CN102617386A - Preparation method for agomelatine - Google Patents
Preparation method for agomelatine Download PDFInfo
- Publication number
- CN102617386A CN102617386A CN2012100624097A CN201210062409A CN102617386A CN 102617386 A CN102617386 A CN 102617386A CN 2012100624097 A CN2012100624097 A CN 2012100624097A CN 201210062409 A CN201210062409 A CN 201210062409A CN 102617386 A CN102617386 A CN 102617386A
- Authority
- CN
- China
- Prior art keywords
- preparation
- agomelatine
- reaction
- methoxyl group
- reagent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides a preparation method for agomelatine. According to the preparation method, 7-methoxy-1-naphthaldehyde which is used as an initial raw material is subjected to three steps of reactions of condensation, reduction and acetylation. The preparation method for agomelatine has the advantages that 1) the whole preparation method is simple, only three steps of reactions are performed, the method is easy to operate, and agomelatine is easy to industrially produce; 2) the raw material is easy to obtain and low in price, and the whole process is low in cost; 3) the agomelatine product produced by the preparation method is high in purity, the purity reaches 99.9 percent, and the quality of the product meets the requirement of Europe and the United States Pharmacopoeia; and 4) the agomelatine product produced by the preparation method is high in yield, and the total yield can reach 51 percent.
Description
Technical field
The present invention relates to a kind of preparation method of antidepressant drug, specifically, relate to a kind of preparation method of Agomelatine.
Background technology
Data shows according to statistics: the expense total that is used for global every year in the dysthymia disorders medical treatment is about 60,000,000,000 dollars.Annual nearly 1,100 ten thousand people of the U.S. suffer from clinical depression, and the expenditure that therefore cause every year reaches 43,700,000,000 dollars, and about 15% patients with depression finally can end one's life with suicide." the calendar year 2001 World Health Report " that the World Health Organization delivers stresses that dysthymia disorders has become the fourth-largest disease in the world at present, may become to the year two thousand twenty to be only second to cardiopathic second largest disease.
At present the morbidity of the dysthymia disorders of China is about 3%～5%, and patients with depression has 3,600 ten thousand people approximately, with high incidence forms distinct contrast be, at present the national prefectural level with the recognition rate to dysthymia disorders of going to the hospital less than 20%.And in existing patients with depression, only accepted the related drugs treatment less than 10% people.Dysthymia disorders is as " sub product " of the modern economy of high speed development, the life of affect people's more and more widely.
Thymoleptic are since coming out the 1950's; Develop very fast; Particularly many in recent ten years novel antidepressants emerge in an endless stream; Thymoleptic can be divided into 7 types: serotonin reuptake transporter Depressant (SSRI), monoamine oxidase inhibitor MAGI, phenylpiperidine derivative, serotonin-norepinephrine reuptake inhibitor medicine (SNRI), aminoketones thymoleptic, tricyclic antidepressant (TCA) and Fourth Ring piperazine azatropylidene class medicine; Because above chemical synthetic drug serious toxic side effect can occur after taking for a long time, compelled the stopping of many patients treated.Melatonin analogue Agomelatine agomelatine is developed by Servier company, and in May, 2009 granted listing in Europe, it is first melatonin receptors agonist, also is serotonin 2C (S-HTx) receptor antagonist.The mechanism of action of Agomelatine and said medicine are all inequality, and clinical study shows that this medicine has antidepressant, anxiety, adjustment sleep rhythm and regulates the physiological clock effect, and its untoward reaction simultaneously is few, and sexual function is had no adverse effects, and does not also see the withdrawal reaction.
Antidepressant drug commonly used clinically at present has oxidase inhibitor, serotonin reuptake inhibitor (SSRIs) etc., and wherein SSRIs accounts for more than 70% of clinical use.Yet the SSRIs medicine has the specificity spinoff, especially influences sexual function, and evidence suggests that SSRIs is effective to mild to moderate dysthymia disorders, and not good enough to the curative effect of utmost point major depressive disorder.
