent can be conventional chemical reaction consumption, and its volume mass with reaction substrate R types-I is than preferably 5~10ml/g.
In step 1) in, radical initiator used is the conventional initiator of radical reaction, tertbutanol peroxide specifically preferred according to the invention and peroxidized t-butyl perbenzoate.The consumption of described radical initiator is the conventional amount used of radical reaction, following dosage scope specifically preferred according to the invention：Described initiator is preferably (1~3) with the mol ratio of R types-I:1.
In step 1) in, catalyst used is mantoquita, copper nitrate specifically preferred according to the invention, copper sulphate, copper acetate and copper chloride.The consumption of the catalyst is the conventional amount used of radical reaction, following dosage scope specifically preferred according to the invention：The catalyst is preferably (0.05~0.3) with the mol ratio of R types-I:1.
In step 1) in, the temperature of described oxidative dehydrogenation can be the temperature commonly used during the such free-radical oxidation in this area reacts, and room temperature specifically preferred according to the invention is to 70 DEG C.
In step 1) in, untill the time of described oxidative dehydrogenation can detect that reaction is completed by conventional detection means, generally 4~8 hours.
Above-mentioned steps 1) oxidative dehydrogenation terminate after, can be by simple post processing, such as extraction is gone out, extracts, washing, drying, concentrating, column chromatography can be prepared by pure compound ii.
In step 2) in, described hydro-reduction reacts the organic solvent that used organic solvent is commonly used for this area class, methyl alcohol specifically preferred according to the invention, ethanol, more preferably one or more of tetrahydrofuran, methyl alcohol.The consumption of organic solvent can be conventional chemical reaction consumption, and its volume mass with compound ii is than preferably 5~10ml/g.
In step 2) in, the palladium carbon that described hydrogenation is used is the conventional palladium carbon of such hydrogenation, and content specifically preferred according to the invention is 5% and 10% palladium carbon.10% palladium carbon is optimal.The consumption of palladium carbon can be conventional chemical reaction consumption, and it is preferably 0.1 with the mass ratio of compound ii:1.
In step 2) in, the temperature of described hydrogenation can be the temperature commonly used in the such hydrogenation in this area, 15 DEG C to 35 DEG C specifically preferred according to the invention.
In step 2) in, the Hydrogen Vapor Pressure of described hydrogenation can be the pressure commonly used in the such hydrogenation in this area, and the optimal Hydrogen Vapor Pressure of the present invention is normal pressure.
In step 2) in, untill the time of described hydrogenation can detect that reaction is completed by conventional detection means, generally 3~12 hours.
Above-mentioned steps 2) hydrogenation terminate after, can be by simple post processing, such as suction filtration, revolving.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and obtain further each preferred embodiments of the invention.
Unless otherwise specified, agents useful for same of the present invention and raw material are commercially available.
Positive effect of the invention is：Preparation method of the invention is avoided and uses expensive catalyst; low cost; and post-process simple; turn waste into wealth, reduce the discharge of the three wastes, be conducive to the protection of environment; product yield is higher; compensate for the resolution reaction of route three causes the relatively low deficiency of yield, can be used for the synthesis of ramelteon, is suitable for industrialized production.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but therefore do not limit the present invention among described scope of embodiments.The specific rotation of R types-I is in wherein all embodiments
