CN1164564C - Process for preparing high purity 2-amino-5-chloro-2'-diphenyl ketone - Google Patents
Process for preparing high purity 2-amino-5-chloro-2'-diphenyl ketone Download PDFInfo
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- CN1164564C CN1164564C CNB011184752A CN01118475A CN1164564C CN 1164564 C CN1164564 C CN 1164564C CN B011184752 A CNB011184752 A CN B011184752A CN 01118475 A CN01118475 A CN 01118475A CN 1164564 C CN1164564 C CN 1164564C
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Abstract
The present invention relates to a preparation method for high-purity 2-amino-5-chlorine-2'-fluorine-benzophenone (FAB for short). The preparation method comprises that o-fluorobenzoyl chloride and parachloroanilinum are condensed at high temperature under the action of zinc chloride. The present invention which uses zinc chloride processed by low-temperature dehydration increases the yield coefficient of FAB and lowers the content of impurities, so that the yield coefficient of FAB is increased from 50 % to 70%, and product purity is increased from less than or equal to 95% to large than or equal to 98%.
Description
The present invention relates to-kind of high purity 2-amino-5-chloro-2 '-preparation method of fluoro-benzophenone.Belong to field of chemical technology.
2-amino-5-chloro-2 '-the fluoro-benzophenone, be called for short FAB, be the intermediate of preparation anxiolytic Dormicum, flutazolam, Dalmadorm.In the prior art, FAB can be by o-fluoro-benzoyl chloride and p-Chlorobenzoic acid amide condensation prepared, and its reaction formula is as follows:
The yield of product is 50%, and fusing point is 88-92 ℃, HPLC content≤95%, and quality does not reach HPLC content 〉=98%, and fusing point is 94-97 ℃ the requirement as intermediate.
The inventor is through testing the back discovery repeatedly and facts have proved, in this reaction, the quality of zinc chloride is the key factor of decision reaction yield and quality product.Zinc chloride can dewater under the effect of vacuum and dewatering agent at a lower temperature.Usually, the zinc chloride that normal pressure (＞180 ℃) dehydration makes is lead, is blocks of solid, is unfavorable for dissolving under reaction conditions, causes product yield low, and by product is many, and the acidifying of aftertreatment is consuming time longer.
Therefore, the object of the present invention is to provide a kind of under the effect of zinc chloride, pyrocondensation prepare 2-amino-5-chloro-2 '-method of fluoro-benzophenone, to improve yield and the product purity of FAB, make it to reach above-mentioned requirements.
The present invention is by the following technical solutions:
The preparation method of FAB is characterized in that: the ZnCl that uses low temperature dewatering
2Being reagent, is raw material with o-fluoro-benzoyl chloride and p-Chlorobenzoic acid amide, and the proportioning of raw material (mass ratio) is: p-Chlorobenzoic acid amide/ZnCl
2/ o-fluoro-benzoyl chloride=1: 0.5～10: 1～10 temperature of reaction are at 100～350 ℃, and the reaction times was at 0.2～10 hour.
The ZnCl of described low temperature dewatering
2, being meant temperature between 40～200 ℃, vacuum tightness is at 0.01mmHg～100mmHg, and the zinc chloride for preparing under the condition that dewatering agent exists, and dehydration was finished at 1～20 hour.
Dewatering agent means Vanadium Pentoxide in FLAKES, the vitriol oil, strong phosphoric acid, molecular sieve, KOH or silica gel etc.
The preparation of FAB is divided into that condensation, acidolysis, ice are separated, crystallization, oven dry do not have individual step.Condensation reaction is a committed step.
Particularly, p-Chlorobenzoic acid amide and o-fluoro-benzoyl chloride are pressed aforementioned ratio, between 100～350 ℃, reacted 0.2～10 hour, under this temperature, the zinc chloride that adds low temperature dewatering by aforementioned ratio, and continue reaction 0.2～10 hour, and be cooled between 60～160 ℃, add dilute sulphuric acid, carry out acidolysis, refluxed 1 hour, and after the cooling, reaction solution was poured in a large amount of ice, ice and separate, by adding NaOH, transferring solution is alkalescence, and FAB just is precipitated out, after the drying, obtain the crude product of FAB, after recrystallizing methanol, obtain high purity FAB.