Agomelatine is all effective to all types of dysthymia disorders, and the mechanism of action of Agomelatine and said medicine are all inequality, and significant advantage and characteristics are arranged in validity and security.At present, domestic Agomelatine preparation leans on import entirely, and commercially available price comparison is high, far can not satisfy patient's needs, be badly in need of the exploitation Agomelatine satisfying the home market, but Shang Weiyou is fit to the industrialization working method of Agomelatine bulk drug.
At present, the preparation technology of existing Agomelatine bulk drug mainly comprises following several kinds:
One, European patent EP 0447285 disclosed preparation method, operational path is shown below:
This method is a raw material with 7-methoxyl group-1-Tetralone an intermediate of Sertraline (9), with bromoethyl acetate and Zn the Reformatsky reaction takes place, and then uses P
2O
5Dewater 7-methoxyl group-3; 4-dihydro-1-(2H)-naphthylene guanidine-acetic acid ethyl ester (10); Under 215 ℃; Compound (10) is vulcanized dehydrogenation get naphthalene derivatives 2-(7-methoxyl group-1-naphthyl) ETHYLE ACETATE (7), further saponification gets 2-(7-methoxyl group-1-naphthyl) acetate (6), (6) and SOCl
2React behind the acyl chlorides; With ammoniacal liquor react acid amides (5); The nitrile that dewaters correspondingly with trifluoroacetic anhydride again (4), Raney-Ni/H2 reduce 2-(7-methoxyl group-1-naphthyl) ethamine, last and Acetyl Chloride 98Min. generates end product Agomelatine (1) in the presence of pyridine.
This method has following weak point: 1) the reproducibility problem of the first step Reformatsky reaction.2) subsequent step of the second step aromizing usually is incomplete, and is difficult to obtain the product of purifying after the good fortune.3) the W-response step is too much, is unfavorable for suitability for industrialized production.
Two, Chinese patent 200910046935.2 disclosed preparing methods, operational path is shown below:
Get (7-methoxyl group-3 with 7-methoxyl group-1-Tetralone an intermediate of Sertraline (9) and nitrile acetic acidreaction; 4-dihydro-1-naphthyl) acetonitrile (8), with 2,3-two chloro-5; 6-dicyano-1; 4-benzoquinones (DDQ) is a dehydrogenating agent, react in the methylene dichloride under the room temperature compound (4), in hydrogen reduction reaction, add diacetyl oxide then and carry out one pot reaction and can directly obtain end product (1).Reaction process is shown below:
Though the whole step of this method is few, key is to adopt DDQ oxydehydrogenation, higher this technology of effect used higher like reagent prices such as DDQ, cyanoacetic acids, so technology cost height.And reaction conditions requires to be unfavorable for industrialization production than higher.
Three, new compound method (the J. Med. Chem. 1994 of Agomelatine that delivers of Pierre Renard and Jean Andrieux; 37; 3231-3239), they are starting raw material with (6), with method one difference be after using Raney-Ni/H2 reduction cyanogen as amine; Directly the acidifying salify joins then and contains K
2CO
3The mixing solutions of chloroform and water in, 0 ℃ of following dripping acetyl chloride, room temperature reaction can obtain end product (1).Reaction process is shown below:
This method is not still avoided shortcomings such as polystep reaction and some expensive raw material uses.
Summary of the invention:
In order to overcome the weak point of prior art, the invention provides a kind of preparation method of new Agomelatine, can avoid the use of noxious chemical, reaction conditions is not harsh, and product is easy to purifying, is fit to the industrialization production of Agomelatine bulk drug.
The preparation method of Agomelatine of the present invention comprises the steps:
1) be starting raw material with structural formula suc as formula the 7-methoxyl group-1-naphthaldehyde shown in (12), with Nitromethane 99Min. generation condensation reaction, the generating structure formula is suc as formula the 7-methoxyl group nitro-naphthalene ethene shown in (11) under the effect of condensing agent;
2) will go up the 7-methoxyl group nitro-naphthalene ethene that makes in the step, the reduction reaction takes place under the effect of reductive agent, the generating structure formula is suc as formula the 7-methoxyl group shown in (3)-1-naphthalene ethylamine hydrochloride;
3) will go up 7-methoxyl group-1-naphthalene ethylamine hydrochloride of making in the step, generation acetylization reaction under the effect of acetylation reagent, the generating structure formula is suc as formula the Agomelatine shown in (1):
Among the preparation method of described Agomelatine, the condensing agent in the said step 1) is a salt of weak acid, and the temperature of reaction of condensation reaction is a reflux temperature.
