CN103880794A - Preparation method for key intermediate of ramelteon - Google Patents
Preparation method for key intermediate of ramelteon Download PDFInfo
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- CN103880794A CN103880794A CN201210560375.4A CN201210560375A CN103880794A CN 103880794 A CN103880794 A CN 103880794A CN 201210560375 A CN201210560375 A CN 201210560375A CN 103880794 A CN103880794 A CN 103880794A
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- 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 a preparation method for a key intermediate of ramelteon (a compound represented by formula (I)). The preparation method includes the steps as follows: dissolving a compound represented by formula 1, a compound represented by formula 2, a metal catalyst, an alkali, norbornene and a ligand in an organic solvent for carrying out a reaction to obtain the compound represented by formula (I). The synthetic route of the invention is a convergent synthesis which is different from a linear synthesis in a conventional synthetic route. The synthetic route of the invention is short in linearity and is high in yield. The reaction equation of the invention is represented by a formula as follows.
Description
Technical field
The present invention relates to a kind of preparation method of compound, relate in particular to a kind of ramelteon key intermediate 2-(6,7-dihydro-1H-indeno [5,4-b] furans-8 (2H)-subunit) new preparation process of ethyl acetate (formula I compound).
Background technology
Ramelteon (Ramelteon), chemistry (S)-N-[2-(1,2,6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-yl) by name] propionic acid amide, researched and developed by Japanese Takeda company, obtain U.S. FDA approval listing in September, 2005.Thunder, for being a kind of melatonin receptors agonist for amine, can be simulated the physiological action of the melatonin of being secreted by pineal gland, contributes to regulate sleep cycle, improves sleep quality.Its mechanism of action is: this product is melatonin receptor agonist, with melatonin MT
1and MT
2acceptor has higher avidity, to MT
1and MT
2acceptor is the complete agonism of specificity, and not with MT
3receptor acting.In addition, it is not combined with neurotransmitter receptors such as GABA receptor complexes, does not also disturb within the specific limits the activity of most enzymes, therefore, can avoid the dispersion attention relevant to GABA medicine and habituation and the dependency [JMed.Chem.2002,45,4222-4239] of medicine.FDA is not included into this product the row of controlled substance, and this belongs to first case in hypnotic drug, is enough to show the safe of this product, without habituation.The chemical structure of ramelteon (Ramelteon) is as follows:
Synthesize and had many synthetic routes for ramelteon.Main reference is as follows:
WO 2008062468; EP 0885210; JP 1998287665; JP 1999152281; WO 2006030739; WO9732871; J Med Chem 2002,45 (19), 4222; Drugs Fut 2003,28 (10), 950; WO 2008151170; US2009069581; EP 2069320; WO 2009106966; Chinese Journal of Pharmaceuticals 2009,40, (3), 162-164; Heterocycles, 85, (1), 2012.
In above-mentioned synthetic method, synthetic route is all linear synthetic, and synthetic route is long, and efficiency is low.
Following structural formula (I) compound is a key intermediate preparing ramelteon, its chemistry 2-(6,7-dihydro-1H-indeno [5,4-b] furans-8 (2H)-subunit) ethyl acetate by name.In current document, still cannot conveniently obtain structural formula (I) compound.
Therefore this area need to develop new efficiently, convergence type synthetic method, reduces synthesizing linear length, improves synthesizing linear total recovery, improves combined coefficient.
Summary of the invention:
The technical problem to be solved in the present invention is to provide a kind of key intermediate 2-(6 for the preparation of ramelteon, 7-dihydro-1H-indeno [5,4-b] furans-8 (2H)-subunit) new preparation process of ethyl acetate (structural formula (I) compound), the synthetic route of the inventive method is convergence type synthetic (linearity that is different from traditional method is synthetic), synthesizing linear is short, and yield is high.
