OA16423A - Agomelatine intermediates and preparation method thereof. - Google Patents
Agomelatine intermediates and preparation method thereof. Download PDFInfo
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- OA16423A OA16423A OA1201200512 OA16423A OA 16423 A OA16423 A OA 16423A OA 1201200512 OA1201200512 OA 1201200512 OA 16423 A OA16423 A OA 16423A
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- Prior art keywords
- compound
- agomelatine
- préparation
- reaction
- nhcoch3
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- YJYPHIXNFHFHND-UHFFFAOYSA-N Agomelatine Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 YJYPHIXNFHFHND-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 229960002629 agomelatine Drugs 0.000 title claims abstract description 36
- 239000000543 intermediate Substances 0.000 title abstract description 18
- 238000002360 preparation method Methods 0.000 title abstract 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 97
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- 239000003795 chemical substances by application Substances 0.000 claims description 23
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 21
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 11
- 229960000583 Acetic Acid Drugs 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 8
- 238000005899 aromatization reaction Methods 0.000 claims description 7
- 239000012362 glacial acetic acid Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 230000002378 acidificating Effects 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 4
- 230000003197 catalytic Effects 0.000 claims description 4
- 230000002829 reduced Effects 0.000 claims description 4
- RQBBFKINEJYDOB-UHFFFAOYSA-N acetic acid;acetonitrile Chemical compound CC#N.CC(O)=O RQBBFKINEJYDOB-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 10
- GABLTKRIYDNDIN-UHFFFAOYSA-N 7-methoxy-3,4-dihydro-2H-naphthalen-1-one Chemical compound C1CCC(=O)C2=CC(OC)=CC=C21 GABLTKRIYDNDIN-UHFFFAOYSA-N 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 4
- 238000004440 column chromatography Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 230000002194 synthesizing Effects 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 238000007796 conventional method Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- -1 allyl méthacrylate Chemical compound 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- RZWGTXHSYZGXKF-UHFFFAOYSA-N 2-(2-methylphenyl)acetic acid Chemical compound CC1=CC=CC=C1CC(O)=O RZWGTXHSYZGXKF-UHFFFAOYSA-N 0.000 description 2
- YAQLSKVCTLCIIE-UHFFFAOYSA-M 2-bromobutanoate Chemical compound CCC(Br)C([O-])=O YAQLSKVCTLCIIE-UHFFFAOYSA-M 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000006680 Reformatsky reaction Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- FWFUSMMVFVVERM-UHFFFAOYSA-N 2-(1,4-dioxan-2-yl)acetic acid Chemical compound OC(=O)CC1COCCO1 FWFUSMMVFVVERM-UHFFFAOYSA-N 0.000 description 1
- YXDUMIVUPSVYLB-UHFFFAOYSA-N 2-(7-methoxynaphthalen-1-yl)ethanamine Chemical compound C1=CC=C(CCN)C2=CC(OC)=CC=C21 YXDUMIVUPSVYLB-UHFFFAOYSA-N 0.000 description 1
- XNLICIUVMPYHGG-UHFFFAOYSA-N 2-Pentanone Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 1
- 102000006902 5-HT2C Serotonin Receptor Human genes 0.000 description 1
- 108010072553 5-HT2C Serotonin Receptor Proteins 0.000 description 1
- 206010060961 Appetite disease Diseases 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N Benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- 208000008787 Cardiovascular Disease Diseases 0.000 description 1
- 206010009191 Circadian rhythm sleep disease Diseases 0.000 description 1
- MLIREBYILWEBDM-UHFFFAOYSA-N Cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 1
- 208000005407 Digestive System Disease Diseases 0.000 description 1
- 206010013980 Dyssomnias Diseases 0.000 description 1
- 206010016256 Fatigue Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N Heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 206010022437 Insomnia Diseases 0.000 description 1
- 208000001456 Jet Lag Syndrome Diseases 0.000 description 1
- 229960003987 Melatonin Drugs 0.000 description 1
- VYQNQWIPOKLVHL-UHFFFAOYSA-N N-[2-(7-methoxy-3,4-dihydronaphthalen-1-yl)ethyl]acetamide Chemical compound C1CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 VYQNQWIPOKLVHL-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 206010039775 Seasonal affective disease Diseases 0.000 description 1