Said salt of weak acid is Ammoniom-Acetate, ammonium formate, propionic acid amine, volatile salt, yellow soda ash or salt of wormwood;
Among the preparation method of described Agomelatine, said step 2) reductive agent in is for reducing the organic or inorganic reagent of nitro alkene, and the temperature of reaction of said reduction reaction is-10
oC to 25
oC.
The said organic or inorganic reagent that can reduce nitro alkene is selected from Lithium Aluminium Hydride or derivatives thereof, borane reagent or can generates the reagent of borine on the spot, and the temperature of reaction of said reduction reaction is 0
oC.
Said Lithium Aluminium Hydride verivate is the tri-tert lithium aluminum hydride.
Said borane reagent is the diethyl ether solution or the tetrahydrofuran solution of borine.
The said reagent that can generate borine on the spot is metal borohydride and Lewis acid.
Said metal borohydride and Lewis acid are Peng Qinghuana and boron trifluoride solution, POTASSIUM BOROHYDRIDE 97MIN and boron trifluoride solution, Peng Qinghuana and aluminum chloride, Peng Qinghuana and iodine.
Among the preparation method of described Agomelatine, the acetylation reagent in the said step 3) is diacetyl oxide or Acetyl Chloride 98Min., and the temperature of reaction of said acetylization reaction is-10
oC to 25
oC.
The preparation method of Agomelatine of the present invention has following technique effect:
1) whole preparation method technology is simple, has only three-step reaction, and operation is also convenient, is easy to suitability for industrialized production;
2) raw material is easy to obtain, and low price, and whole technology cost is very low;
3) the Agomelatine product purity of this preparing method's production is high, reaches 99.9%, and quality meets American-European pharmacopeia requirement;
4) the Agomelatine product yield of this preparing method's production is high, and total recovery reaches 51%.
Description of drawings
Fig. 1 prepares the schema of Agomelatine for the present invention;
Fig. 2 is the proton nmr spectra of Agomelatine of the present invention.
Embodiment
Following examples are to specify the present invention, and unrestricted the present invention.
The preparation method of present embodiment may further comprise the steps:
The preparation of step 1 7-methoxyl group nitro-naphthalene ethene
In reaction flask, add 12mmol 7-methoxyl group-1-naphthaldehyde, 18mL (332mmol) Nitromethane 99Min., 0.5g (6.5mmol) ammonium acetate, small amount of toluene azeotropic dehydration number hour, about 1/2 solvent of pressure reducing and steaming leaves standstill and is cooled to 10
oC obtains brown solid 2.2g, is 7-methoxyl group nitro-naphthalene ethene, yield 88.1%.
The preparation of step 2 7-methoxyl group-1-naphthalene ethylamine hydrochloride
In the 2.5L reaction flask, add the anhydrous THF of 500mL, 11g (0.3mol) LiAlH
4, drip the anhydrous THF solution 50mL that contains 15g (69mmol) 7-methoxyl group nitro-naphthalene ethene under the room temperature, reflux then.TLC monitors reaction, after reacting completely, is cooled to 0
oC slowly drips 11mL water, the 11mL15% aqueous sodium hydroxide solution, and 30mL water is after the cancellation; Filter, the most of solvent of pressure reducing and steaming, low temperature drips concentrated hydrochloric acid down, and residuum is with alcohol-water (3:5) recrystallization; Oven dry is separated out 7-methoxyl group-1-naphthalene ethylamine hydrochloride, 11g, yield: 84%.
The preparation of step 3 Agomelatine
7-methoxyl group-1-naphthalene ethylamine hydrochloride 123g (1mmol) that the last step was made adds in the 2L there-necked flask, adds the 850mL absolute ethyl alcohol, mechanical stirring; Add 46.7g (1.1 equivalent) sodium acetate and 56.2g (1.1 equivalent) diacetyl oxide, reflux 1h, TLC monitoring; React completely, the concentrating under reduced pressure solvent, it is semi-solid to obtain white; Add 1.5L ETHYLE ACETATE, add saturated NaHCO
3Solution is washed till no bubble and emerges, and uses 2 * 800ml water washing organic phase then, and the dry organic phase of anhydrous Na 2SO4 is filtered, concentrate do native white solid 122g.Use the 200mL re-crystallizing in ethyl acetate then, add gac 20g simultaneously and carry out heat filtering, finally obtain white solid 108g, be Agomelatine, yield 86%.