For solving the problems of the technologies described above, the invention provides a kind of preparation method of ramelteon key intermediate, described ramelteon key intermediate 2-(6,7-dihydro-1H-indeno [5,4-b] furans-8 (2H)-subunit) ethyl acetate is structural formula (I) compound, structural formula (I) compound is a pair of cis-trans-isomer, and structural formula (I) compound can be single compound or its mixture:
Structural formula of the present invention (I) compound 2-(6,7-dihydro-1H-indeno [5,4-b] furans-8 (2H)-subunit) ethyl acetate can prepare by following method, its chemical equation following (scheme 1):
Scheme 1: the synthetic route of formula (I) compound
Formula 1 compound passes through document Tetrahedron 2007,63:10528-10533, and the method (its chemical equation is as Scheme 2) in Chem.Commun.1999:1337 – 1338 is synthesized, synthetic route following (scheme 2):
Scheme 2: the synthetic route of formula 1 compound
Formula 2 compounds pass through document Org.Lett.2006, and 8 (16): the method (its chemical equation is as Scheme3) in 3601-3604 is synthesized, synthetic route following (scheme 3):
Scheme 3: the synthetic route of formula 2 compounds
The synthetic method that has provided formula (I) compound in Scheme 1, concrete step is:
At suitable temperature, formula 1 compound, formula 2 compounds, metal catalyst, alkali, norbornylene and part, add organic solvent dissolution, and reaction obtains formula (I) compound.
Above-mentioned organic solvent is selected non-protonic solvent, preferably DME(glycol dimethyl ether), DMF(N, dinethylformamide), acetonitrile and toluene.Catalyzer is palladium, Palladous chloride, preferably palladium; The molar ratio of metal catalyst and formula 2 compounds is 0.01-0.1, is preferably 0.03-0.1 equivalent; The molar ratio of norbornylene and formula 2 compounds is 0.01-10.0, is preferably 0.05-5 equivalent; Part is triphenylphosphine, three (furans-2-yl) phosphine, tri-butyl phosphine a tetrafluoro borate or tricyclohexyl phosphine a tetrafluoro borate, is preferably triphenylphosphine; The molar ratio of part and formula 2 compounds is 0.01-10.0, is preferably 0.01-5 equivalent; Alkali organic bases and mineral alkali, preferably salt of wormwood, cesium carbonate, sodium carbonate; Alkali and formula 2 compound molar ratio 1.0-10.0, be preferably 3-6 equivalent.Formula 2 compounds and formula 1 compound molar ratio 1.0-10.0, be preferably 1-5 equivalent; Temperature of reaction is 40 DEG C-160 DEG C, is preferably 90-110 DEG C; Reaction times is 5-48 hour, is preferably 5-15 hour.
Formula (I) compound carries out chemical conversion by the method in PCT patent application WO/2008/106179, WO/2010/045565 (its chemical equation is as Scheme 4), can complete the synthetic of ramelteon.
Scheme 4: the synthetic route of ramelteon (Ramelteon)
The invention has the advantages that starting raw material is cheap and easy to get, sharpest edges are that the synthetic route of the inventive method is convergence type synthetic (linearity that is different from traditional method is synthetic), and synthesizing linear is short, and yield is high.Whole synthetic route novelty simultaneously, for the preparation of ramelteon provides a good new way.
Embodiment:
By following embodiment, the present invention will be further elaborated, and content of the present invention is not limited to embodiment.One of skill in the art is appreciated that and is not deviating under the prerequisite of the spirit and scope of the present invention, can carry out various modifications and variation to the present invention.
Synthesizing of embodiment 1.2-(6,7-dihydro-1H-indeno [5,4-b] furans-8 (2H)-subunit) ethyl acetate (I)
The chemical equation of embodiment 1 is as follows:
In dry tube sealing, add formula 1 compound (76g, 367mmol), formula 2 compound (24g, 73.4mmol), triphenylphosphine (3.85g, 14.7mmol), cesium carbonate (143.5g, 440mmol), norbornylene (34.6g, 367mmol), palladium (1.65g, 7.34mmol) after, after adding the dry DME of 240mL to dissolve, 100 DEG C of tube sealings 48 hours, react completely, filter, concentrated, EA(ethyl acetate) dissolve after, wash 2 times, saturated aqueous common salt, anhydrous sodium sulfate drying, concentrated, first PE column chromatography, do not separate pure, sherwood oil: ethyl acetate (PE:EA, volume ratio)=30:1 column chromatography, obtain a pair of cis-trans-isomer: 3.55g (faint yellow solid) and 11g (yellow oil), productive rate is respectively 20% and 61%.