Embodiment
1
：
2-(1,2,6,7-
Tetrahydrochysene
-8H-
Indeno
-[5,4,-b]
Furans
-8-
Subunit
)
The preparation of acetic acid
R type-I (10.0g, 0.046mol) with acetic acid (100ml) in three-necked bottle, stirring is molten clear, sequentially add Cu (NO3) 23H2O (2.214g, 0.009mol) with 65%TBHP (tertbutanol peroxide), 21.2ml, 0.137mol), it is warming up to 70 DEG C, reaction 8h, TLC detection raw materials disappear substantially, it is cooled to room temperature, reaction solution is added in 500ml water, stirring 2h, ethyl acetate extracts (100ml × 3 time), merge organic phase, saturated common salt is washed 3 times, anhydrous sodium sulfate drying, suction filtration, revolving, cross post and obtain (the 7.46g of yellow oil II, 75%), ESI-MS (m/z):215 [M-H]+, 1HNMR (400MHz, CDCl3) δ:3.02~3.04 (t, 2H), 3.34 (s, 2H), 3.40~3.44 (t, 2H), 4.64~4.69 (t, 2H), 6.15 (s, 1H), 6.85~6.87 (d, 1H), 7.11~7.13 (d, 1H)
Embodiment
2
：
2-(1,2,6,7-
Tetrahydrochysene
-8H-
Indeno
-[5,4,-b]
Furans
-8-
Subunit
)
The preparation of acetic acid
R type-I (10.0g, 0.046mol), acetonitrile (90ml) and acetic acid (10ml) are in three-necked bottle, stirring is molten clear, sequentially add Cu (NO3) 23H2O (2.214g, 0.009mol) with 65%TBHP (21.2ml, 0.137mol), it is warming up to 70 DEG C, reaction 8h, TLC detection raw materials disappear substantially, it is cooled to room temperature, reaction solution is added in 500ml water, stirring 2h, ethyl acetate extracts (100ml × 3 time), merge organic phase, saturated common salt is washed 3 times, anhydrous sodium sulfate drying, suction filtration, revolving, cross post and obtain (the 7.40g of yellow oil II, 75%), ESI-MS (m/z):215 [M-H]+, 1HNMR (400MHz, CDCl3) δ:3.02~3.04 (t, 2H), 3.34 (s, 2H), 3.40~3.44 (t, 2H), 4.64~4.69 (t, 2H), 6.15 (s, 1H), 6.85~6.87 (d, 1H), 7.11~7.13 (d, 1H)
Embodiment
3
：
2-(1,2,6,7-
Tetrahydrochysene
-8H-
Indeno
-[5,4,-b]
Furans
-8-
Subunit
)
The preparation of acetic acid
R type-I (10.0g, 0.046mol) with acetic acid (100ml) in three-necked bottle, stirring is molten clear, sequentially add Cu (NO3) 23H2O (2.214g, 0.009mol) with 65%TBHP (21.2ml, 0.137mol), it is warming up to 30 DEG C, reaction 24h, TLC detection raw materials disappear substantially, it is cooled to room temperature, reaction solution is added in 500ml water, stirring 2h, ethyl acetate extracts (100ml × 3 time), merge organic phase, saturated common salt is washed 3 times, anhydrous sodium sulfate drying, suction filtration, revolving, cross post and obtain (the 7.34g of yellow oil II, 74%), ESI-MS (m/z):215 [M-H]+, 1HNMR (400MHz, CDCl3) δ:3.02~3.04 (t, 2H), 3.34 (s, 2H), 3.40~3.44 (t, 2H), 4.64~4.69 (t, 2H), 6.15 (s, 1H), 6.85~6.87 (d, 1H), 7.11~7.13 (d, 1H)
Embodiment
4
：
2-(1,2,6,7-
Tetrahydrochysene
-8H-
Indeno
-[5,4,-b]
Furans
-8-
Subunit
)
The preparation of acetic acid
R type-I (10.0g, 0.046mol) with acetic acid (100ml) in three-necked bottle, stirring is molten clear, sequentially add Cu (CH3COO) 2H2O (1.800g, 0.009mol) with 65%TBHP (21.2ml, 0.137mol), it is warming up to 70 DEG C, reaction 8h, TLC detection raw materials disappear substantially, it is cooled to room temperature, reaction solution is added in 500ml water, stirring 2h, ethyl acetate extracts (100ml × 3 time), merge organic phase, saturated common salt is washed 3 times, anhydrous sodium sulfate drying, suction filtration, revolving, cross post and obtain (the 7.1g of yellow oil II, 72%), ESI-MS (m/z):215 [M-H]+, 1HNMR (400MHz, CDCl3) δ:3.02~3.04 (t, 2H), 3.34 (s, 2H), 3.40~3.44 (t, 2H), 4.64~4.69 (t, 2H), 6.15 (s, 1H), 6.85~6.87 (d, 1H), 7.11~7.13 (d, 1H)
Embodiment
5
：
2-(1,2,6,7-
Tetrahydrochysene
-8H-
Indeno
-[5,4,-b]
Furans
-8-
Subunit
)
The preparation of acetic acid