- JXYRIQRQKAUQIY-UHFFFAOYSA-N acetic acid;oxolane Chemical compound CC(O)=O.C1CCOC1 JXYRIQRQKAUQIY-UHFFFAOYSA-N 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 230000003042 antagnostic Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 150000001868 cobalt Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- VPXDDUIYFMKQBI-UHFFFAOYSA-N ethyl 2-(7-methoxynaphthalen-1-yl)acetate Chemical compound C1=C(OC)C=C2C(CC(=O)OCC)=CC=CC2=C1 VPXDDUIYFMKQBI-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000011031 large scale production Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 150000002815 nickel Chemical class 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Abstract
The present invention relates to the Intermediate compounds for preparation of agomelatine, as well as the preparation methods thereof. The intermediate of the present invention for preparation of agomelatine is compound A as shown in the following formula. Also provided are two novel intermediate compounds. When we use thse new intermediate compounds to prepare agomelatine, it is simple to manipulate, wellcontrolled and with high prity, without complicated operations such as rectification and column chromatography separation, and suitable for industrial production. Meanwhile, the preparation methods of the two new intermediates themselves is simple and high yield, only using the most commonly-used 7-methoxy-tetralone as original starting material and undergoing one step of reaction to obtain the intermediates, followed by one more step of converting the intermediate compounds to desired product agomelatine. Said reaction processes are greatly simplified, with the reaction yield being improved and the difficulty in purification of previous method being overcome, as compare with the previous technique for preparation of agomelatine. Typically, the yield of the present invention is over 70%.
Description
Field of the invention
The invention relates to intermediate compounds for préparation of agomelatine, as well as the préparation methods thereof.
Background of the invention
Agomelatine has a chemical structure as shown in Fomula (I), with the chemical name N-[2(7-methoxy-l-naphthyl)ethyl]acetamide and trade name Valdoxan. It has dual pharmacological effects, which is not only the agonist of melatonergic System receptors, but also the antagonist of 5HT2C receptor. Said properties confer activity in the centrai nervous System, especially in the treatment of major dépréssion, seasonal affective disorders, dyssomnia, cardiovascular diseases, digestive System diseases, insomnia and fatigue caused by jet lag, appetite disorders and obesity. It is the first melatonin type antidepressive agent, which can effectively treat dépressive disorders, improve the sleep parameters and maintain sexual function. It was approved by EU on Feb 24th, 2009, with the trade name Valdoxan®/Thymanax®.
Taking into account the compound’s pharmaceutical value, it is important to obtain the compound in an effective industrial synthetic method, which can be easily converted into iargescale production in the industry and obtain agomelatine in good yield and high purity.
Many synthetic methods for agomelatine hâve been reported, which can be roughly divided into four types, in which ail of the starting materials are the compound of formula (II). European patent spécification EP0447285 reported a method for préparation of agomelatine (I): reacting 7methoxy-tetralone (II) with ethyl bromoacetate by Reformatsky reaction, and then dehydroaromatization with sulfur to obtain (7-methoxy-l-naphthyl)acetic acid ethyl ester (IV), followed by hydrolysis, acyl chlorination, ammonification, déhydration and réduction to yield the
ORIGINAL compound (VIII), which is finally acetylated to obtain agomelatine (I), as shown below:
However, there are some defects in the above method, which comprise:
(1) it takes eight steps to synthesize 2-(7-methoxy-l-naphthyl)ethylamine, thereby rendering the average yield being less than 30%;
(2) when the above method is converted into industrial scale, it is difficult to carry out the reaction, mainly due to the poor reproducibility of the first step; the first step comprises reacting 7-methoxy-tetraIone (II) with ethyl bromoacetate by Reformatsky reaction to produce ethyl (7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)acetate, which requires benzene as the solvent; considering the envîronmental factors, said step does not meet the requirements of large-scale production; and (3) the next step for aromatization of ethyl (7-methoxy-3,4-dihydronaphthalen-l(2H)ylîdene)acetate is usually incomplète, and after saponification often results in a mixture, from which it is difficult to separate pure product (IV).