Formula (I) compound isomers one:
1h NMR (400MHz, CDCl
3) δ 7.09 (d, J=8.0Hz, 1H), 6.81 (d, J=8.0Hz, 1H), 6.09 (t, 1H), 4.63 (t, 2H), 4.20 (q, 2H), 3.40 (t, 2H), 3.32-3.28 (m, 2H), 3.00 (t, 2H), 1.31 (t, 3H).
Formula (I) compound isomers two:
1h NMR (300MHz, CDCl
3) δ 7.18 (d, J=7.9Hz, 1H), 6.67 (d, J=7.9Hz, 1H), 6.46 (s, 1H), 4.59 (t, J=8.6Hz, 2H), 4.18 (q, 2H), 3.61 (d, J=1.3Hz, 2H), 3.38 (t, J=8.7Hz, 2H), 3.34 (s, 2H), 1.28 (t, 3H).
Synthesizing of embodiment 2.2-(6,7-dihydro-1H-indeno [5,4-b] furans-8 (2H)-subunit) ethyl acetate (I)
The chemical equation of embodiment 2 is as follows:
In dry tube sealing, add formula 1 compound (1.52g, 7.34mmol), formula 2 compound (2.4g, 7.34mmol), triphenylphosphine (385mg, 1.47mmol), cesium carbonate (14.35g, 44mmol), norbornylene (3.46g, 36.7mmol), palladium (165mg, 0.74mmol), after adding the dry DME of 15mL to dissolve, 100 DEG C of tube sealings 48 hours, react completely, filter, concentrated, after EA dissolves, wash 2 times, saturated aqueous common salt, anhydrous sodium sulfate drying, concentrated, first PE column chromatography, do not separate pure, PE:EA=30:1 column chromatography, obtain a pair of cis-trans-isomer: 181mg (faint yellow solid) and 540mg (yellow oil), productive rate is respectively 10% and 31%.
Synthesizing of embodiment 3.2-(6,7-dihydro-1H-indeno [5,4-b] furans-8 (2H)-subunit) ethyl acetate (I)
The chemical equation of embodiment 3 is as follows:
In dry tube sealing, add formula 1 compound (4.56g, 22mmol), formula 2 compound (2.4g, 7.34mmol), triphenylphosphine (385mg, 1.47mmol), cesium carbonate (14.35g, 44mmol), norbornylene (3.46g, 36.7mmol), palladium (165mg, 0.74mmol), after adding the dry DME of 240mL to dissolve, 100 DEG C of tube sealings 48 hours, react completely, filter, concentrated, after EA dissolves, wash 2 times, saturated aqueous common salt, anhydrous sodium sulfate drying, concentrated, first PE column chromatography, do not separate pure, PE:EA=30:1 column chromatography, obtain a pair of cis-trans-isomer: 287mg (faint yellow solid) and 880mg (yellow oil), productive rate is respectively 16% and 49%.
Synthesizing of embodiment 4.2-(6,7-dihydro-1H-indeno [5,4-b] furans-8 (2H)-subunit) ethyl acetate (I)
The chemical equation of embodiment 4 is as follows:
In dry tube sealing, add formula 1 compound (3.8g, 18.4mmol), formula 2 compound (1.2g, 3.67mmol), triphenylphosphine (193mg, 734 μ mol), salt of wormwood (3.04g, 22mmol), norbornylene (1.73g, 18.4mmol), palladium (83mg, 367 μ mol) after, after adding the dry DME of 20mL to dissolve, 100 DEG C of tube sealings 48 hours, react completely, filter, concentrated, after EA dissolves, wash 2 times, saturated aqueous common salt, anhydrous sodium sulfate drying, concentrated, first PE column chromatography, do not separate pure, PE:EA=30:1 column chromatography, obtain a pair of cis-trans-isomer: 152mg (faint yellow solid) and 460mg (yellow oil), productive rate is respectively 17% and 54%.
