CN102432571A - Novel method for preparing ramelteon key intermediate - Google Patents
Novel method for preparing ramelteon key intermediate Download PDFInfo
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- CN102432571A CN102432571A CN2011103578310A CN201110357831A CN102432571A CN 102432571 A CN102432571 A CN 102432571A CN 2011103578310 A CN2011103578310 A CN 2011103578310A CN 201110357831 A CN201110357831 A CN 201110357831A CN 102432571 A CN102432571 A CN 102432571A
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- ramelteon
- tetrahydrochysene
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Abstract
The invention discloses a novel method for preparing a ramelteon key intermediate 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride (I). The method is characterized by comprising the following steps of: performing dehydration condensation and heated decarboxylation on 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (II) and cyanoacetic acid (III) under the action of a catalyst to obtain a compound (IV); and directly hydrogenating and salifying the compound (IV) without separating and purifying to obtain the ramelteon key intermediate 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride (I). The invention provides the novel method for preparing the ramelteon key intermediate hydrochloride (I). In the method, the cheap and readily available cyanoacetic acid (II) is used; and the method is high in yield and low in cost, is easy and convenient to operate, is environment-friendly and is suitable for industrialized production.
Description
Technical field
The invention belongs to the chemical pharmaceutical technical field, relate to the new preparation method of a kind of ramelteon key intermediate hydrochloride.
Technical background
Ramelteon (ramelteon), chemical name (S)-N-[2-(1,2,6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-yl)] propionic acid amide, structural formula is following, by the research and development of Japanese Takeda company, obtains the drugs approved by FDA listing in September, 2005.It is a kind of novel melatonin receptors agonist; Exciting melatonon 1 receptor of ability selectivity and 2 receptors (MT1, MT2); Increase slow wave sleep (SWS) and REM sleep (REW); Helping to regulate sleep cycle, improve sleep quality, is first not as the non-habituation aypnia disease medicine of special control.
Ramelteon
2-(1,2,6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-yl) ethylamine hydrochloride is the key intermediate of synthetic ramelteon, and its structural formula is following:
Chiral separation again after compound (I) is free, last amidation promptly gets highly purified ramelteon.
In the prior art, 2-(1,2,6; 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-yl) synthetic route of ethamine mainly is 1,2,6; 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone (II) and the condensation of cyanogen methyl-phosphorous acid diethyl ester obtain compound (IV), and then hydro-reduction (EP 0885210); Or compound (II) and the phosphonium salt condensation of cyanogen methylene tri phenyl season, obtain (IV) (CN101654445); Or compound (II) and phosphine acyl acetic acid three ethyl reaction, become acid amides to restore (WO2010045565) then.Above method is all used poisonous or irritating phosphonate reagent, and yield is not high.
Summary of the invention
The object of the invention is exactly the defective to existing prior art, and a kind of ramelteon key intermediate 2-(1,2,6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-yl) is provided the new preparation method of ethylamine hydrochloride (I), and synthetic route of the present invention is following:
The present invention is by 1,2,6, the cyanoacetic acid (III) that 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone (II) and cheap safety are easy to get under catalyst action dehydrating condensation, receive thermal decarboxylation, compound (IV); Compound (IV) obtains ramelteon key intermediate 2-(1,2,6 without separation and purification direct hydrogenation, salify; 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-yl) ethylamine hydrochloride (I), this route reaction step is short; Yield is high, and reaction conditions is gentle, and aftertreatment is simple; Cost is low, is fit to suitability for industrialized production.
Synthesis step of the present invention:
(1) by compound (II) and compound (III) under catalyst action dehydrating condensation, receive thermal decarboxylation to get compound (IV).
Compound (II) is 1: 0.8～3.5 with the reaction mol ratio of compound (III) dehydrating condensation, preferred 1: 1.5～2.5.
The catalyzer of compound (II) and compound (III) dehydrating condensation is organic acid such as acetate, methylsulfonic acid, benzene methanesulfonic acid, nicotinic acid, Yi Yansuan, proline(Pro); Or organic bases such as n n dimetylaniline, diethylamine, triethylamine, pyridine, piperidines, piperazine, N methyl piperazine; Or salt such as ammonium acetate, Secondary ammonium phosphate, potassiumphosphate, Potassium monofluoride.
Compound (II) was 1: 0.05%～2% with the mol ratio of catalyzer during compound (II) reacted with compound (III), preferred 1: 0.5～1.5%.