The preparation method of present embodiment may further comprise the steps:
The preparation of step 1 7-methoxyl group nitro-naphthalene ethene
In reaction flask, add 12mmol 7-methoxyl group-1-naphthaldehyde, 18mL (332mmol) Nitromethane 99Min., 0.4g (6.5mmol) ammonium formiate, small amount of toluene azeotropic dehydration number hour, about 1/2 solvent of pressure reducing and steaming leaves standstill and is cooled to 10
oC obtains brown solid 2.8g, is 7-methoxyl group nitro-naphthalene ethene, yield 72.1%.
The preparation of step 2 7-methoxyl group-1-naphthalene ethylamine hydrochloride
In the 2.5L reaction flask, add the anhydrous THF of 500mL, 11g (300mmol) LiAlH4 drips the anhydrous THF solution 50mL that contains 15g (69mmol) 7-methoxyl group nitro-naphthalene ethene under the room temperature, reflux then.TLC monitors reaction, after reacting completely, is cooled to 0
oC slowly drips 11mL water, the 11mL15% aqueous sodium hydroxide solution, and 30mL water is after the cancellation; Filter, the most of solvent of pressure reducing and steaming, low temperature drips concentrated hydrochloric acid down, and residuum is with alcohol-water (3:5) recrystallization; Oven dry is separated out 7-methoxyl group-1-naphthalene ethylamine hydrochloride, 10g, yield: 77%.
The preparation of step 3 Agomelatine
7-methoxyl group-1-naphthalene ethylamine hydrochloride 123g (1mmol) that the last step was made adds in the 2L there-necked flask, adds the 850mL absolute ethyl alcohol, mechanical stirring; Add 46.7g (1.1 equivalent) sodium acetate and 56.2g (1.1 equivalent) diacetyl oxide, reflux 1h, TLC monitoring; React completely, the concentrating under reduced pressure solvent, it is semi-solid to obtain white; Add 1.5L ETHYLE ACETATE, add saturated NaHCO
3Solution is washed till no bubble and emerges, and uses 2 * 800ml water washing organic phase then, anhydrous Na
2SO
4Dry organic phase is filtered, concentrate do native white solid 122g.Use the 200mL re-crystallizing in ethyl acetate then, add gac 20g simultaneously and carry out heat filtering, finally obtain white solid 110g, be Agomelatine, yield 88%.
The preparation method of present embodiment may further comprise the steps:
The preparation of step 1 7-methoxyl group nitro-naphthalene ethene
In reaction flask, add 12mmol 7-methoxyl group-1-naphthaldehyde, 18mL (332mmol) Nitromethane 99Min., 0.4g (6.5mmol) ammonium formiate, small amount of toluene azeotropic dehydration number hour, about 1/2 solvent of pressure reducing and steaming leaves standstill and is cooled to 10
oC obtains brown solid 2.8g, is 7-methoxyl group nitro-naphthalene ethene, yield 72.1%.
The preparation of step 2 7-methoxyl group-1-naphthalene ethylamine hydrochloride
In the 2.5L reaction flask, add 15g (69mmol) 7-methoxyl group nitro-naphthalene ethene, be cooled to 0
oC drips 0.3mol borine THF solution, and control reaction temperature is 25
oBelow the C, drip off the back room temperature reaction.TLC monitors reaction, after reacting completely, is cooled to 0
oC slowly drips saturated ammonium chloride solution 11mL water, after the cancellation, and the most of solvent of pressure reducing and steaming, residuum is with alcohol-water (3:5) recrystallization, and oven dry is separated out 7-methoxyl group-1-naphthalene ethylamine hydrochloride 8g, yield: 62%.