Synthesizing of embodiment 5.2-(6,7-dihydro-1H-indeno [5,4-b] furans-8 (2H)-subunit) ethyl acetate (I)
The chemical equation of embodiment 5 is as follows:
In dry tube sealing, add formula 1 compound (3.8g, 18.4mmol), formula 2 compound (1.2g, 3.67mmol), triphenylphosphine (193mg, 734 μ mol), salt of wormwood (3.04g, 22mmol), norbornylene (1.73g, 18.4mmol), palladium (8.3mg, 37 μ mol) after, after adding the dry DME of 20mL to dissolve, 100 DEG C of tube sealings 48 hours, react completely, filter, concentrated, after EA dissolves, wash 2 times, saturated aqueous common salt, anhydrous sodium sulfate drying, concentrated, first PE column chromatography, do not separate pure, PE:EA=30:1 column chromatography, obtain a pair of cis-trans-isomer: 148mg (faint yellow solid) and 458mg (yellow oil), productive rate is respectively 16% and 51%.
Synthesizing of embodiment 6.2-(6,7-dihydro-1H-indeno [5,4-b] furans-8 (2H)-subunit) ethyl acetate (I)
The chemical equation of embodiment 6 is as follows:
In dry tube sealing, add formula 1 compound (3.8g, 18.4mmol), formula 2 compound (1.37g, 3.67mmol), triphenylphosphine (193mg, 734 μ mol), cesium carbonate (7.17g, 22mmol), norbornylene (1.73g, 18.4mmol), palladium (8.3mg, 37 μ mol) after, after adding the dry DME of 20mL to dissolve, 100 DEG C of tube sealings 48 hours, react completely, filter, concentrated, after EA dissolves, wash 2 times, saturated aqueous common salt, anhydrous sodium sulfate drying, concentrated, first PE column chromatography, do not separate pure, PE:EA=30:1 column chromatography, obtain a pair of cis-trans-isomer: 135mg (faint yellow solid) and 431mg (yellow oil), productive rate is respectively 15% and 48%.
Synthesizing of embodiment 7.2-(6,7-dihydro-1H-indeno [5,4-b] furans-8 (2H)-subunit) ethyl acetate (I)
The chemical equation of embodiment 7 is as follows:
In dry tube sealing, add formula 1 compound (3.8g, 18.4mmol), formula 2 compound (1.37g, 3.67mmol), triphenylphosphine (193mg, 734 μ mol), cesium carbonate (7.17g, 22mmol), norbornylene (1.73g, 18.4mmol), palladium (8.3mg, 37 μ mol) after, after adding the dry acetonitrile of 20mL to dissolve, 100 DEG C of tube sealings 48 hours, react completely, filter, concentrated, after EA dissolves, wash 2 times, saturated aqueous common salt, anhydrous sodium sulfate drying, concentrated, first PE column chromatography, do not separate pure, PE:EA=30:1 column chromatography, obtain a pair of cis-trans-isomer: 117mg (faint yellow solid) and 395mg (yellow oil), productive rate is respectively 13% and 44%.
Synthesizing of embodiment 8.2-(6,7-dihydro-1H-indeno [5,4-b] furans-8 (2H)-subunit) ethyl acetate (I)
The chemical equation of embodiment 8 is as follows:
In dry tube sealing, add formula 1 compound (3.8g, 18.4mmol), formula 2 compound (1.37g, 3.67mmol), tri-butyl phosphine a tetrafluoro borate (149mg, 734 μ mol), cesium carbonate (7.17g, 22mmol), norbornylene (1.73g, 18.4mmol), Palladous chloride (8.3mg, 37 μ mol) after, after adding the dry DMF of 20mL to dissolve, 100 DEG C of tube sealings 48 hours, react completely, filter, concentrated, after EA dissolves, wash 2 times, saturated aqueous common salt, anhydrous sodium sulfate drying, concentrated, first PE column chromatography, do not separate pure, PE:EA=30:1 column chromatography, obtain a pair of cis-trans-isomer: 135mg (faint yellow solid) and 431mg (yellow oil), productive rate is respectively 15% and 48%.
