CN108191620A - A kind of method that amitriptyline intermediate is prepared using solid acid catalyst - Google Patents
A kind of method that amitriptyline intermediate is prepared using solid acid catalyst Download PDFInfo
- Publication number
- CN108191620A CN108191620A CN201810020812.0A CN201810020812A CN108191620A CN 108191620 A CN108191620 A CN 108191620A CN 201810020812 A CN201810020812 A CN 201810020812A CN 108191620 A CN108191620 A CN 108191620A
- Authority
- CN
- China
- Prior art keywords
- zsm
- amitriptyline
- molecular sieve
- benzoic acid
- dihydro
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
It the present invention relates to the use of the method that solid acid catalyst prepares amitriptyline intermediate,Amitriptyline intermediate green can effectively be solved,Cleaning,The problem of safety in production,Its solve technical solution be,Adjacent phenethyl benzoic acid and 5 molecular sieves of ZSM are added to adjacent phenethyl benzoic acid at 0 40 DEG C,In 5 20 times of solvents of 5 molecular sieve quality summations of ZSM,It is warming up to 60 100 DEG C,It is heated at reflux 6 12 hours of stirring,After reaction solution is cooled down,It is filtered under diminished pressure,5 molecular sieve filtrations of ZSM are removed,After filtrate water is washed,It is dry,Concentration,Obtain 10,11 dihydro-dibenzo [a,B] 5 ketone crude product of cycloheptene,Absolute ethyl alcohol recrystallizes,Obtain amitriptyline intermediate sterling,The present invention can substantially reduce the discharge that waste is polluted in production,And production cost can be reduced,It is the innovation in the method for prepare amitriptyline intermediate.
Description
Technical field
The present invention relates to pharmaceutical intermediate preparation fields, particularly a kind of to be prepared in amitriptyline using solid acid catalyst
The method of mesosome.
Background technology
Amitriptyline is clinically common tricyclic antidepressant, is widely used in treatment depression, neurosis, slow
The other diseases such as chronic ache are solved, belong to national essential drugs, there is very big market demand.The life used in production
Production. art is first by raw material neighbour's phenethyl benzoic acid（II）Synthesize intermediate 10,11- dihydro-dibenzos [a, b] cycloheptene-
5- ketone（I）, dimethylaminopropyl side chain is then introduced by grignard reaction again.
At present industrially by II prepares I main stream approach be using compounding phosphoric acid does catalyst, pass through pay gram an acylation
Product I is obtained by the reaction.Catalyst raw material used in this method is easy to get, and cost is relatively low, but is generated after reacting and largely contain organic impurities
Waste phosphoric acid be difficult to handle, also without recycle value, after discharge for a long time in larger pollution can be all caused to environment.With
It is more and more stringenter to environmentally friendly requirement society, the green synthesis process for using low stain instead is very urgent.
ZSM-5 molecular sieve is the solid acid catalyst that a kind of high silicon 3 D intersects straight channel, has stronger acidity.In it
The unique pore structure in portion is not only that shape selective catalysis provides space restriction effect, and provide for reactants and products abundant
Access way, the power at acidity of catalyst center can be adjusted by changing the silica alumina ratio of molecular sieve, at present extensively should
For multiple fields such as petrochemical industry, fine chemistry industries, however, with ZSM-5 molecular sieve synthetic intermediate 10,11- dihydro-dibenzos
[a, b] cycloheptene -5- ketone（I）And relevant report is there are no, therefore it provides a kind of green, cleaning, simplicity are prepared in amitriptyline
Mesosome 10,11- dihydro-dibenzos [a, b] cycloheptene -5- ketone（I）Method it is imperative.
Invention content
For the above situation, to solve the defect of the prior art, the purpose of the present invention, which is just to provide, a kind of utilizes solid acid
The method of catalyst preparation amitriptyline intermediate, can effectively solve amitriptyline intermediate green, cleaning, safety in production ask
Topic.
