CN104529736A - Preparation method of p-fluorophenyl butanone - Google Patents
Preparation method of p-fluorophenyl butanone Download PDFInfo
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- CN104529736A CN104529736A CN201410782007.3A CN201410782007A CN104529736A CN 104529736 A CN104529736 A CN 104529736A CN 201410782007 A CN201410782007 A CN 201410782007A CN 104529736 A CN104529736 A CN 104529736A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
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- 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
- C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
- C07C45/54—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition of compounds containing doubly bound oxygen atoms, e.g. esters
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Abstract
The invention provides a preparation method of p-fluorophenyl butanone. The preparation method comprises the following steps: dissolving p-fluorobenzoic acid, carbonyldiimidazole and N,O-dimethylhydroxylamine hydrochloride into a solvent, adding triethylamine, and reacting for 24-48 hours at room temperature to obtain 4-fluoro-N-methoxy-N-methyl benzoyl amide; and then dissolving obtained 4-fluoro-N-methoxy-N-methyl benzoyl amide by using the solvent, adding n-propyl magnesium chloride or n-propyl magnesium bromide or n-propyl lithium to react, and performing purification to obtain p-fluorophenyl butanone. The preparation method of p-fluorophenyl butanone provided by the invention is mild in condition, is suitable for industrial production, and is relatively high in yield.
Description
Technical field
The present invention relates to medical synthesis technical field, particularly relate to the preparation method of p fluorophenyl propyl ketone.
Background technology
P fluorophenyl propyl ketone is the intermediate producing antipsychotic drug haloperidol, tranquilizer fluorine resources, and is the important intermediate during pharmaceuticals synthesis transforms, and applies extremely extensive.Its synthesis at present has two kinds of methods, and a kind of method take fluorobenzene as raw material, under lewis acidic catalysis, reacts and obtain with n-butyryl chloride, though this method is simple, but can produce ortho position and a position by product, bring difficulty to purified product; Another kind method take parafluorobenzoic acid as raw material, under catalyst action, with butanic acid at high temperature condensation reaction, after reacting completely, then rise to 280 DEG C and carry out decarboxylation, then obtain p fluorophenyl propyl ketone, this method is at high temperature carried out, and energy consuming ratio is comparatively large, brings difficulty to suitability for industrialized production.
Summary of the invention
The invention provides a kind of preparation method of p fluorophenyl propyl ketone, mild condition, be applicable to suitability for industrialized production, and yield is higher.
Technological process of the present invention is as follows:
Step one, is dissolved in solvent by parafluorobenzoic acid, carbonyl dimidazoles, N, O-dimethyl hydroxylamine hydrochloride, adds triethylamine, react 24-48 hour under room temperature, obtains 4-fluoro-N-methoxy-. N-methyl benzamide.
Step 2, by the 4-fluoro-N-methoxy-. N-methyl benzamide dissolution with solvents obtained, adds n-propyl magnesium chloride or n-propyl magnesium bromide or n-propyl lithium and reacts, purified, obtains p fluorophenyl propyl ketone.
Operational path is as follows:
In formula, A is n-propyl magnesium chloride or n-propyl magnesium bromide or n-propyl lithium.
Further, described in step one is 1:1 ~ 2:1 ~ 2:1.2 ~ 2.4 to fluorinated acid, carbonyl dimidazoles, N, O-dimethyl hydroxylamine and triethylamine molar ratio.
Further, solvent described in step one is methylene dichloride or DMF.
Further, the fluoro-N-methoxy-. N-methyl benzamide of the 4-described in step 2 and n-propyl magnesium chloride or n-propyl magnesium bromide or n-propyl lithium molar ratio are 1:1 ~ 1.5.
Further, the solvent described in step 2 is anhydrous tetrahydro furan or anhydrous diethyl ether.
Further, the reaction described in step 2 is carried out at temperature is-30 ~ 0 DEG C.
Beneficial effect of the present invention: the preparation method of a kind of p fluorophenyl propyl ketone provided by the present invention, selects parafluorobenzoic acid as reaction substrate, reacts under room temperature or lesser temps, energy consumption is little, mild condition, is applicable to suitability for industrialized production, and yield is higher, purify simple.
Embodiment
In order to make object of the present invention, technical scheme and advantage clearly understand, the following specific embodiment of the present invention is described further technical scheme of the present invention.