Chinese patent spécification CN1680284 reported another method for agomelatine synthesis: reaction of 7-methoxy-tetralone (II) with cyano-acetic acid produces intermediate compound (IX), the intermediate (IX) is dehydrogenated in the presence of hydrogénation
ORIGINAL S catalyst Pd-C, with allyl méthacrylate as the dehydrogenating agent, followed by réduction to generate compound (VIII), and fînally the compound (VIII) is converted to agomelatine (I) by acétylation. The total yield is about 72%, as shown below:
But there are some defects in the above method:
(l) some carcinogenic agents are used in the reaction route, for example, benzylamine/heptanoic acid catalyst System with great toxicity is used in the conversion of formula (II) to formula (IX);
(2) propyl méthacrylate is used as the dehydrogenating agent during the conversion of formula (IX) to (VII), which results in a lot of environmental pollution, moreover, this step of reaction actually was found to be low yield and difficult to reproduce; and (3) during the hydrogénation process of conversion of formula (VII) to (VIII), a by-product having formula (XII) generated; since the nature of the by-product is similar to the 15 desired product and this step is the penultimate step, it is difficult to purify the desired product and the yield loss after recrystallization is large.
JF
ORIGINAL
Considering the médicinal value and good market prospects of agomelatine, it is important to synthesize the compound of formula (I) in an effective manner for industrialization.
Disclosure of the invention
One objective of the présent invention is to provide two novel intermediate compounds for préparation of agomelatine. When we use these new compounds to préparé agomelatine, it is simple to manipulate and easy for working-up (without complicated operations such as rectification and column chromatography séparation), well-controlled, with high purity and yield, and suitable for industrial production.
Another objective of the présent invention is to provide préparation methods for the two intermediate compounds above and the use thereof.
For these purposes, the following technical solutions are used in the présent invention.
The compound of formula (A) is used:
ORIGINAL
The method for préparation of the compound of formula (A) is reductive acylation of the compound of formula (C) under the condition of catalytic hydrogénation, in the presence of acetîc anhydride.
Métal catalyst/Ac2O
NHCOMe
The catalyst used in the conversion of the compound of formula (C) to the compound of formula (A) is conventional métal catalyst, such as activated cobalt, activated nickel (Ni), preferably Raney-Ni; the amount of catalyst can be 0.1-0.3 times the amount of the compound C by weight; the amount of acetic anhydride is l-3 times the molar amount of the compound C, more preferably 1-1.3 times. The organic solvent used in this reaction is commonly-used organic 10 solvents, such as dioxane, THF, acetonitrile or acetic anhydride, preferably THF. The optimal reaction température is 10-50 °C, more preferably 20-30 °C. The reaction time dépends on the complété consumption of reactants detected, typically is 6-12 hours. After the reaction is completed, the working-up procedure can be performed according to conventional methods in the art.
The method for préparation of agomelatine using the compound A is provided in the présent
ORIGINAL invention, comprising déhydration and aromatization of the compound A to obtain the desired product of formula I:
Dehydrogenating agent
NHCOCH3
NHCOCH3
In the conversion of the compound A to the compound I by aromatization as shown above, the 5 dehydrogenating agent is preferably dichloro-dicyanobenzoquinone (DDQ), the amount of said dehydrogenating agent is preferably l-3 times the molar amount of the compound A, more preferably 1-1.3 times. The organic solvent used in this reaction is commonly-used organic solvents, eg. one of toluene, dioxane, THF, acetonitrile or glacial acetic acid, or any mixture thereof, preferably the mixture of toluene and glacial acetic acid, the mixture of acetonitrile and IO glacial acetic acid, or glacial acetic acid. The amount of said organic solvent is generally 10-50 ml/g of the compound A. The reaction température is preferably 30-150 °C, more preferably 50l00°C. The reaction time dépends on the complété consumption of reactants detected, typically is from 30 minutes to 12 hours. After the reaction is completed, the working-up procedure can be performed according to conventional methods in the art.