The technical solution that the present invention solves is, by adjacent phenethyl benzoic acid at 0-40 DEG C（II）With ZSM-5 molecular sieve plus
Enter to adjacent phenethyl benzoic acid（II）, ZSM-5 molecular sieve quality summation 5-20 times of solvent in（Solid is in terms of g, and liquid is with mL
Meter）, 60-100 DEG C is warming up to, 6-12 hour of stirring is heated at reflux, after reaction solution is cooled down, is filtered under diminished pressure, with adjacent phenethyl
Benzoic acid（II）, ZSM-5 molecular sieve quality summation 1-2 times of solvent rinse twice, ZSM-5 molecular sieve is filtered to remove, filtrate
Dry after being washed with water, concentration obtains 10,11- dihydro-dibenzos [a, b] cycloheptene -5- ketone（I）Crude product adds in adjacent phenethyl benzene first
Acid（II）, ZSM-5 molecular sieve quality summation 2-3 times of absolute ethyl alcohol recrystallization, obtain amitriptyline intermediate 10,11- dihydros two
Benzo [a, b] cycloheptene -5- ketone（I）Sterling.
Silicon in the ZSM-5 molecular sieve：Aluminium ratio is 200-25：1（Silica alumina ratio refers to two in ZSM-5 molecular sieve skeleton
The molar ratio of silica and aluminium oxide）.
The solvent is dichloroethanes, ethyl acetate, benzene, toluene, dichloromethane, Di Iso Propyl Ether, methyl tertbutyl
One kind of ether.
The ZSM-5 molecular sieve and adjacent phenethyl benzoic acid（II）Mass ratio be 1:5-20.
The present invention makees catalyst using adjacent phenethyl benzoic acid as raw material, using solid acid ZSM-5 molecular sieve, gram anti-by paying
Cyclization is answered, obtains amitriptyline key intermediate 10 in high yield, 11- dihydro-dibenzos [a, b] cycloheptene -5- ketone can significantly subtract
The discharge of waste is polluted in few production, and production cost can be reduced, is the innovation in the method for prepare amitriptyline intermediate.
Description of the drawings
Fig. 1 is the nucleus magnetic hydrogen spectrum figure of intermediate 10,11- dihydro-dibenzos [a, b] cycloheptene -5- ketone of the present invention.
Fig. 2 is the mass spectrogram of intermediate 10,11- dihydro-dibenzos [a, b] cycloheptene -5- ketone of the present invention.
Fig. 3 is the high performance liquid chromatography of intermediate 10,11- dihydro-dibenzos [a, b] cycloheptene -5- ketone of the present invention.
Specific embodiment
The specific embodiment of the present invention is described in further detail with reference to embodiments.
Embodiment 1
At 0 DEG C, nitrogen protection, 22.6g neighbour's phenethyl benzoic acid（II）With 2.3g ZSM-5 molecular sieves（Silica alumina ratio is 25）Add
Enter into the dichloroethanes of 250mL, be warming up to 90 DEG C, be heated at reflux stirring 6 hours, after reaction solution is cooled down, be filtered under diminished pressure, two
Chloroethanes 30mL rinses twice, recycle ZSM-5 molecular sieve, and filtrate is washed once, and saturated common salt washing is primary, anhydrous sodium sulfate
After drying, filtrate is concentrated in vacuo, obtains 208g10,11- dihydro-dibenzos [a, b] cycloheptene -5- ketone（I）Crude product, add in 60mL without
Water-ethanol recrystallization is primary, obtains 198g sterlings, yield 95%.
Liquid chromatogram normalization purity is more than 99%.
Nuclear magnetic resonance spectroscopy：1HNMR (400MHz, CDCl3) δ 7.45~7.43 (m, 2H), 7.37~7.34 (m,
2H), 7.30~7.28 (m, 4H), 2.93 (dd, J=6.6Hz, 4H).
Low Resolution Mass Spectra：ESI–MS m/z：209.1 { [M+H]+}.
