CN101121673A - Technique for synthesizing o-chloroacetaminophenol - Google Patents
Technique for synthesizing o-chloroacetaminophenol Download PDFInfo
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- CN101121673A CN101121673A CNA2007101443613A CN200710144361A CN101121673A CN 101121673 A CN101121673 A CN 101121673A CN A2007101443613 A CNA2007101443613 A CN A2007101443613A CN 200710144361 A CN200710144361 A CN 200710144361A CN 101121673 A CN101121673 A CN 101121673A
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- Prior art keywords
- chloroacetyl chloride
- aminophenol
- reaction
- chloroacetaminophenol
- yield
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 23
- KZKLPYFXZLECRJ-UHFFFAOYSA-N n-(2-chloro-3-hydroxyphenyl)acetamide Chemical compound CC(=O)NC1=CC=CC(O)=C1Cl KZKLPYFXZLECRJ-UHFFFAOYSA-N 0.000 title claims description 18
- 230000002194 synthesizing effect Effects 0.000 title 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 41
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 19
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 230000035484 reaction time Effects 0.000 claims abstract description 12
- 238000005917 acylation reaction Methods 0.000 claims abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 claims description 47
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 abstract description 6
- 238000005516 engineering process Methods 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 abstract 2
- CWDQPXOPAVMWCE-UHFFFAOYSA-N 1-(2-amino-6-hydroxyphenyl)-2-chloroethanone Chemical compound ClCC(=O)C1=C(C=CC=C1N)O CWDQPXOPAVMWCE-UHFFFAOYSA-N 0.000 abstract 2
- JIJUXAOARIMNAO-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O.NC1=CC=CC=C1O JIJUXAOARIMNAO-UHFFFAOYSA-N 0.000 abstract 1
- 229940106681 chloroacetic acid Drugs 0.000 abstract 1
- 239000000047 product Substances 0.000 description 29
- 239000002904 solvent Substances 0.000 description 13
- 239000000460 chlorine Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KDUPPIHDHQPSIS-UHFFFAOYSA-N ClCC(=O)NC1=C(C=CC=C1)O.ClCC(=O)NC1=C(C=CC=C1)O Chemical compound ClCC(=O)NC1=C(C=CC=C1)O.ClCC(=O)NC1=C(C=CC=C1)O KDUPPIHDHQPSIS-UHFFFAOYSA-N 0.000 description 1
- HQFSRZXGYXOEEE-UHFFFAOYSA-N ClOC1=C(C=CC=C1)NC(=O)C Chemical compound ClOC1=C(C=CC=C1)NC(=O)C HQFSRZXGYXOEEE-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 101000595193 Homo sapiens Podocin Proteins 0.000 description 1
- 101900297506 Human immunodeficiency virus type 1 group M subtype B Reverse transcriptase/ribonuclease H Proteins 0.000 description 1
- 102100036037 Podocin Human genes 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis technology for the o-chloroacetyl aminophenol. The specific process conditions are: the number proportion of the mol of the o-aminophenol aminophenol and the chloroacetyl chloride and the 1,2-dichloroethane is one to from 2.0 to 3.5 to from 10 to 30; the acylate reagent of the acylation reaction is the chloroacetyl chloride containing 5 to 10 percent of the chloroacetic acid; the dropping temperature of the acylate reagent is 0 to 10 Celsius system; the dropping time is 30 to 90 minutes; the reaction temperature is 45 to 85 Celsius system; the reaction time is 1 to 4 hours; the production rate of the synthesis technology for the o-chloroacetyl aminophenol can reach 70 to 92 percent.
Description
Technical field:
The present invention relates to a kind of synthesis technique of o-chloroacetaminophenol, concrete is the technology that adopts o-aminophenol and chlorine, Acetyl Chloride 98Min. acylation reaction to synthesize o-chloroacetaminophenol.