ORIGINAL
The compound of formula (B) is used:
NHCOCH3
The method for préparation of the compound of formula (B) is déhydration of the compound
A under acidic condition:
Acid
NHCOCH3
NHCOCH3
The acid used in the conversion of the compound A to the compound B is a conventional acid, such as hydrohalogen acid, sulfuric acid, acetic acid, and the like. The organic solvent used is commonly-used organic solvent, such as alcohols, dioxane, THF, or acetonitrile, preferably alcohol solvent, eg., ethyl acetate, acetone and the like. The amount of said organic solvent is ÎO generally 10-50 ml/g of the compound A. The reaction température is preferably -20-40 °C,more
ORIGINAL preferably 0-30 °C. The reaction time dépends on the complété consumption of reactants detected, typically is l-3 hours. After the reaction is completed, the working-up procedure can be performed according to conventional methods in the art.
The method for préparation of agomelatine using the compound B is provided in the présent invention, comprising reaction of the compound B with a dehydrogenating agent, to obtain the desired product of formula I:
Dehydrogenating agent
In the conversion of the compound B to the compound I, the dehydrogenating agent is preferably dichloro-dicyanobenzoquinone (DDQ), the amount of said dehydrogenating agent is 10 preferably l-3 times the molar amount of the compound B, more preferably 1-1.3 times. The organic solvent used in this reaction is commonly-used organic solvents, such as dichloromethane, dioxane, THF, acetonitrile, glacial acetic acid, or the like, preferably dichloromethane or toluene. The amount of said organic solvent is generally 10-50 ml/g of the compound B. The reaction température is preferably 0-50°C, more preferably 10-30°C. The reaction time dépends on the complété consumption of reactants detected, typically is from 30 & ORIGINAL minutes to 6 hours. After the reaction is completed, the working-up procedure can be performed according to conventional methods in the art.
The method for préparation of agomelatine comprises the following steps:
a. reductive acylation of the compound C under the condition of catalytic hydrogénation and in the presence of acetic anhydride to obtain compound A
Métal catalyst/Ac2O
NHCOMe
J
b. déhydration and aromatization of the compound A with a dehydrogenating agent, to obtain the desired product of formula I
ORIGINAL
Dehydrogenating agent
NHCOCH3
NHCOCH3
In the method for préparation of agomelatine in the présent invention, we can also use the following route, comprising firstly dehydrating compound A under acidic condition to produce compound B, then reacting compound B with a dehydrogenating agent to obtain the desired 5 product of formula I
ORIGINAL
Dehydrogenating agent
NHCOCH3
NHCOCH3
The intermediate compound of formula C can be made by the condensation of formula II and acetonitrile in the presence of catalyst
ORIGINAL
The catalyst used in the conversion of the compound of formula II to the compound of formula (C) is butyl lithium. Both the amount of catalyst and the amount of acetonitrile are l-3 times the molar amount of the compound II, more preferably 1-1.3 times. The organic solvent 5 used in this reaction is anhydrous organic solvent, such as dioxane, THF, and the like, which needs déhydration treatment or can be purchased directly from commercial suppliers. The amount of said organic solvent usually is 5-20 ml/g of the compound IL The optimal reaction température is from -80 to -50°C, more preferably from -70 to -60°C. The reaction time dépends on the complété consumption of reactants detected, typically is from 1 minute to 3 hours. After the 10 reaction is completed, the working-up procedure can be performed according to conventional methods in the art.
The compound C can also be prepared according to the methods disclosed in related literatures such as Journal of Médicinal Chemistry, 1976, 19(6), 803.