Embodiment 2
At 20 DEG C, nitrogen protection, 22.6g neighbour's phenethyl benzoic acid（II）With 3.6g ZSM-5 molecular sieves（Silica alumina ratio is 50）
It is added in the ethyl acetate of 400mL, is warming up to 80 DEG C, be heated at reflux stirring 12 hours, after reaction solution is cooled down, depressurized
Filter, ethyl acetate profit 30mL rinses twice, recycle ZSM-5 molecular sieve, filtrate are washed once, and saturated common salt washing is primary, nothing
After aqueous sodium persulfate drying, filtrate is concentrated in vacuo, obtains 204g10,11- dihydro-dibenzos [a, b] cycloheptene -5- ketone（I）Crude product adds
It is primary to enter 60mL absolute ethyl alcohols recrystallization, obtains 195g sterlings, yield 93%.
Liquid chromatogram normalization purity is more than 99%.
Nuclear magnetic resonance spectroscopy：1HNMR (400MHz, CDCl3) δ 7.45~7.43 (m, 2H), 7.37~7.34 (m,
2H), 7.30~7.28 (m, 4H), 2.93 (dd, J=6.6Hz, 4H).
Low Resolution Mass Spectra：ESI–MS m/z：209.1 { [M+H]+}.
Embodiment 3
At 40 DEG C, nitrogen protection, 22.6g neighbour's phenethyl benzoic acid（II）With 3.6g ZSM-5 molecular sieves（Silica alumina ratio is 200）
It is added in the dichloromethane of 250mL, is warming up to 90 DEG C, be heated at reflux stirring 6 hours, after reaction solution is cooled down, be filtered under diminished pressure,
Dichloromethane 30mL rinses twice, recycle ZSM-5 molecular sieve, and filtrate is washed once, and saturated common salt washing is primary, anhydrous slufuric acid
After sodium drying, filtrate is concentrated in vacuo, obtains 202g10,11- dihydro-dibenzos [a, b] cycloheptene -5- ketone（I）Crude product adds in 60mL
Absolute ethyl alcohol recrystallization is primary, obtains 191g sterlings, yield 90%.
Liquid chromatogram normalization purity is more than 99%.
Nuclear magnetic resonance spectroscopy：1HNMR (400MHz, CDCl3) δ 7.45~7.43 (m, 2H), 7.37~7.34 (m,
2H), 7.30~7.28 (m, 4H), 2.93 (dd, J=6.6Hz, 4H).
Low Resolution Mass Spectra：ESI–MS m/z：209.1 { [M+H]+}.
Structural Identification
Intermediate 10,11- dihydro-dibenzos [a, b] cycloheptene -5- ketone（I）, synthetic route is as follows：
, it is carried out using NMR spectrum
Structural Identification, collection of illustrative plates are shown in attached drawing 1-3.
The present invention prepares amitriptyline intermediate 10,11- dihydro-dibenzos [a, b] cycloheptene -5- ketone（I）Method be one
Kind of green, cleaning, low stain production method, ZSM-5 zeolite molecular sieve used is a kind of efficient solid acid catalyst, energy
It applies mechanically repeatedly repeatedly, activity can pass through high temperature sintering after reducing and handle activity recovery, and existing so as to effectively reducing production cost
Production technology compare, organic pollution and spent acid discharge can be greatly reduced, environmental protection, using answering in the technique of solving over
The phosphoric acid does catalyst matched generates mass production waste, serious the problem of polluting environment, prepares amitriptyline intermediate
Innovation in method has good economic and social benefit.
Claims (5)
- A kind of 1. method that amitriptyline intermediate is prepared using solid acid catalyst, which is characterized in that will be adjacent at 0-40 DEG C Phenethyl benzoic acid and ZSM-5 molecular sieve be added to adjacent phenethyl benzoic acid, ZSM-5 molecular sieve quality summation 5-20 times of solvent In, 60-100 DEG C is warming up to, 6-12 hour of stirring is heated at reflux, after reaction solution is cooled down, is filtered under diminished pressure, with adjacent phenethyl benzene Formic acid, ZSM-5 molecular sieve quality summation 1-2 times of solvent rinse twice, ZSM-5 molecular sieve is filtered to remove, filtrate water is washed Afterwards, dry, concentration obtains 10,11- dihydro-dibenzos [a, b] cycloheptene -5- ketone crude products, adds in adjacent phenethyl benzoic acid, ZSM-5 The 2-3 times of absolute ethyl alcohol recrystallization of molecular sieve quality summation, obtains amitriptyline intermediate 10,11- dihydro-dibenzos [a, b] cycloheptyl Alkene -5- ketone sterlings；Silicon in the ZSM-5 molecular sieve：Aluminium ratio is 200-25：1；The solvent is dichloroethanes, acetic acid Ethyl ester, benzene, toluene, dichloromethane, Di Iso Propyl Ether, methyl tertiary butyl ether(MTBE) one kind；The ZSM-5 molecular sieve and adjacent benzene second The mass ratio of yl benzoic acid is 1:5-20.