R type-I (10.0g, 0.046mol) with acetic acid (100ml) in three-necked bottle, stirring is molten clear, sequentially add CuSO4 (1.436g, 0.009mol) with 65%TBHP (21.2ml, 0.137mol), it is warming up to 70 DEG C, reaction 8h, TLC detection raw materials disappear substantially, it is cooled to room temperature, reaction solution is added in 500ml water, stirring 2h, ethyl acetate extracts (100ml × 3 time), merge organic phase, saturated common salt is washed 3 times, anhydrous sodium sulfate drying, suction filtration, revolving, cross post and obtain (the 7.27g of yellow oil II, 73%), ESI-MS (m/z):215 [M-H]+, 1HNMR (400MHz, CDCl3) δ:3.02~3.04 (t, 2H), 3.34 (s, 2H), 3.40~3.44 (t, 2H), 4.64~4.69 (t, 2H), 6.15 (s, 1H), 6.85~6.87 (d, 1H), 7.11~7.13 (d, 1H)
Embodiment
6
：
2-(1,2,6,7-
Tetrahydrochysene
-8H-
Indeno
-[5,4,-b]
Furans
-8-
Subunit
)
The preparation of acetic acid
R type-I (10.0g, 0.046mol) with acetic acid (100ml) in three-necked bottle, stirring is molten clear, sequentially add Cu (NO3) 23H2O (2.214g, 0.009mol) with peroxidized t-butyl perbenzoate (26.803g, 0.137mol), room temperature reaction 24h, TLC detection raw materials disappear substantially, it is cooled to room temperature, reaction solution is added in 500ml water, stirring 2h, ethyl acetate extracts (100ml × 3 time), merge organic phase, saturated common salt is washed 3 times, anhydrous sodium sulfate drying, suction filtration, revolving, cross post and obtain (the 6.8g of yellow oil II, 69%), ESI-MS (m/z):215 [M-H]+, 1HNMR (400MHz, CDCl3) δ:3.02~3.04 (t, 2H), 3.34 (s, 2H), 3.40~3.44 (t, 2H), 4.64~4.69 (t, 2H), 6.15 (s, 1H), 6.85~6.87 (d, 1H), 7.11~7.13 (d, 1H)
Embodiment
7:(1,2,6,7-
Tetrahydrochysene
-8H-
Indeno
[5,4-b]
Furans
-8-
Base
)
The preparation of acetic acid
To methyl alcohol 20ml is added in the single port bottle equipped with compound ii (2.2g, 0.01.mol), stir molten clear, palladium carbon 0.2g is added, hydrogen (normal pressure), room temperature reaction 24h are passed through after vacuumizing, stop reaction, suction filtration, filtrate is spin-dried for, and obtains off-white powder, add 10ml n-hexanes, stirring, backflow 1h is cooled to room temperature, suction filtration.Obtain white solid raceme-I (1.94g, yield 88%), mp126~128 DEG C, [α] D25=+0.8 (c=1, CH3OH) .1H NMR (400MHz, DMSO-d6) δ:1.72~1.80 (m, 1H), 2.19~2.28 (m, 2H), 2.64~2.72 (m, 2H), 2.79~2.86 (q, 1H), 3.00~3.15 (m, 2H), 3.38 (q, 1H), 4.40~4.53 (m, 2H), 4.53~6.52 (d, 1H), 6.88~6.91 (d, 1H)
Embodiment
8:(1,2,6,7-
Tetrahydrochysene
-8H-
Indeno
[5,4-b]
Furans
-8-
Base
)
The preparation of acetic acid
To methyl alcohol 10ml and tetrahydrofuran 10ml is added in the single port bottle equipped with compound ii (2.2g, 0.01.mol), stir molten clear, palladium carbon 0.2g is added, hydrogen (normal pressure), room temperature reaction 24h are passed through after vacuumizing, stop reaction, suction filtration, filtrate is spin-dried for, and obtains off-white powder, add 10ml n-hexanes, stirring, backflow 1h is cooled to room temperature, suction filtration.Obtain white solid raceme-I (2.00g, yield 89%), mp126~128 DEG C, [α] D25=+0.8 (c=1, CH3OH) .1H NMR (400MHz, DMSO-d6) δ:1.72~1.80 (m, 1H), 2.19~2.28 (m, 2H), 2.64~2.72 (m, 2H), 2.79~2.86 (q, 1H), 3.00~3.15 (m, 2H), 3.38 (q, 1H), 4.40~4.53 (m, 2H), 4.53~6.52 (d, 1H), 6.88~6.91 (d, 1H)
Embodiment
9:(1,2,6,7-
Tetrahydrochysene
-8H-
Indeno
[5,4-b]
Furans
-8-
Base
)
The preparation of acetic acid
To methyl alcohol 20ml is added in the single port bottle equipped with compound ii (2.2g, 0.01.mol), stir molten clear, palladium carbon 0.2g is added, hydrogen (0.5MPa), room temperature reaction 2h are passed through after vacuumizing, stop reaction, suction filtration, filtrate is spin-dried for, and obtains off-white powder, add 10ml n-hexanes, stirring, backflow 1h is cooled to room temperature, suction filtration.Obtain white solid raceme-I (2.10g, yield 94%), mp126~128 DEG C, [α] D25=+0.5 (c=1, CH3OH) .1H NMR (400MHz, DMSO-d6) δ:1.72~1.80 (m, 1H), 2.19~2.28 (m, 2H), 2.64~2.72 (m, 2H), 2.79~2.86 (q, 1H), 3.00~3.15 (m, 2H), 3.38 (q, 1H), 4.40~4.53 (m, 2H), 4.53~6.52 (d, 1H), 6.88~6.91 (d, 1H).