Embodiment 1, step one, under room temperature, by parafluorobenzoic acid (50g, 0.357mol, 1eq), carbonyl dimidazoles (92.6 g, 0.571mol, 1.7eq), N, O-dimethyl hydroxylamine hydrochloride (52.2g, 0.571mol, 1.7eq) insert in three mouthfuls of reaction flasks and add DMF(150ml) dissolve, then, slowly add triethylamine (100ml, 0.714mol, 2eq), stirred at ambient temperature more than 24 hours, react completely, in reaction solution, add 450 ml dilute hydrochloric acid adjust PH to 3-5, with ethyl acetate (200ml χ 3) extraction three times, merge three extraction organic solutions, an organic layer is washed with 1N aqueous sodium hydroxide solution, and then wash three organic layers with water, each 50ml χ 3, last salt is washed, dry, when being concentrated into 1/5 solvent, crystallizing from ether is added under lesser temps, dry, obtain 4-fluoro-N-methoxy-. N-methyl benzamide 58g, yield is 89.2%, record purity HPLC content and be greater than 97%, without the need to being further purified, next step can be directly used in.
Step 2, under nitrogen protection, by fluoro-for 4-N-methoxy-. N-methyl benzamide (58g, 0.317 mol, 1eq) insert in 1000 ml, tri-mouthfuls of reaction flasks, add 200ml anhydrous tetrahydro furan to dissolve, after dissolving, when being cooled to-30 ~-20 DEG C, slow instillation n-propyl magnesium chloride (2mol/L tetrahydrofuran solution, 190 ml, 0.38 mol, 1.2eq), careful temperature control, instill complete, reaction is monitored by the mode of thin plate chromatography, after raw material reaction, stop immediately, also promptly stir in slow for reaction solution impouring frozen water, strict temperature control is below 0 DEG C, prevent grignard reagent from reacting further, a large amount of by product is caused to generate, after cancellation, add a small amount of diatomite, suction filtration, filtrate is extracted with ethyl acetate three times, each 200ml, merge organic layer, wash an organic layer with water, then wash once with salt, each 50 ml, then, dry, concentrated, by the concentrated liquid obtained, add a small amount of ethyl acetate, then zero degree is cooled the temperature to, add ether, rapid stirring, treat that a large amount of solid is separated out, suction filtration, obtain yellow solid 45.6g, yield 86.7%.
Embodiment 2 step one, under room temperature, by parafluorobenzoic acid (3 kg, 21.43 mol, 1eq), carbonyl dimidazoles (4.1 kg, 25.7mol, 1.2eq), N, O-dimethyl hydroxylamine hydrochloride (2.49 kg, 25.7 mol, 1.2eq) insert in 100L reactor and add methylene dichloride (50 L) dissolving, then, slowly add triethylamine (2.8 kg, 27.6mol, 1.3eq), stirred at ambient temperature more than 24 hours, thin plate chromatography monitoring reaction, after reacting completely, in reaction solution, add dilute hydrochloric acid adjust PH to 3-5, then layering, water layer methylene dichloride (5 L χ 3) extraction three times, merge all organic solution, an organic layer is washed with 1N aqueous sodium hydroxide solution, and then wash an organic layer with water, last salt is washed, dry, concentrate after doing, with acetic acid ethyl dissolution and then when being concentrated into 1/5 solvent, normal hexane crystallization is added under lesser temps, dry, obtain 4-fluoro-N-methoxy-. N-methyl benzamide 3.78 kg, yield is 96.9%, record purity HPLC content and be greater than 98%, without the need to being further purified, next step can be directly used in.
Step 2, under nitrogen protection, by fluoro-for 4-N-methoxy-. N-methyl benzamide (3.78 kg, 20.65 mol, 1eq) insert in 100L reactor, add 50 L anhydrous tetrahydro furans to dissolve, after dissolving, when being cooled to-20 ~-10 DEG C, slow instillation n-propyl magnesium chloride (4mol/L tetrahydrofuran solution, 5.93 L, 23.74mol, 1.15eq), careful temperature control, instill complete, reaction is monitored by the mode of thin plate chromatography, after raw material reaction, stop immediately, by in another frozen water reactor of slow for reaction solution negative pressure mode suction, and enter in reacting kettle jacketing with condensing agent, and promptly stir, strict control inside center temperature is below 0 DEG C, prevent grignard reagent from reacting further, a large amount of by product is caused to generate, after cancellation, suction filtration, filtrate is extracted with ethyl acetate three times, each 5 L, merge organic layer, wash an organic layer with water, then wash once with salt, each 1 L of volume, then, dry, concentrated, by the concentrated liquid obtained, add a small amount of ethyl acetate, then zero degree is cooled the temperature to, add normal hexane, rapid stirring, treat that a large amount of solid is separated out, suction filtration, filtrate collection is also crossed post, obtain micro-yellow solid 3.15 kg, yield 92.6%.