- 2. the method according to claim 1 that amitriptyline intermediate is prepared using solid acid catalyst, which is characterized in that At 0 DEG C, nitrogen protection, 22.6g neighbour's phenethyl benzoic acid is added to the dichloroethanes of 250mL with 2.3g ZSM-5 molecular sieves In, be warming up to 90 DEG C, be heated at reflux stirring 6 hours, after reaction solution is cooled down, be filtered under diminished pressure, dichloroethanes 30mL rinses twice, ZSM-5 molecular sieve is recycled, filtrate is washed once, saturated common salt washing is primary, after anhydrous sodium sulfate drying, is concentrated in vacuo and filters Liquid, obtains 208g10, and 11- dihydro-dibenzos [a, b] cycloheptene -5- ketone crude products add in 60mL absolute ethyl alcohols recrystallization once, obtain 198g sterlings, yield 95%.
- 3. the method according to claim 1 that amitriptyline intermediate is prepared using solid acid catalyst, which is characterized in that At 20 DEG C, nitrogen protection, 22.6g neighbour's phenethyl benzoic acid is added to the ethyl acetate of 400mL with 3.6g ZSM-5 molecular sieves In, 80 DEG C are warming up to, stirring 12 hours is heated at reflux, after reaction solution is cooled down, is filtered under diminished pressure, ethyl acetate profit 30mL rinses two It is secondary, ZSM-5 molecular sieve is recycled, filtrate is washed once, saturated common salt washing is primary, after anhydrous sodium sulfate drying, is concentrated in vacuo Filtrate, obtains 204g10, and 11- dihydro-dibenzos [a, b] cycloheptene -5- ketone crude products add in 60mL absolute ethyl alcohols recrystallization once, obtain 195g sterlings, yield 93%.
- 4. the method according to claim 1 that amitriptyline intermediate is prepared using solid acid catalyst, which is characterized in that At 40 DEG C, nitrogen protection, 22.6g neighbour's phenethyl benzoic acid is added to the dichloromethane of 250mL with 3.6g ZSM-5 molecular sieves In, be warming up to 90 DEG C, be heated at reflux stirring 6 hours, after reaction solution is cooled down, be filtered under diminished pressure, dichloromethane 30mL rinses twice, ZSM-5 molecular sieve is recycled, filtrate is washed once, saturated common salt washing is primary, after anhydrous sodium sulfate drying, is concentrated in vacuo and filters Liquid, obtains 202g10, and 11- dihydro-dibenzos [a, b] cycloheptene -5- ketone crude products add in 60mL absolute ethyl alcohols recrystallization once, obtain 191g sterlings, yield 90%.