The reagents and starting materials used in the présent invention are commercially available, unless specified otherwise.
The advantages of the présent invention are:
the invention provides two novel intermediate compounds; when we use these new compounds to préparé agomeiatine, it is simple to manipulate and easy for working-up, without complicated operations such as rectification and column chromatography séparation, wellORIGINAL __ controlled, with high purity, and suitable for industrial production. Meanwhile, the préparation method of the two new intermediates themselves is simple and high yield, only using the most commonly-used 7-methoxy-tetralone (II) as original starting material and undergoing one step of reaction to obtain the intermediates, followed by one more step of converting the intermediate compounds to desired product agomelatine. Said reaction processes are greatly simplified, with the reaction yield being improved and the difficulty in purification of previous method being overcome, as compare with the previous technique for préparation of agomelatine. Typically, the yield of the présent invention is over 70%.
Examplcs
The foilowing examples are utilized for further illustration of the présent invention, but they are not intended to limit the scope of the invention in any manner.
Example 1:
1) Synthesis of 2-(l-hydroxyl-7-methoxy-l,2,3,4-tetrahydro-naphthalen-l-yl)-acetonitrile (the compound C)
To a reaction vessel was added acetonitrile (19.0 ml) and anhydrous THF (50 ml), cooled to -70°C with dry ice/ethanol, then the solution of n-Butyl Lithium in n-hexane (2.5 M, 142.0 ml) was added dropwise slowly. After stirring for half an hour under this température, the solution of the compound II (44.6 g) in anhydrous THF (300 ml) was added dropwise slowly, and stirred for 1 h at the same température. The reaction is quenched by adding saturated aqueous ammonium chloride (700 ml), extracted with ethyl acetate (350 ml x 3). The organic layers were combined, washed with saturated aqueous NaCl (350 ml), dried over anhydrous sodium sulfate, and concentrated to obtain the off-white title product (54.3 g). Yield: 98.3%.
Example 2:
2) Synthesis of N-[2-(l-hydroxyl-7-methoxy-l,2,3,4-tetrahydro-naphthalen-l-yl)ethyl]acetamide (the compound A)
The compound C (54.3 g) was dissolved in THF (500 ml), and acetic anhydride (33.1 g) and Raney-Ni (10 g) were then added. The reaction mixture was hydrogenated with the hydrogen pressure maintaining 1.1 Mpa at température 30°C, until the reaction is completed. The mixture
ORIGINAL was cooled to room température, filtered and concentrated to remove THF. The residue was diluted with ethyl acetate (500ml), washed with saturated aqueous NaHCOj (150 ml), water (150 ml) and saturated aqueous NaCl (150 ml). The resulting organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the off-white product A (56.0 g). Yield: 85% ‘HNMR(CDC13) S: 1.77-1.98 (m, 4H), 1.92 (s, 3H), 2. 01-2.11 (m, 2H), 2. 28 (s,
0H) , 2. 67-2.77(m, 2H) , 3.28-3. 50(m, 2H), 3.80 (s, 3H), 6.32 (s, NH),
6.74-7.27 (m, 3H)O
ESI-MS (m/z): 286.1 (M+Na).
Mp: 106-109°C.
Example 3:
3) Synthesis of N-[2-(7-methoxy-1 -naphthyl)ethyl]acetamide (the compound I)
The compound A (56.0 g) was dissolved in toluene (500 ml) and acetic acid (50 ml), DDQ (53.2g) was added, and the mixture was heated at 40°C for about 5 h. After the reaction was completed, the mixture was filtered, and the filtrate was washed with saturated aqueous NaHCCh ORIGINAL (250 ml x 2), water (250 ml) and saturated aqueous NaCl (250 ml). The resulting organic phase was dried over anhydrous sodium sulfate, filtered and the solvent was evaporated off. The residue was recrystallized from ethanol-water (1:1), dried in an oven to obtain the title product as white powder (43.8 g). Yield: 85%.