The preparation of step 3 Agomelatine
7-methoxyl group-1-naphthalene ethylamine hydrochloride 123g (1mmol) that the last step was made adds in the 2L there-necked flask, adds the 850mL absolute ethyl alcohol, mechanical stirring; Add 46.7g (1.1 equivalent) sodium acetate and 56.2g (1.1 equivalent) diacetyl oxide, reflux 1h, TLC monitoring; React completely, the concentrating under reduced pressure solvent, it is semi-solid to obtain white; Add 1.5L ETHYLE ACETATE, add saturated NaHCO
3Solution is washed till no bubble and emerges, and uses 2 * 800ml water washing organic phase then, anhydrous Na
2SO
4Dry organic phase is filtered, concentrate do native white solid 122g.Use the 200mL re-crystallizing in ethyl acetate then, add gac 20g simultaneously and carry out heat filtering, finally obtain white solid 110g, be Agomelatine, yield 88%.
Through detecting, the chemistry and the physical parameter of Agomelatine of the present invention are following: M.p 106-108
oC.ESI-MS(m/z):244(M+H)。1HNMR (CDCl3) δ: 1.93 (s, 3H), 3.24 (t, 2H), 3.62 (m, 2H), 3.97 (s, 3H), (m, 6H), wherein proton nmr spectra is as shown in Figure 2 for 7.14-7.75.
Claims (10)
1. the preparation method of an Agomelatine is characterized in that, comprises the steps:
1) be starting raw material with structural formula suc as formula the 7-methoxyl group-1-naphthaldehyde shown in (12), with Nitromethane 99Min. generation condensation reaction, the generating structure formula is suc as formula the 7-methoxyl group nitro-naphthalene ethene shown in (11) under the effect of condensing agent;
2) will go up the 7-methoxyl group nitro-naphthalene ethene that makes in the step, the reduction reaction takes place under the effect of reductive agent, the generating structure formula is suc as formula the 7-methoxyl group shown in (3)-1-naphthalene ethylamine hydrochloride;
3) will go up 7-methoxyl group-1-naphthalene ethylamine hydrochloride of making in the step, generation acetylization reaction under the effect of acetylation reagent, the generating structure formula is suc as formula the Agomelatine shown in (1):
2. the preparation method of Agomelatine according to claim 1 is characterized in that, the condensing agent in the said step 1) is a salt of weak acid, and the temperature of reaction of condensation reaction is a reflux temperature.
3. the preparation method of Agomelatine according to claim 2 is characterized in that, said salt of weak acid is Ammoniom-Acetate, ammonium formate, propionic acid amine, volatile salt, yellow soda ash or salt of wormwood.
4. the preparation method of Agomelatine according to claim 1 is characterized in that, said step 2) in reductive agent for reducing the organic or inorganic reagent of nitro alkene, the temperature of reaction of said reduction reaction is-10
oC to 25
oC.
5. the preparation method of Agomelatine according to claim 4; It is characterized in that; The said organic or inorganic reagent that can reduce nitro alkene is selected from Lithium Aluminium Hydride or derivatives thereof, borane reagent or can generates the reagent of borine on the spot, and the temperature of reaction of said reduction reaction is 0
oC.
6. the preparation method of Agomelatine according to claim 5 is characterized in that, said Lithium Aluminium Hydride verivate is the tri-tert lithium aluminum hydride.
7. the preparation method of Agomelatine according to claim 5 is characterized in that, said borane reagent is the diethyl ether solution or the tetrahydrofuran solution of borine.
8. the preparation method of Agomelatine according to claim 5 is characterized in that, the said reagent that can generate borine on the spot is metal borohydride and Lewis acid.
9. the preparation method of Agomelatine according to claim 8; It is characterized in that said metal borohydride and Lewis acid are Peng Qinghuana and boron trifluoride solution, POTASSIUM BOROHYDRIDE 97MIN and boron trifluoride solution, Peng Qinghuana and aluminum chloride, Peng Qinghuana and iodine.