Above-described embodiment is only in order to illustrate technical scheme of the present invention but not to limit design of the present invention and protection domain; those of ordinary skill of the present invention is modified to technical scheme of the present invention or equivalent replacement; and not departing from aim and the scope of technical scheme, it all should be encompassed in right of the present invention.
Claims (6)
1. a preparation method for p fluorophenyl propyl ketone, is characterized in that, comprises the following steps:
Step one, is dissolved in solvent by parafluorobenzoic acid, carbonyl dimidazoles, N, O-dimethyl hydroxylamine hydrochloride, adds triethylamine, react 24-48 hour under room temperature, obtains 4-fluoro-N-methoxy-. N-methyl benzamide;
Step 2, by the 4-fluoro-N-methoxy-. N-methyl benzamide dissolution with solvents obtained, adds n-propyl magnesium chloride or n-propyl magnesium bromide or n-propyl lithium and reacts, purified, obtains p fluorophenyl propyl ketone;
Operational path is as follows:
In formula, A is n-propyl magnesium chloride or n-propyl magnesium bromide or n-propyl lithium.
2. the preparation method of a kind of p fluorophenyl propyl ketone according to claim 1, is characterized in that,
Parafluorobenzoic acid described in step one: carbonyl dimidazoles: N, O-dimethyl hydroxylamine hydrochloride: triethylamine molar ratio is 1:1 ~ 2:1 ~ 2:1.2 ~ 2.4.
3. the preparation method of a kind of p fluorophenyl propyl ketone according to claim 1, is characterized in that, solvent described in step one is methylene dichloride or DMF.
4. the preparation method of a kind of p fluorophenyl propyl ketone according to claim 1, is characterized in that,
Described 4-fluoro-N-methoxy-. N-methyl benzamide and n-propyl magnesium chloride or n-propyl magnesium bromide or n-propyl lithium molar ratio are 1:1 ~ 1.5.
5. the preparation method of a kind of p fluorophenyl propyl ketone according to claim 1, is characterized in that, the solvent described in step 2 is anhydrous tetrahydro furan or anhydrous diethyl ether.
6. the preparation method of a kind of p fluorophenyl propyl ketone according to claim 1, is characterized in that,
Reaction described in step 2 is carried out at temperature is-30 ~ 0 DEG C.
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| CN201410782007.3A CN104529736A (en) | 2014-12-18 | 2014-12-18 | Preparation method of p-fluorophenyl butanone |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106810524A (en) * | 2017-02-10 | 2017-06-09 | 万全万特制药（厦门）有限公司 | The preparation method of escitalopram process contaminants |
| CN109553517A (en) * | 2018-12-03 | 2019-04-02 | 苏州杉洋新材料有限公司 | The preparation method of 3,7- diethyl nonane -4,6- diketone |
| CN110343134A (en) * | 2019-08-04 | 2019-10-18 | 张震 | A kind of preparation method of bis- (2,4,6- trimethylbenzoyl) phenyl phosphine oxides of photoinitiator |
-
2014
- 2014-12-18 CN CN201410782007.3A patent/CN104529736A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106810524A (en) * | 2017-02-10 | 2017-06-09 | 万全万特制药（厦门）有限公司 | The preparation method of escitalopram process contaminants |
| CN109553517A (en) * | 2018-12-03 | 2019-04-02 | 苏州杉洋新材料有限公司 | The preparation method of 3,7- diethyl nonane -4,6- diketone |
| CN110343134A (en) * | 2019-08-04 | 2019-10-18 | 张震 | A kind of preparation method of bis- (2,4,6- trimethylbenzoyl) phenyl phosphine oxides of photoinitiator |
| CN110343134B (en) * | 2019-08-04 | 2022-03-15 | 张震 | Preparation method of photoinitiator bis (2,4, 6-trimethylbenzoyl) phenylphosphine oxide |
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Application publication date: 20150422 |