*HNMR(CDCl3)ô: 1.922 (s, 3H), 3.21-3.24(t, 2H), 3.56-3.61(q, 2H) , 3.96(s, 3H), 5.97 (s, 1H), 7.14-7.16 (q, 1H), 7.22-7.26 (m, 2H), 7.46-7.47 (m, 1H), 7.64-7.67 (m, 1H), 7.72-7.74 (d, 1H). ESI -MS(m/z): 244.14 (M+H).
Example 4:
1) Synthesis of 2-(l-hydroxyl-7-methoxy-l,2,3,4-tetrahydro-naphthalen-l-yl)-acetonitrile (the compound C)
To a reaction vessel was added acetonitrile (9.5 ml) and anhydrous THF (25 ml), cooled to 70°C with dry ice/ethanol, and then the solution of n-Butyl Lithium in n-hexane (2.5 M, 71.0 ml) was added dropwise slowly. After stirring for half an hour under this température, the solution of the compound II (22.3 g) in anhydrous THF (150 ml) was added dropwise slowly, and stirred for 1 h at the same température. The reaction is quenched by adding saturated aqueous ammonium chloride (350 ml), extracted with ethyl acetate (200 ml x 3). The organic layers were combined, washed with saturated aqueous NaCl (200 ml), dried over anhydrous sodium sulfate, and concentrated to obtain the off-white title product (27.2 g) e. Yield: 98.4%.
Example 5 :
2) Synthesis of N-[2-(l-hydroxyl-7-methoxy-I,2,3,4-tetrahydro-naphthalen-l-yl)ethyl]acetamide (the compound A)
The compound C (27.2 g) was dissolved in THF (250 ml), and acetic anhydride (15.6 g) and Raney-Ni (4 g) were then added. The reaction mixture was hydrogenated with the hydrogen pressure maintaining 1.1 Mpa at température 30°C, until the reaction is completed. The mixture was cooled to room température, filtered and concentrated to remove THF. The residue was diluted with ethyl acetate (250 ml), washed with saturated aqueous NaHCO3 (100 ml), water (100 ml) and saturated aqueous NaCl (100 ml). The resulting organic phase was dried over anhydrous
OR1G1NAL sodium sulfate, filtered and concentrated to obtain the off-white title product (28.0 g). Yield:
85%.
’HNMR (CDCls) 5 : 1.77-1.98 (m, 4H), 1.92 (s, 3H), 2.01-2.11 (m,2H), 2. 28 (s,
OH) , 2.67-2.77(m, 2H) , 3.28-3.50(m,2H), 3.80 (s, 3H), 6.32 (s, NH),
6.74-7.27 (m, 3H) »
ESI-MS (m/z): 286.1 (M+Na).
Mp: 106-109°C.
Example 6:
3) Synthesis of N-[2-(7-methoxy-3,4-dîhydro-naphthalen-l-yl)ethyl]acetamide (the compound B)
The compound A (28.0 g) was dissolved in ethyl acetate (300ml) to form a suspension, to 10 which concentrated HCl (12 M, 13.3 ml) was then added dropwise at RT. The suspension gradually tumed clear. The réaction solution was further stirred for 2 h and poured into water (150 ml). After the layers separated, the organic phase was washed with saturated aqueous
ORIGINAL
NaHCOî (150 ml x 2) and saturated aqueous NaCl (150 ml), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title product as oil (25.5 g). Yield: 97.8%.
lHNMR(CDCls) δ : 1,944 (s, 3H), 2. 21-2. 27 (m, 2H), 2. 61-2.69 (m, 4H) ,
3.40-3.45(m,2H), 3.80 (s, 3H), 5.59 (s, NH), 5.90-5.93 (m, IH) , 6.68-7.05 (m, 3H) «
ESI -MS (m/ z) : 268. 3 (M+Na) »
Example 7:
4) Synthesis of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (the compound I)
The compound B (25.5 g) was dissolved in dichloromethane (250 ml), DDQ (26.1 g) was added portionwîse, and the mixture was stirred overnight at RT. After the reaction was completed, the mixture was filtered, and the filtrate was washed with saturated aqueous NaHCCh (150 ml x
2), water (150 ml) and saturated aqueous NaCl (150 ml). The organic phase obtained was dried 10 over anhydrous sodium sulfate, filtered and the solvent was evaporated off. The residue was recrystallized from ethanol-water (1:1), dried in an oven to obtain white powder (46.4 g). Yield: 91.8%.