10. the preparation method of Agomelatine according to claim 1 is characterized in that, the acetylation reagent in the said step 3) is diacetyl oxide or Acetyl Chloride 98Min., and the temperature of reaction of said acetylization reaction is-10
oC to 25
oC.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100624097A CN102617386A (en) | 2012-03-12 | 2012-03-12 | Preparation method for agomelatine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100624097A CN102617386A (en) | 2012-03-12 | 2012-03-12 | Preparation method for agomelatine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102617386A true CN102617386A (en) | 2012-08-01 |
Family
ID=46557654
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012100624097A Pending CN102617386A (en) | 2012-03-12 | 2012-03-12 | Preparation method for agomelatine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102617386A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102838504A (en) * | 2012-09-12 | 2012-12-26 | 福建广生堂药业股份有限公司 | Novel agomelatine crystal form L and preparation method thereof |
| CN108373422A (en) * | 2018-04-08 | 2018-08-07 | 无锡富泽药业有限公司 | A kind of preparation method of agomelatine |
| CN109796349A (en) * | 2019-03-01 | 2019-05-24 | 西南石油大学 | A method of it going back original aromatic nitro compound and prepares aromatic amine compounds |
-
2012
- 2012-03-12 CN CN2012100624097A patent/CN102617386A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| CHIH-WEI CHIEN, ET AL.: "Enantioselective synthesis of 1-vinyltetrahydroisoquinolines via Pd-catalyzed intramolecular asymmetric allylic amination reactions", 《TETRAHEDRON》 * |
| PATRICK DEPREUX, ET AL.: "Synthesis and Structure-Activity Relationships of Novel Naphthalenic and Bioisosteric Related Amidic Derivatives as Melatonin Receptor Ligands", 《J. MED. CHEM》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102838504A (en) * | 2012-09-12 | 2012-12-26 | 福建广生堂药业股份有限公司 | Novel agomelatine crystal form L and preparation method thereof |
| CN108373422A (en) * | 2018-04-08 | 2018-08-07 | 无锡富泽药业有限公司 | A kind of preparation method of agomelatine |
| CN109796349A (en) * | 2019-03-01 | 2019-05-24 | 西南石油大学 | A method of it going back original aromatic nitro compound and prepares aromatic amine compounds |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101709036B (en) | Preparation of agomelatine midbody, 2-(7-anisyl-1-naphthyl) ethylamine | |
| CN101654445B (en) | Compound for preparing ramelteon, preparation method thereof and application thereof | |
| CN106365986B (en) | Compound and preparation method thereof and the purposes in synthesis Bu Waxitan | |
| CN102659605B (en) | Synthesizing method of spermidine | |
| EP2123628A1 (en) | A process for preparing optical pure milnacipran and its pharmaceutically accepted salts | |
| CN102617386A (en) | Preparation method for agomelatine | |
| CN102001960A (en) | Method for preparing agomelatine | |
| CN103664677A (en) | Asymmetric synthesis method of (R,R)-formoterol tartrate | |
| CN104263797A (en) | Preparation method of R-1-aminotetralin | |
| CN109485638A (en) | A kind of uncommon preparation method for Buddhist nun's intermediate difficult to understand | |
| CN101654419A (en) | Preparation method of fluvoxamine maleate | |
| CN103896795B (en) | The preparation method and its usage of benzamide compound, its intermediate | |
| CN104628577A (en) | Method for synthesizing bromhexine hydrochloride | |
| CN103304524A (en) | Preparation method of ramelteon intermediate | |
| CN106748966A (en) | A kind of synthetic method of Ramipril key intermediate | |
| CN102432571A (en) | Novel method for preparing ramelteon key intermediate | |
| CN108373422A (en) | A kind of preparation method of agomelatine | |
| US11299451B2 (en) | Method for synthesizing 2-(1-cyclohexenyl)ethylamine | |
| CN102050748B (en) | Method for preparing expectorant, namely ambroxol key intermediate trans-4-[(2-amino benzyl) amino]-cyclohexanol | |
| CN101503365B (en) | Preparation of venlafaxine intermediate 1-[2-amino-1-(4-methoxy phenyl)ethyl] cyclohexanol | |
| CN104529958A (en) | Preparation method of Ramelteon | |
| CN102367228A (en) | Method for synthesizing agomelatine | |
| CN109879800B (en) | Preparation process of bepotastine drug intermediate | |
| CN102875499B (en) | The preparation method of 3-aminomethyl trimethylene oxide and organic acid salt thereof | |
| CN101723879B (en) | Method for synthesizing (R)-3-ethyl piperidine hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20120801 |