CN106518635A - Synthesis method for 3-methoxypropiophenone - Google Patents
Synthesis method for 3-methoxypropiophenone Download PDFInfo
- Publication number
- CN106518635A CN106518635A CN201610924744.1A CN201610924744A CN106518635A CN 106518635 A CN106518635 A CN 106518635A CN 201610924744 A CN201610924744 A CN 201610924744A CN 106518635 A CN106518635 A CN 106518635A
- Authority
- CN
- China
- Prior art keywords
- acetone
- methoxy
- meta
- thf
- methoxybenzenes
- 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
- C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
- C07F3/02—Magnesium compounds
Abstract
The invention discloses a synthesis method for 3-methoxypropiophenone. The synthesis method comprises the steps of enabling magnesium and m-bromoanisole to produce a Grignard reagent in a tetrahydrofuran (THF) solution under the catalytic action of aluminum chloride, and then, subjecting the Grignard reagent to a reaction with propionitrile, thereby producing the 3-methoxypropiophenone. According to the synthesis method, the operation is simple, the process is advanced, the solvent can be recycled, and thus, the industrial production is facilitated. According to the 3-methoxypropiophenone prepared by the synthesis method, the yield reaches 88.6%, and the liquid-phase purity reaches up to 99.44% or more.
Description
Technical field
The invention belongs to pharmaceutical intermediate compound synthesis field, and in particular to a kind of synthesis side of 3- methoxybenzenes acetone
Method.
Technical background
Tapentadol hydrochloride (tapentadol hydrochloride), chemical entitled 3- [(1R, 2R) -3- (dimethylamine
Base) -1- Ethyl-2-Methyl propyl group] phenol hydrochloride, for releasing to severe acute pain in adult human central nervous' system,
Clinical efficacy is good.3- methoxybenzene acetone is the key intermediate of synthetic hydrochloric acid tapentadol hydrochloride, at present, domestic and international 3- methoxyl groups
The traditional handicraft of propiophenone industrialized production, obtains 3- methoxyl group phenylpropyl alcohols using 3- hydroxypropiophenonepreparations with dimethyl sulfate reaction
Ketone, high cost, by-product are more, and yield is low, and dimethyl sulfate toxicity is big, and industrialized production is difficult.Therefore seek technique advanced, it is raw
Low cost is produced, the green production. art of exploitation 3- methoxybenzenes acetone life is imperative.
The method that the following is improved 2 kinds of synthesis 3- methoxybenzene acetone in recent years：
1. patent (Authorization Notice No.：CN101671245B), with m-hydroxybenzoic acid as raw material, first synthesize meta-methoxy
Benzenecarbonyl chloride., meta-methoxy Benzoylamide, then make meta-methoxy benzonitrile, last meta-methoxy benzonitrile and ethylmagnesium bromide
Reaction obtains propiophenone, and reactions steps are long, and high cost, yield are very low, while being also easy to produce substantial amounts of emulsion layer, cause production process
Middle equipment corrosion is serious, causes environmental pollution.
2. the meta-methoxy that document (Canadian Journal of Chemistry, 65 (11), 2568-2574) is reported
The preparation method of propiophenone is, with m-methoxybenzaldehyde as raw material, first to generate meta-methoxy phenylpropyl alcohol with ethyl phosphonium bromide reactive magnesium
Alcohol, then Jing CrO3Oxidation obtains 3- methoxybenzene acetone, and yield 74%, m-methoxybenzaldehyde price are high, using CrO3, a huge sum of money
Category pollution environment and product chromium residues and without industrial value.