Zinc chloride can be under the effect of vacuum and dewatering agent, dehydration at a lower temperature, usually, the zinc chloride that constant-pressure and high-temperature (＞180 ℃) dehydration makes is lead, is blocks of solid, be unfavorable under reaction conditions, dissolving, cause product yield low, by product is many, and the acidifying of aftertreatment is consuming time longer.
By o-fluoro-benzoyl chloride and p-Chlorobenzoic acid amide, under the effect of zinc chloride, pyrocondensation prepares FAB, use the zinc chloride of low temperature dewatering processing, can improve the yield of FAB, be increased to 70% by 50%, product purity by≤95% be increased to 〉=98%, see also the quality product comparison sheet:
Table 1. quality product synopsis
| Project | Prior art | The present invention |
| Fusing point | 88-92℃ | 94-97℃ |
| HPLC content | ≤95％ | ≥98％ |
| Total recovery | 50％ | 70％ |
The invention will be further described below in conjunction with embodiment:
Embodiment 1: the preparation of low temperature dewatering zinc chloride:
With 100 gram technical grade zinc chloride (5mmHg) under vacuum, be heated to 160 ℃, under agitation be incubated 6 hours, the moisture that steams absorbs with an amount of Vanadium Pentoxide in FLAKES, obtains about 80 gram white powder zinc chloride.
The preparation method of embodiment 2:FAB:
In 2 liters reaction flask, add o-fluoro-benzoyl chloride 280 grams, p-Chlorobenzoic acid amide 100 grams, under 200 ℃, stirred 2 hours, and added 150 gram Zinc Chloride Anhydrouss again, reacted 2 hours, be cooled to 150 ℃, add (20%) 1 liter of dilute sulphuric acid again, refluxed 1 hour, be chilled to room temperature, pour in 1 kg of ice, transfer to weakly alkaline with NaOH solution, FAB is precipitated out, and filters, use the 500ml water washing, dry crude product FAB, behind 300ml water heating for dissolving FAB crude product, crystallisation by cooling, filtering drying obtains 70 gram high purity FAB.
Claims (3)
1, a kind of 2-amino-5-chloro-2 '-preparation method of fluoro-benzophenone, it is characterized in that: with the ZnCl that dewaters in the 40-200 ℃ of scope
2Being reagent, is raw material with o-fluoro-benzoyl chloride and p-Chlorobenzoic acid amide, raw materials quality ratio: p-Chlorobenzoic acid amide: ZnCl
2: o-fluoro-benzoyl chloride is 1: 0.5～10: 1～10, and temperature of reaction is at 100～350 ℃, 0.2～10 hour reaction times.
2,2-amino according to claim 1-5-chloro-2 '-preparation method of fluoro-benzophenone, it is characterized in that: described zinc chloride is meant that temperature is between 40-200 ℃, vacuum tightness is at 0.01mmHg～100mmHg, and the zinc chloride that under the condition that dewatering agent exists, prepares, dehydration was finished at 1～20 hour.
3, high purity 2-amino according to claim 1-5-chloro-2 '-preparation method of fluoro-benzophenone, it is characterized in that: dewatering agent means Vanadium Pentoxide in FLAKES, the vitriol oil, strong phosphoric acid, molecular sieve, KOH or silica gel.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011184752A CN1164564C (en) | 2001-06-01 | 2001-06-01 | Process for preparing high purity 2-amino-5-chloro-2'-diphenyl ketone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011184752A CN1164564C (en) | 2001-06-01 | 2001-06-01 | Process for preparing high purity 2-amino-5-chloro-2'-diphenyl ketone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1326924A CN1326924A (en) | 2001-12-19 |
| CN1164564C true CN1164564C (en) | 2004-09-01 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB011184752A Expired - Fee Related CN1164564C (en) | 2001-06-01 | 2001-06-01 | Process for preparing high purity 2-amino-5-chloro-2'-diphenyl ketone |
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| CN (1) | CN1164564C (en) |
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2001
- 2001-06-01 CN CNB011184752A patent/CN1164564C/en not_active Expired - Fee Related
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| CN1326924A (en) | 2001-12-19 |
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