Claims (10)
1. a kind of racemization method of R types-I, comprises the following steps：
1), in organic solvent, in the presence of radical initiator and catalyst, the oxidized dehydrogenation reactions of R types-I are converted into
Compound ii；
2), in organic solvent, compound II is reacted by hydro-reduction obtain raceme-I in the presence of a hydrogenation catalyst.
2. racemization method as claimed in claim 1, it is characterised in that：In step 1) in, the oxidative dehydrogenation institute
Organic solvent is conventional acid, such as：Acetic acid, hydrochloric acid etc., or acid and other common solvents such as acetonitrile, methyl alcohol, second
The arbitrary proportion mixed system that one or more of alcohol, pyridine etc..
3. racemization method as claimed in claim 2, it is characterised in that：In step 1) in, the oxidative dehydrogenation institute
Organic solvent is acetic acid.
4. racemization method as claimed in claim 1, it is characterised in that：In step 1) in, described initiator is peroxide
Change the tert-butyl alcohol or peroxidized t-butyl perbenzoate.
5. racemization method as claimed in claim 1, it is characterised in that：In step 1) in, described initiator and R types
The mol ratio of-I is preferably (1~3):1.
6. racemization method as claimed in claim 1, it is characterised in that：In step 1) in, described catalyst be selected from
The mantoquita of copper nitrate, copper sulphate, copper acetate and copper chloride.
7. racemization method as claimed in claim 5, it is characterised in that：In step 1) in, described mantoquita and R types-I
Mol ratio be (0.05~0.3):1.
8. racemization method as claimed in claim 1, it is characterised in that：In step 2) in, described hydro-reduction reaction
The hydrogenation catalyst for being used is palladium carbon, and preferred content is 5% and 10% palladium carbon.
9. racemization method as claimed in claim 1, it is characterised in that：It is organic molten that described hydro-reduction reaction is used
Agent is methyl alcohol, ethanol, one or more of tetrahydrofuran.
10. racemization method as claimed in claim 1, it is characterised in that：The temperature of described hydro-reduction reaction is room temperature,
Pressure is normal pressure.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021210920A1 (en) * | 2020-04-16 | 2021-10-21 | 제이투에이치바이오텍 주식회사 | Method for producing ramelteon, and intermediate compound used for same |
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| GB2357082A (en) * | 1999-11-10 | 2001-06-13 | Glaxo Group Ltd | Pharmaceutically active indanylidene-acetamide derivatives |
| 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 |
| CN103570651A (en) * | 2012-07-30 | 2014-02-12 | 北京万生药业有限责任公司 | Preparation method of Ramelteon intermediate |
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2015
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| GB2357082A (en) * | 1999-11-10 | 2001-06-13 | Glaxo Group Ltd | Pharmaceutically active indanylidene-acetamide derivatives |
| 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 |
| CN103570651A (en) * | 2012-07-30 | 2014-02-12 | 北京万生药业有限责任公司 | Preparation method of Ramelteon intermediate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021210920A1 (en) * | 2020-04-16 | 2021-10-21 | 제이투에이치바이오텍 주식회사 | Method for producing ramelteon, and intermediate compound used for same |
| KR20210128263A (en) * | 2020-04-16 | 2021-10-26 | 제이투에이치바이오텍 (주) | A method for manufacturing ramelteon and intermediate compounds used therein |
| KR102359229B1 (en) | 2020-04-16 | 2022-02-07 | 제이투에이치바이오텍 (주) | A method for manufacturing ramelteon and intermediate compounds used therein |
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| CN106749131B (en) | 2019-03-08 |
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