The content of the invention
It is an object of the invention to overcome industrial synthesis 3- methoxybenzene acetone at present to exist, high cost, yield are low to be lacked
A kind of point, there is provided green synthesis method of 3- meta-methoxies propiophenone.For solving above-mentioned technical problem, the present invention adopts following skill
Art scheme：
Magnesium powder, aluminum trichloride (anhydrous) is added in equipped with reflux condensing tube, the reactor of Dropping funnel, from Dropping funnel
Meta-methoxy bromobenzene and tetrahydrofuran (THF) mixed solution is slowly added to, 30-80 DEG C of reacting liquid temperature is controlled, is made solution always
Keep slight boiling condition, completion of dropping post-heating backflow 0.5-1.0h, it is ensured that reactive magnesium completely, obtains Grignard reagent.Under stirring, will
Propionitrile is slowly added drop-wise in Grignard reagent, after dripping slowly, then reacts 1.0-2.0h.Reaction is finished, and is slowly added dropwise under psychrolusia
The hydrochloric acid of 3mol/L, decomposes addition compound product, separates inorganic phase, and the air-distillation of organic faciess Jing removes THF, and vacuum distillation obtains 3-
Methoxybenzene acetone.
Beneficial effects of the present invention are as follows：
1st, the 3- methoxybenzene acetone methods for providing, low cost are simple to operate, and technique is advanced, solvent recoverable, easily
In industrialized production.
2nd, with 3- methoxybenzenes acetone obtained in the synthetic method, yield reaches 88.6%, liquid phase high purity 99.44%
More than.
Description of the drawings
Fig. 1 is the 3- methoxybenzene acetone of embodiment 11H NMR scheme.
GC-MS figures of the Fig. 2 for the 3- methoxybenzene acetone of embodiment 1.
GC figures of the Fig. 3 for the 3- methoxybenzene acetone of embodiment 1.
Fig. 1 is Figure of abstract.
Specific embodiment
The invention will be further described with reference to embodiments, but the scope of protection of present invention is not limited to reality
Apply the scope of example statement.
The synthetic method of 3- methoxybenzene acetone is as follows：
Embodiment 1：
Magnesium powder 24.0g (1.0mol), aluminum trichloride (anhydrous) is added in equipped with reflux condensing tube, the reaction bulb of Dropping funnel
3.0g, tetrahydrofuran (THF) solution 300mL, heating.Meta-methoxy bromobenzene 187.1g (1.0mol) is slowly added in Dropping funnel
With the mixed solution of 300mL tetrahydrofurans (THF), 50-55 DEG C of reacting liquid temperature is controlled, makes solution be always maintained at slight boiling condition,
Completion of dropping post-heating backflow 0.5-1.0h, it is ensured that reactive magnesium completely, obtains Grignard reagent.Under stirring, by propionitrile 55.1g
(1.0mol) it is added slowly in Grignard reagent, after being added dropwise to complete, then reacts 1.0-2.0h.Reaction is finished, and is slowly dripped under psychrolusia
Plus the hydrochloric acid of 3.0mol/L is added dropwise over, and to decompose addition compound product, separate inorganic phase, the air-distillation of organic faciess Jing removes THF.Control
To 180-185 DEG C, vacuum distillation (pressure described in vacuum distillation is -0.095MPa, vapo(u)rizing temperature is 185 DEG C) is obtained temperature
3- methoxybenzene acetone, yield 78.3%.1H NMR(CDCl3,400MHz)δ:7.52-7.46(m,1H,Ar-H),7.44-7.41
(m,2H,Ar-H),7.22-7.19(m,1H,Ar-H),3.82(s,3H,OCH3),2.04(q,2H,CH2),1.08(t,3H,
CH3) .GC-MS m/z (%):164(M+,30.21),135(100.00),107(60.25),92(30.28),77(63.25)。
Analysis result table of the table 1 for the GC figures of 3- methoxybenzene acetone.
Table 1
Analysis result table
Embodiment 2：
The amount of meta-methoxy bromobenzene increases to 205.7g (1.1mol), propionitrile 60.5g (1.1mol), and other are with example 1,3-
The yield of methoxybenzene acetone is 82.5%.
Embodiment 3：
The amount of meta-methoxy bromobenzene increases to 224.5g (1.2mol), propionitrile 66.1g (1.2mol), and other are with example 1,3-
The yield of methoxybenzene acetone is 85.8%.
Embodiment 4：
The amount of meta-methoxy bromobenzene increases to 243.2g (1.3mol), propionitrile 71.6g (1.3mol), and other are with example 1,3-
The yield of methoxybenzene acetone is 88.6%.