Background technology:
O-chloroacetaminophenol, chemical name: 2-chloro-N-(2-hydroxy phenyl)-ethanamide (2-chloro-N-(2-hydroxyphenyl) acetamide), it is a kind of organic raw material intermediate, can be used for synthetic intermediates such as medicine, dyestuff, material with memory and thermal transfer material, particularly having been widely used aspect the medicine of anti-AIDS, and bigger export volume is being arranged.At present, though the producer that produces o-chloroacetaminophenol is arranged in the world, the quality of product and quantity all can not satisfy market demand.Conrad R.Burkholder, William R.Dolbier Jr., Maurice
The syntheses of nonnucleoside, HIV-1 reverse transcriptase inhibitors containing a CF
2Group The SRN1 reactions of2-(bromodi-uoromethyl) benzoxazole with the anions derived from heterocyclicthiols and phenolic compounds[J] .Journal of Fluorine Chemistry; 2000; the synthetic method that 102 (1-2): 369-376 introduce is in the 50ml ethyl acetate solvent; with 5g (0.458mol) o-aminophenol and 5.18g (0.459mol) chloroacetyl chloride is that raw material carries out acylation reaction, and yield has only 59%.Wherein the dropping temperature of the dripping quantity of solvent adding amount, chloroacetyl chloride, acylting agent and reaction times are of great impact to the yield of this reaction product; and the key that influences product yield is determining of its synthesis condition; therefore, how to determine that the synthesis condition optimized is significant to the production of o-chloroacetaminophenol and relevant industry.
Summary of the invention:
Technical problem to be solved by this invention provides the synthesis technique of the high o-chloroacetaminophenol of a kind of yield.
For achieving the above object; technical solution of the present invention is: o-aminophenol: chloroacetyl chloride: 1; the mol ratio of 2-ethylene dichloride is 1: 2.0～3.5: 10～30; the acylation reaction acylating reagent is 5%～10% chloroacetic chloroacetyl chloride for containing molar percentage; 0～10 ℃ of the dropping temperature of acylating reagent; the dropping time is 30～90min, 45～85 ℃ of temperature of reaction, reaction times 1～4h.
Described o-aminophenol: chloroacetyl chloride: 1, the mol ratio of 2-ethylene dichloride is 1: 2.1: 10.
The described reaction times is 3h.
Synthesis mechanism of the present invention is that amino phenol not only contains hydroxyl but also contain amino; the nucleophilicity of phenates is greater than amino in alkaline medium; and therefore amino nucleophilie nucleus ability might make aminoacylization and keep hydroxyl greater than hydroxyl in acidic medium in neutrality or weak acidic medium.
Technique effect of the present invention is: adopt this synthesis technique to produce its productive rate of o-chloroacetaminophenol and can reach 70%～92%, existing production technique yield only is 59% high, has both adopted this synthesis technique can substitute traditional synthesis process fully.
Embodiment:
Embodiment one
Preparation earlier contains 5% chloroacetic chloroacetyl chloride C
2H
2Cl
2(molecular weight: 112.94) four parts: get chloroacetyl chloride 43.5ml (0.546mol) (Chemical Reagent Co., Ltd., Sinopharm Group) respectively, Mono Chloro Acetic Acid 1.6mL (0.027mol) mixes O.
Thermometer, electric mixer being housed and placing the 1000ml three-necked bottle of ice-water bath, add o-aminophenol C
6H
7NO (molecular weight: 109.13) 28.37g (0.26mol) (Tianjin recovery fine chemistry industry institute) and solvent 1,2-ethylene dichloride (molecular weight: 98.96 relative densities, d
20 41.250～1.256), the add-on of solvent is respectively 210ml, 315ml, 420ml, 625ml (2.6～7.8mol), and to drip the molar percentage that contains that the front prepared respectively be 5% chloroacetic chloroacetyl chloride, solution temperature remains on 0～10 ℃ in the three-necked bottle, the dropping time is 50min, slowly be warming up to 45-85 ℃ of system reflux temperature (being that the condensation mouth of pipe has drop slowly to drip) after dropwising, reaction 3h.At last reaction solution has been cooled to crystal and has separated out, suction filtration, washing, vacuum-drying obtains thick product, uses 1 then, and 2-ethylene dichloride recrystallization promptly gets the purpose product.
Table 1 quantity of solvent changes the influence to product yield
According to 4 groups of data in the table 1 as can be known, at o-aminophenol: chloroacetyl chloride: 1, under the condition of 2-ethylene dichloride=1: 2.1: 10～30 (mol ratio), the yield of purpose product is 75.6～90.2%; At o-aminophenol: chloroacetyl chloride: 1, under the condition of 2-ethylene dichloride=1: 2.1: 10 (mol ratio), the yield of purpose product is 90.2%; Under the condition of the add-on that changes solvent successively, the yield of o-chloroacetaminophenol is along with the increase of quantity of solvent as can be seen, and product yield reduces gradually.Its reason is to add excessive solvent portioned product is dissolved among the solvent.But the solvent usage quantity can not be very few, because in dripping the process of chloroacetyl chloride, quantity of solvent crosses that I haven't seen you for ages increases the viscosity of reaction solution, and very few solvent will cause stirring inhomogeneous, is unfavorable for the carrying out that reacts.In addition, solvent is crossed that I haven't seen you for ages and is caused in the crystallisation by cooling process impurity and separates out manyly, and the purity of product is low.Thereby we determine that this synthesis technique is preferably o-aminophenol: 1, and 2-ethylene dichloride=1: 10～30 (mol ratio), most preferably o-aminophenol: 1,2-ethylene dichloride=1: 10 (mol ratio).