Claims (2)
1. a preparation method for ramelteon key intermediate, described ramelteon key intermediate is structural formula (I) compound, and structural formula (I) compound is a pair of cis-trans-isomer, and structural formula (I) compound is single compound or its mixture,
It is characterized in that, the method comprises the steps:
At suitable temperature, formula 1 compound, formula 2 compounds, metal catalyst, alkali, norbornylene and part, add organic solvent dissolution, and reaction obtains formula (I) compound; Described organic solvent is selected non-protonic solvent; Described metal catalyst is palladium or Palladous chloride; The molar ratio of described metal catalyst and formula 2 compounds is 0.01-0.1; The molar ratio of norbornylene and formula 2 compounds is 0.01-10.0; Part is triphenylphosphine, three (furans-2-yl) phosphine, tri-butyl phosphine a tetrafluoro borate or tricyclohexyl phosphine a tetrafluoro borate; The molar ratio of part and formula 2 compounds is 0.01-10.0; Described alkali is organic bases or mineral alkali; Described alkali and formula 2 compound molar ratio 1.0-10.0; The molar ratio 1.0-10.0 of formula 2 compounds and formula 1 compound; Temperature of reaction is 40 DEG C-160 DEG C; Reaction times is 5-48 hour;
Its reaction formula is as follows:
2. the method for claim 1, is characterized in that, described organic solvent is glycol dimethyl ether, DMF, acetonitrile or toluene; Described metal catalyst is palladium; The molar ratio of metal catalyst and compound 2 is 0.03-0.1 equivalent; The molar ratio of norbornylene and formula 2 compounds is 0.05-5 equivalent; Described part is triphenylphosphine; The molar ratio of part and formula 2 compounds is 0.01-5 equivalent; Described alkali is salt of wormwood, cesium carbonate or sodium carbonate; The molar ratio of alkali and structural formula 2 compounds is 3-6 equivalent; The molar ratio of formula 2 compounds and formula 1 compound is 1-5 equivalent; Temperature of reaction is 90-110 DEG C; Reaction times is 5-15 hour.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104402848A (en) * | 2014-09-22 | 2015-03-11 | 珠海联邦制药股份有限公司 | Preparation method of impurity compound in ramelteon and prepared standard substance |
| CN110483456A (en) * | 2019-08-16 | 2019-11-22 | 武汉大学 | The synthetic method of ramelteon |
Citations (4)
| 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 |
| WO2009056993A2 (en) * | 2007-11-01 | 2009-05-07 | Teva Pharmaceutical Industries Ltd. | A 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 |
-
2012
- 2012-12-21 CN CN201210560375.4A patent/CN103880794B/en active Active
Patent Citations (4)
| 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 |
| WO2009056993A2 (en) * | 2007-11-01 | 2009-05-07 | Teva Pharmaceutical Industries Ltd. | A 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 |
Non-Patent Citations (1)
| Title |
|---|
| XIAODAN FU ET AL.: "Synthesis of the melatonin receptor agonist Ramelteon using a tandem C–H activation–alkylation/Heck reaction and subsequent asymmetric Michael addition", 《TETRAHEDRON: ASYMMETRY》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104402848A (en) * | 2014-09-22 | 2015-03-11 | 珠海联邦制药股份有限公司 | Preparation method of impurity compound in ramelteon and prepared standard substance |
| CN104402848B (en) * | 2014-09-22 | 2017-02-08 | 珠海联邦制药股份有限公司 | Preparation method of impurity compound in ramelteon and prepared standard substance |
| CN110483456A (en) * | 2019-08-16 | 2019-11-22 | 武汉大学 | The synthetic method of ramelteon |
| CN110483456B (en) * | 2019-08-16 | 2021-03-16 | 武汉大学 | Method for synthesizing ramelteon |
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Effective date of registration: 20210812 Address after: No. 1, Hengfei Road, Xingang economic and Technological Development Zone, Nanjing, Jiangsu 210038 Patentee after: Nanjing Changao Pharmaceutical Science & Technology Co.,Ltd. Address before: 201203 4th floor, building 7, Lane 1690, Cailun Road, Zhangjiang High Tech Park, Pudong New Area, Shanghai Patentee before: Shanghai Sun-Sail Pharmaceutical Science & Technology Co.,Ltd. |