Selected solvent is alcohols such as methyl alcohol, ethanol, Virahol, or benzene class such as benzene,toluene,xylene, ethylbenzene, methyl-phenoxide, or other solvents soluble in water such as acetonitrile, acetone, THF, DMF, acetate.Preferentially select for use boiling point to be higher than water or equal the reaction solvent of water, more preferably select for use and water forms the azeotropic reaction solvent, like toluene, YLENE, methyl-phenoxide.
Compound (II) and compound (III) dehydrating condensation carry out under the condition of solvent refluxing, preferentially select for use under the condition of refluxing toluene and carry out.
Compound (II) filters after reacting with compound (III), and the concentrating under reduced pressure solvent adds entry, and ethyl acetate extraction concentrates behind the alkali liquid washing and obtains compound (IV).
(2) compound (IV) hydrogenation, salify obtain ramelteon key intermediate 2-(1,2,6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-yl) ethylamine hydrochloride (I).
Compound (IV) reduces with hydrogen in the presence of Raney nickel in ammoniated alcoholic medium earlier, adds palladium carbon catalytic hydrogenation then, converts it into salt at last.
Compound (IV) hydrogenation is carried out at 20～80 ℃, preferentially under 40 ℃, carries out.
The used hydrogenation catalyst of compound (IV) is Raney nickel and palladium carbon, preferentially selects Raney nickel for use, 5% or 10% palladium carbon.
Add hydrochloric acid after compound (IV) hydrogenation and separate out solid, or feeding hydrogen chloride gas separates out solid.Preferentially select for use logical hydrogen chloride gas to separate out solid, promptly get ramelteon key intermediate 2-(1,2,6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-yl) ethylamine hydrochloride (I).
Embodiment
Following instance further specifies the present invention, but the present invention is not limited.
Embodiment: 2-(1,2,6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-yl) ethylamine hydrochloride (I)
Step (1):
1,2,6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone (II) (34.8g, 0.200mol), cyanoacetic acid (III) (25.5g, 0.300mol) and piperidines (0.084g 0.986mmol) adds in the toluene (160ml), stirs reflux.After compound (II) reacts completely, filter, the concentrating under reduced pressure solvent adds entry (140ml), ETHYLE ACETATE (50ml * 3) extraction, saturated sodium-chloride water solution is washed till neutrality, and the concentrating under reduced pressure solvent obtains solid chemical compound (IV) (36.4g, 92.4%).
Fusing point: 144-147 ℃
Step (2):
(34.5g, 0.175mol), Raney nickel (6.9g) and the saturated ethanolic soln (800ml) of ammonia add in the 2L autoclave, logical hydrogen is to 40kg/m for compound (IV)
2, be heated to 40 ℃, stir 5h.Filter, filtrating adds 10% palladium carbon (3.6g), and logical hydrogen is to 40kg/m
2, be heated to 40 ℃ of stirring reaction 4h.Filter, remove filtrating under reduced pressure, get faint yellow oily thing, add ETHYLE ACETATE (80ml) dissolving.In solution, lead to hydrogen chloride gas, separate out deposition.Filter, deposition is with the ETHYLE ACETATE washing, and drying gets off-white color solid 2-(1,2,6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-yl) ethylamine hydrochloride (I) (32.3g, 77.0%).
Fusing point: 267-268 ℃.
Claims (10)
1. ramelteon key intermediate 2-(1,2,6; 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-yl) preparation method of ethylamine hydrochloride (I) is characterized in that 1; 2; 6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone (II) and cyanoacetic acid (III) under catalyst action dehydrating condensation, receive thermal decarboxylation to get compound (IV); Compound (IV) obtains ramelteon key intermediate 2-(1,2,6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-yl) ethylamine hydrochloride (I) without separation and purification direct hydrogenation, salify, and its reaction formula is following:
2. the preparation method of ramelteon key intermediate 2-according to claim 1 (1,2,6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-yl) ethylamine hydrochloride (I), wherein compound (II) is 1: 0.8～3.5 with the reaction mol ratio of compound (III).
3. ramelteon key intermediate 2-(1 according to claim 1; 2; 6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-yl) preparation method of ethylamine hydrochloride (I); Wherein compound (II) and compound (III) catalyst for reaction are organic acid such as acetate, methylsulfonic acid, benzene methanesulfonic acid, nicotinic acid, Yi Yansuan, proline(Pro); Or organic bases such as n n dimetylaniline, diethylamine, triethylamine, pyridine, piperidines, piperazine, N methyl piperazine, or salt such as ammonium acetate, Secondary ammonium phosphate, potassiumphosphate, Potassium monofluoride.