Embodiment 5：
The amount of meta-methoxy bromobenzene increases to 261.8 (1.4mol), propionitrile 77.3g (1.4mol), and other are with example 1,3-
The yield of methoxybenzene acetone is 83.2%.
Embodiment 5：
The amount of meta-methoxy bromobenzene increases to 280.5 (1.5mol), propionitrile 82.5g (1.5mol), and other are with example 1,3-
The yield of methoxybenzene acetone is 80.1%.
Claims (3)
1. a kind of synthetic method of 3- methoxybenzenes acetone, it is characterised in that the method is comprised the following steps：Equipped with returned cold
Magnesium powder, aluminum trichloride (anhydrous) are added in solidifying pipe, the reactor of Dropping funnel, meta-methoxy bromobenzene is slowly added to from Dropping funnel
With tetrahydrofuran (THF) mixed solution, 30-80 DEG C of reacting liquid temperature is controlled, makes solution be always maintained at slight boiling condition, completion of dropping
Post-heating backflow 0.5-1.0h, it is ensured that reactive magnesium completely, obtains Grignard reagent；Under stirring, propionitrile is slowly added drop-wise to grignard slowly
In reagent, after dripping, then 1.0-2.0h is reacted, reaction is finished, under psychrolusia, be slowly added dropwise the hydrochloric acid of 3mol/L, decompose addition
Product, separates inorganic phase, and the air-distillation of organic faciess Jing removes THF, and vacuum distillation obtains 3- methoxybenzene acetone.
2. the synthetic method of a kind of 3- methoxybenzenes acetone according to claim 1, it is characterised in that：Magnesium powder, a methoxy
Bromide benzene, the ratio of the amount of the material of propionitrile are 1.0：1.0-1.5：The weight of 1.0-1.5, solvent THF is magnesium powder, meta-methoxy bromine
Benzene weight 7-10 times.
3. the synthetic method of a kind of 3- methoxybenzenes acetone according to claim 1, it is characterised in that：Synthesis 3- methoxyl groups
The reaction temperature of propiophenone is 50-55 DEG C；Pressure described in vacuum distillation is -0.095MPa～-0.10MPa, vapo(u)rizing temperature is
180-190℃。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610924744.1A CN106518635A (en) | 2016-10-24 | 2016-10-24 | Synthesis method for 3-methoxypropiophenone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610924744.1A CN106518635A (en) | 2016-10-24 | 2016-10-24 | Synthesis method for 3-methoxypropiophenone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106518635A true CN106518635A (en) | 2017-03-22 |
Family
ID=58291585
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610924744.1A Pending CN106518635A (en) | 2016-10-24 | 2016-10-24 | Synthesis method for 3-methoxypropiophenone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106518635A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456164A (en) * | 2018-11-03 | 2019-03-12 | 浙江大学 | The preparation method of isobutyrophenone |
| CN112255357A (en) * | 2020-11-20 | 2021-01-22 | 济南悟通生物科技有限公司 | Analysis method for qualitative determination of unknown impurities in m-methoxypropiophenone process by gas chromatography-mass spectrometry |
| CN113979844A (en) * | 2021-12-08 | 2022-01-28 | 山东华安新材料有限公司 | Preparation method of hexafluoroacetone |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101671245A (en) * | 2009-09-28 | 2010-03-17 | 唐保清 | Process for preparing 3-methoxypropiophenone |
| CN103664564A (en) * | 2012-09-06 | 2014-03-26 | 重庆博腾制药科技股份有限公司 | Preparation method of analgesic intermediate compound |
-
2016
- 2016-10-24 CN CN201610924744.1A patent/CN106518635A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101671245A (en) * | 2009-09-28 | 2010-03-17 | 唐保清 | Process for preparing 3-methoxypropiophenone |