Embodiment two
Preparation earlier contains 5% chloroacetic chloroacetyl chloride C
2H
2Cl
2O (molecular weight: 112.94) four parts: get chloroacetyl chloride 43.5ml (0.546mol), 87.0ml, 103.5ml, 145.0ml respectively, and add Mono Chloro Acetic Acid 1.6mL (0.027mol), 3.2mL (0.054mol) respectively, 3.8mL (0.064mol), 5.3mL (0.090mol) mix.
According to embodiment one described reaction conditions, in the 1000ml three-necked bottle, add o-aminophenol 56.74g (0.52mol), 1,2-ethylene dichloride 420ml (5.2mol), it is 5% chloroacetic chloroacetyl chloride that different experiments drips the molar percentage that contains that the front prepared respectively, makes that solution temperature remains on 0～10 ℃ in the three-necked bottle, and the dropping time is 1.5h, after dropwising, chloroacetyl chloride slowly is warming up to 45-85 ℃ of system reflux temperature, reaction 3h.Last handling process obtains the purpose product with embodiment 1.
Table 2 chloroacetyl chloride consumption changes the influence to product yield
According to 4 groups of data in the table 2 as can be known, at o-aminophenol: chloroacetyl chloride: 1, under the condition of 2-ethylene dichloride=1: 2.0～3.5: 10 (mol ratio), the yield of purpose product is 79.4～90.2%; At o-aminophenol: chloroacetyl chloride: 1, under the condition of 2-ethylene dichloride=1: 2.1: 10 (mol ratio), the yield of purpose product is 90.2%; Under the condition of the dripping quantity that changes chloroacetyl chloride successively, the yield of o-chloroacetaminophenol is along with the difference of chloroacetyl chloride consumption presents following variation: at o-aminophenol: chloroacetyl chloride: 1, during 2-ethylene dichloride=1: 2.1: 10 (mol ratio), the yield of o-chloroacetaminophenol is for the highest; And at o-aminophenol: chloroacetyl chloride: 1, during 2-ethylene dichloride=1: 2.5～3.5: 10 (mol ratio), the yield of o-chloroacetaminophenol reduces again gradually.Hence one can see that, in reaction process, drips an amount of chloroacetyl chloride and help the carrying out that react, and the raw material o-aminophenol is reacted completely.But too much chloroacetyl chloride not only causes the waste of raw material, changes the acidity of system, directly the carrying out of influence reaction, and in the process of later stage product treatment, be difficult for removing, dry recrystallization to product impacts, and product colour is deepened, and causes the yield of product to reduce.Thereby we determine that this synthesis technique is preferably o-aminophenol: chloroacetyl chloride=1: 2.0～3.5 (mol ratio); Most preferably be o-aminophenol: chloroacetyl chloride=1: 2.1 (mol ratio).
Embodiment three
Preparation earlier contains 10% chloroacetic chloroacetyl chloride C
2H
2Cl
2O (molecular weight: 112.94) four parts: get chloroacetyl chloride 87.0ml (1.10mol) respectively, and add Mono Chloro Acetic Acid 6.4mL (0.109mol) respectively and mix.
According to embodiment one described reaction conditions, in the 1000ml three-necked bottle, add o-aminophenol 56.74g (0.52mol), 1,2-ethylene dichloride 420ml (5.2mol), the molar percentage that contains that has prepared before dripping respectively is 10% chloroacetic chloroacetyl chloride, makes that system temperature remains between 0～30 ℃ in the three-necked bottle, and the dropping time is 1h, after dropwising, chloroacetyl chloride slowly is warming up to 45-85 ℃ of system reflux temperature, reaction 3h.Last handling process obtains the purpose product with embodiment 1.