4. ramelteon key intermediate 2-(1,2,6 according to claim 1; 7-tetrahydrochysene-8H-indeno [5; 4-b] furans-8-yl) preparation method of ethylamine hydrochloride (I), wherein compound (II) reacts in solvent with compound (III), and selected solvent is alcohols such as methyl alcohol, ethanol, Virahol; Or benzene class such as benzene,toluene,xylene, methyl-phenoxide, or other solvents soluble in water such as acetonitrile, acetone, THF, DMF, acetate.
5. the preparation method of ramelteon key intermediate 2-according to claim 1 (1,2,6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-yl) ethylamine hydrochloride (I), wherein compound (II) is 20～150 ℃ with the temperature of reaction of compound (III).
6. according to claim 1 or 3 described ramelteon key intermediate 2-(1; 2; 6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-yl) preparation method of ethylamine hydrochloride (I); During wherein compound (II) reacted with compound (III), compound (II) was 1: 0.05%～2% with the mol ratio of catalyzer.
7. ramelteon key intermediate 2-(1,2,6 according to claim 1; 7-tetrahydrochysene-8H-indeno [5; 4-b] furans-8-yl) preparation method of ethylamine hydrochloride (I), wherein compound (IV) is converted in the reaction of compound (I), and compound (IV) reduces with hydrogen in the presence of Raney nickel in ammoniated alcoholic medium earlier; Add palladium carbon catalytic hydrogenation then, convert it into salt with hydrochloric acid or logical hydrogen chloride gas at last.
8. according to the preparation method of claim 1 or 7 described ramelteon key intermediate 2-(1,2,6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-yl) ethylamine hydrochloride (I), wherein compound (IV) hydrogenation is carried out at 20～80 ℃.
9. according to the preparation method of claim 1 or 7 described ramelteon key intermediate 2-(1,2,6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-yl) ethylamine hydrochloride (I), wherein compound (IV) hydrogenation catalyst is a Raney nickel, 5% or 10% palladium carbon.
10. according to claim 1 or 7 described ramelteon key intermediate 2-(1; 2; 6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-yl) preparation method of ethylamine hydrochloride (I); Wherein convert it into salt with hydrochloric acid or logical hydrogen chloride gas after compound (IV) hydrogenation, preferably feed the hydrogen chloride gas salify.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102924410A (en) * | 2012-10-29 | 2013-02-13 | 华润赛科药业有限责任公司 | Preparation method and intermediate of ramelteon |
| CN103304524A (en) * | 2013-07-08 | 2013-09-18 | 中国药科大学 | Preparation method of ramelteon intermediate |
| CN103664849A (en) * | 2012-08-31 | 2014-03-26 | 上海阳帆医药科技有限公司 | Method for preparing 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-idenethamine |
| CN106632177A (en) * | 2016-12-05 | 2017-05-10 | 万特制药(海南)有限公司 | Preparation method of ramelteon intermediate |
-
2011
- 2011-11-14 CN CN2011103578310A patent/CN102432571A/en active Pending
Non-Patent Citations (2)
| Title |
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| NATALIA A.LOZINSKAYA ET AL.: "Simple Synthesis of Some 2-Substituted Melatonin Derivatives", 《SYNTHESIS》 * |
| 蒋龙等: "雷美替胺的合成", 《中国医药工业杂志》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664849A (en) * | 2012-08-31 | 2014-03-26 | 上海阳帆医药科技有限公司 | Method for preparing 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-idenethamine |
| CN103664849B (en) * | 2012-08-31 | 2017-03-29 | 上海阳帆医药科技有限公司 | Prepare the 2 (methods of 1,6,7,8 tetrahydrochysene 2H indenos [5,4 b] furan, 8 subunit ethamine |
| CN102924410A (en) * | 2012-10-29 | 2013-02-13 | 华润赛科药业有限责任公司 | Preparation method and intermediate of ramelteon |
| CN103304524A (en) * | 2013-07-08 | 2013-09-18 | 中国药科大学 | Preparation method of ramelteon intermediate |
| CN106632177A (en) * | 2016-12-05 | 2017-05-10 | 万特制药(海南)有限公司 | Preparation method of ramelteon intermediate |
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Application publication date: 20120502 |