- 5. -4 any one of them of claims 1 or 2 is prepared using the method that solid acid catalyst prepares amitriptyline intermediate Application of obtained 10,11- dihydro-dibenzos [a, the b] cycloheptene -5- ketone in amitriptyline drug is prepared.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810020812.0A CN108191620A (en) | 2018-01-10 | 2018-01-10 | A kind of method that amitriptyline intermediate is prepared using solid acid catalyst |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810020812.0A CN108191620A (en) | 2018-01-10 | 2018-01-10 | A kind of method that amitriptyline intermediate is prepared using solid acid catalyst |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108191620A true CN108191620A (en) | 2018-06-22 |
Family
ID=62588508
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810020812.0A Pending CN108191620A (en) | 2018-01-10 | 2018-01-10 | A kind of method that amitriptyline intermediate is prepared using solid acid catalyst |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108191620A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1372536A (en) * | 1999-08-30 | 2002-10-02 | 哈尔曼及赖默股份有限公司 | Production of dibenzosuberenone derivatives by catalytic dehydrogenation |
| CN1651386A (en) * | 2004-11-24 | 2005-08-10 | 大连理工大学 | Synthesis method of 2-alkyl anthraquinone |
| CN103833534A (en) * | 2014-03-25 | 2014-06-04 | 黑龙江大学 | Method for catalytically preparing 2-ethyl anthraquinone by alkali desilicicated modified Hbeta molecular sieve |
-
2018
- 2018-01-10 CN CN201810020812.0A patent/CN108191620A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1372536A (en) * | 1999-08-30 | 2002-10-02 | 哈尔曼及赖默股份有限公司 | Production of dibenzosuberenone derivatives by catalytic dehydrogenation |
| CN1651386A (en) * | 2004-11-24 | 2005-08-10 | 大连理工大学 | Synthesis method of 2-alkyl anthraquinone |
| CN103833534A (en) * | 2014-03-25 | 2014-06-04 | 黑龙江大学 | Method for catalytically preparing 2-ethyl anthraquinone by alkali desilicicated modified Hbeta molecular sieve |
Non-Patent Citations (1)
| Title |
|---|
| TAKEHIKO YAMATO等: "Organic Reactions Catalyzed by Solid Superacids. 5.1 Perfluorinated Sulfonic Acid Resin (Nafion-H) Catalyzed Intramolecular Friedel-Crafts Acylation", 《J. ORG. CHEM.》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112142638A (en) | Chiral binaphthyl-aza polycyclic ligand and preparation method thereof | |
| Setsune et al. | Synthesis and atropisomerism of meso-tetraarylporphyrins with mixed meso-aryl groups having ortho-substituents | |
| CN102757346A (en) | Preparation method of dimethyl fumarate | |
| CN108191620A (en) | A kind of method that amitriptyline intermediate is prepared using solid acid catalyst | |
| CN102911151B (en) | Method for water-phase synthesis of benzoxanthene derivatives | |
| CN102850313A (en) | Synthesis of benzoxanthene derivatives by aqueous phase catalysis of ionic liquid | |
| CN101628889B (en) | Method for preparing improved donepezil hydrochloride key intermediate | |
| CN108191814B (en) | Method for synthesizing cyclohexanone ethylene ketal under catalysis of titanium ammonium phosphotungstate composite salt | |
| CN114516817B (en) | Chemical intermediate and preparation method thereof | |
| CN112500337B (en) | Synthetic method of 3-bromo-6-chloropyridine formamide | |
| CN103193660B (en) | Synthetic method of 4-alkoxy phenylamine compound | |
| CN102584848B (en) | Preparation method for cyclohexyl diketone glycol monoketal | |
| CN102850314B (en) | Synthesis of benzoxanthene derivatives by aqueous phase catalysis of difunctional alkaline ionic liquid | |
| CN110845410B (en) | Method for preparing 6, 7-dimethoxy-3, 4-dihydroisoquinoline hydrochloride by one-pot method | |
| CN109824520B (en) | Preparation method of cis-4-methylcyclohexylamine | |
| CN109836374B (en) | Environment-friendly preparation method of vitamin B6 | |
| CN112047815A (en) | Preparation method of cannabidiol compound | |
| CN109942516A (en) | Compound R A is preparing the purposes in Bu Waxitan intermediate chirality butyrolactone | |
| JPH04364147A (en) | 1,3-dihydroxy-4,6-bis(alpha-methyl-alpha-(4'-hydroxyphenyl) ethyl)benzene and its production | |
| CA2346900A1 (en) | Method of producing ketimines | |
| CN101747294B (en) | Method for purifying N-(2,6-xylyl)-2-(1-piperazinyl)acetamide | |
| Mirjalili et al. | Acetalization of carbonyl compounds by using silica-bound sulfuric acid under green condition | |
| CN110724169A (en) | Method for preparing 1-ferrocenyl-3-aryl-3-diacetyl methylene-acetone | |
| CN116874411B (en) | Synthesis method of 1-bromocarbazole | |
| CN101412667A (en) | Preparation of 2-pimelie kelone compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180622 |
|
| WD01 | Invention patent application deemed withdrawn after publication |