Table 3 adds the influence of material variation of temperature to product yield
According to 4 groups of data in the table 3 as can be known, at o-aminophenol: chloroacetyl chloride: 1, under the identical condition of 2-ethylene dichloride=1: 2.1: 10 (mol ratio) and reaction times, the yield of o-chloroacetaminophenol presents following rule with the variation of charge temperature.Yield is the variation that descends gradually to the yield of o-chloroacetaminophenol along with the continuous rising of charge temperature (0～30 ℃); When reinforced temperature changes between 0～10 ℃, the yield of product changes hardly, and more helps technological operation during more near 10 ℃ when charge temperature; Just cause the increase of side reaction when charge temperature continues to raise, the purity of product is lowered, color burn, and then the yield of purpose product is reduced.Thereby we determine that the best charge temperature of this synthesis technique is 0～10 ℃.
Embodiment four
Preparation earlier contains 10% chloroacetic chloroacetyl chloride C
2H
2Cl
2O (molecular weight: 112.94) four parts: get chloroacetyl chloride 87.0ml (1.10mol) respectively, and add Mono Chloro Acetic Acid 6.4mL (0.109mol) respectively and mix.
According to embodiment one described reaction conditions, in the 1000ml three-necked bottle, add o-aminophenol 56.74g (0.52mol), 1,2-ethylene dichloride 420ml (5.2mol), the molar percentage that contains that has prepared before dripping respectively is 10% chloroacetic chloroacetyl chloride, make that solution temperature remains on 0～10 ℃ in the three-necked bottle, the dropping time is 1h.Slowly be warming up to 45-85 ℃ of system reflux temperature after chloroacetyl chloride dropwises, the reaction times is respectively 2～5h.Last handling process obtains the purpose product with embodiment 1.
Table 4 reaction times changes the influence to product yield
According to 4 groups of data in the table 4 as can be known; at feed ratio is o-aminophenol: chloroacetyl chloride: 1; during 2-ethylene dichloride=1: 2.1: 10 (mol ratio); and under the identical condition of acylation reaction temperature; the yield of o-chloroacetaminophenol makes reaction more thorough along with the proper extension of reacting by heating time, and the yield of product constantly improves.When the reaction times was 1～3h, the yield of product was along with the prolongation in reaction times improves very fast; After reaction 3 hours, the yield increase of product tends towards stability, and from the angle of producing, after the reaction times surpassed 3 hours, the consumption of the energy improved the output value of being brought much larger than the yield of product.Thereby we determine that the optimum reacting time of this synthesis technique is 3 hours.
Claims (3)
1. the synthesis technique of an o-chloroacetaminophenol; the concrete processing condition that adopted are: o-aminophenol: chloroacetyl chloride: 1; the mol ratio of 2-ethylene dichloride is 1: 2.0～3.5: 10～30; the acylation reaction acylating reagent is for containing 5%～10% chloroacetic chloroacetyl chloride; 0～10 ℃ of the dropping temperature of acylating reagent; the dropping time is 30～90min, 45～85 ℃ of temperature of reaction, reaction times 1～4h.
2. according to the synthesis technique of the described o-chloroacetaminophenol of claim 1, it is characterized in that: described o-aminophenol: chloroacetyl chloride: 1, the mol ratio of 2-ethylene dichloride is 1: 2.1: 10.
3. according to the synthesis technique of the described o-chloroacetaminophenol of claim 1, it is characterized in that: the described reaction times is 3h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007101443613A CN100569735C (en) | 2007-09-26 | 2007-09-26 | Synthetic process of o-chloroacetaminophen |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007101443613A CN100569735C (en) | 2007-09-26 | 2007-09-26 | Synthetic process of o-chloroacetaminophen |
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| Publication Number | Publication Date |
|---|---|
| CN101121673A true CN101121673A (en) | 2008-02-13 |
| CN100569735C CN100569735C (en) | 2009-12-16 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104529799A (en) * | 2014-11-26 | 2015-04-22 | 南京化学试剂有限公司 | Method for preparing (2-hydroxyphenylamino)acetyl chloride |
-
2007
- 2007-09-26 CN CNB2007101443613A patent/CN100569735C/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104529799A (en) * | 2014-11-26 | 2015-04-22 | 南京化学试剂有限公司 | Method for preparing (2-hydroxyphenylamino)acetyl chloride |
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| Publication number | Publication date |
|---|---|
| CN100569735C (en) | 2009-12-16 |
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Granted publication date: 20091216 Termination date: 20130926 |