| CN103664564A (en) * | 2012-09-06 | 2014-03-26 | 重庆博腾制药科技股份有限公司 | Preparation method of analgesic intermediate compound |
Non-Patent Citations (3)
| Title |
|---|
| JOHN F. CASALE，PATRICK A. HAYS: "Differentiation of 3,4-Dimethylmethcathinone (3,4-DMMC) from its Dimethyl Aryl-Positional Isomers", 《MICROGRAM JOURNAL》 * |
| LEO A. PAQUETTE 等: "Intramolecular Cyclization of Tethered Phenyl Ketones.Complementary Stereochemical Results Arising from the Indium-Promoted Ring Closure of Allyl Bromides and the Fluoride Ion-Induced Desilylation of Allylsilanes", 《J.ORG.CHEM.》 * |
| 吉卯祉等: "《有机化学》", 31 December 2002, 科学出版社 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456164A (en) * | 2018-11-03 | 2019-03-12 | 浙江大学 | The preparation method of isobutyrophenone |
| CN112255357A (en) * | 2020-11-20 | 2021-01-22 | 济南悟通生物科技有限公司 | Analysis method for qualitative determination of unknown impurities in m-methoxypropiophenone process by gas chromatography-mass spectrometry |
| CN112255357B (en) * | 2020-11-20 | 2021-12-03 | 济南悟通生物科技有限公司 | Analysis method for qualitative determination of unknown impurities in m-methoxypropiophenone process by gas chromatography-mass spectrometry |
| CN113979844A (en) * | 2021-12-08 | 2022-01-28 | 山东华安新材料有限公司 | Preparation method of hexafluoroacetone |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106518635A (en) | Synthesis method for 3-methoxypropiophenone | |
| US8198487B2 (en) | Method for lithium exchange reactions | |
| CN102304024B (en) | Method for synthesizing difluoroethanol | |
| CN101712603A (en) | Method for preparing halogenated methyl-benzaldehyde by Grignard reaction | |
| Karagoz et al. | Regio-and stereoselective synthesis of 2, 3, 5-trienoates by palladium-catalyzed alkoxycarbonylation of conjugated enyne carbonates | |
| CN108752172B (en) | Method for synthesizing hexafluoroisopropyl methyl ether | |
| CN103553884B (en) | Method for preparing trifluoromethoxybenzene | |
| CN109942393B (en) | Preparation method of 1,1, 1-trifluoroacetone | |
| CN108409802A (en) | The preparation process of one kind (S) -1- ferrocene dimethylamines | |
| CN107056590A (en) | One kind prepares and purifies the commercial run of 4,4 ' dimethoxytrityl chloromethanes | |
| CN102503794B (en) | Method for preparing fluorine-containing substituted phenyl ketone | |
| CN106365951B (en) | Prepare the recycling technique of 2- N-Propyl Bromide during 2,2- diisopropyl propionitrile | |
| CN104817444B (en) | A kind of preparation method of anisyl propionaldehyde | |
| CN109651194B (en) | Synthesis method of (E) -4-aryl-3-butenenitrile compound | |
| CN108456235B (en) | Preparation of N, N-dimethyl- (R) -1- [ (S) -2- (diphenylphosphine) ferrocenyl ] ethylamine by microreactor | |
| CN112375091A (en) | Green synthesis process of alkynol double Grignard reagent | |
| CN107118084B (en) | Method for synthesizing 1, 3-disubstituted-2-propanol by two-step method | |
| CN112724120A (en) | Method for synthesizing piperonyl chloride through continuous flow reaction | |
| CN106699527A (en) | Method for synthesizing m-chlorophenylacetone | |
| KR20150066878A (en) | Method for producing 3-mercaptopropionic acid using reactive distillation | |
| CN102344359B (en) | Method for preparing 3-butenoic acid | |
| CN108299152A (en) | A kind of synthetic method of 4- cyclopropyl biphenyl fluorochemical | |
| CN1302001C (en) | Production of o-chlorobenzyl dimethyl phosphonate | |
| CN115850232B (en) | Preparation method and application of flupentixol EP impurity H | |
| CN107721969B (en) | Preparation method of chiral catalyst ligand TADDOLs in asymmetric synthesis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170322 |