ORIGINAL ‘HNMR(CDCl3)5: 1.922 (st 3H), 3.2l-3.24(t, 2H), 3.56-3.6l(q, 2H), 3.96(s, 3H), 5.97 (s, ÎH),
7.14-7.16 (q, 1H), 7.22-7.26 (m, 2H), 7.46-7.47 (m, 1H), 7.64-7.67 (m, 1H), 7.72-7.74 (d, 1H).
ESl -MS(w/z): 244.14 (M+H).
Claims (16)
- CLAIMSi1. The compound A of the following formulaNHCOMe
- 2. The compound B of following formula:NHCOCH3
- 3. A method for the préparation of the compound A of claim 1, comprising reductive acylation of the compound C under the condition of catalytic hydrogénation and in the presence of acetic anhydrideORIGINALMétalNHCOMe
- 4. The method according to claim 3, characterized in that said métal catalyst is Raney-Ni, the amount of which is 0.1-0.3 times the amount of the compound C by weight.
- 5. The method according to claim 3, characterized in that the amount of said acetic anhydride is5 1-1.3 times the molar amount of the compound C.
- 6. The method for préparation of agomelatine using the compound A, comprising déhydration and aromatization of the compound A to obtain the desired product of formula I:ORIGINALDehydrogenating agentNHCOCH3 nhcoch3
- 7. The method for préparation of agomelatine using the compound A according to claim 6, characterized in that the dehydrogenating agent used in said aromatization îs dichlorodicyanobenzoquinone.5
- 8. The method for préparation of agomelatine using the compound A according to claim 6, characterized in that the amount of dehydrogenating agent is 1-3 times the molar amount of the compound A.
- 9. The method for préparation of agomelatine using the compound A according to claim 6, characterized in that the solvent used in the reaction is the mixture of toluene and glacial acetic
- 10 acid, the mixture of acetonitrile and glacial acetic acid, or glacial acetic acid.10. A method for the préparation of the compound B of claim 2, comprising déhydration of the compound A under acidic condition:ORIGINALAcidNHCOCH3NHCOCH3
- 11. A method for préparation of agomelatine using the compound B, comprising reaction of the compound B with a dehydrogenating agent to obtain the desired product of formula I:ORIGINALDehydrogenating agentNHCOCH3NHCOCH3
- 12. The method for préparation of agomelatine using the compound B according to claim 11, characterized in that said dehydrogenating agent is dichloro-dicyanobenzoquînone.
- 13. The method for préparation of agomelatine using the compound B according to claim 11,5 characterized in that the amount of said dehydrogenating agent is 1-3 times the molar amount of the compound B.
- 14. The method for préparation of agomelatine using the compound B according to claim 11, characterized in that the organic solvent used in the reaction is dichloromethane or toluene.
- 15. A method for préparation of agomelatine, comprising the following steps:10 a. reductive acylation of the compound C under the condition of catalytic hydrogénation and in the presence of acetic anhydride to obtain compound AORIGINALMétal catalyst/AcîON H CO Meb. déhydration and aromatization of the compound A with a dehydrogenating agent, to obtain the desired product of formula 1ORIGINALDehydrogenating agentNHCOCH3
- 16. The method for préparation of agomelatine according to claim 15, characterized in firstly dehydrating the compound A under acidic condition to produce the compound B, then reacting compound B with a dehydrogenating agent to obtain the desired product of formula I t
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CN201010197370.0 | 2010-06-08 |
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