CN106242957A - A kind of preparation method of 2 bromine 3 ' methoxyacetophenones - Google Patents
A kind of preparation method of 2 bromine 3 ' methoxyacetophenones Download PDFInfo
- Publication number
- CN106242957A CN106242957A CN201610616400.4A CN201610616400A CN106242957A CN 106242957 A CN106242957 A CN 106242957A CN 201610616400 A CN201610616400 A CN 201610616400A CN 106242957 A CN106242957 A CN 106242957A
- Authority
- CN
- China
- Prior art keywords
- reaction
- preparation
- methoxyacetophenone
- bromo
- sulphuric acid
- 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
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- 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
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to the preparation method of a kind of medicine intermediate, be specifically related to the preparation method of a kind of 2 bromine 3 ' methoxyacetophenones.The preparation method that the present invention uses, with 1-Phenylethanone., dimethyl sulfate and bromating agent as primary raw material, through nitrification, reduction, diazotising, hydrolyzes, methylates and the step such as bromination reaction prepares target product.The advantage of the preparation method that the present invention provides is, each step reaction yield is all more than 80%, and the purity of gained target product 2 bromine 3 ' methoxyacetophenone is up to 99.2%, and it has the advantages such as low cost, productivity is high, purity is good.In preparation process, reaction condition is gentle, and simple to operate, the harm to environment is little, and this preparation method is applicable to large-scale production.
Description
Technical field
The present invention relates to the preparation method of a kind of medicine intermediate, be specifically related to a kind of bromo-3 '-methoxyacetophenone of 2-
Preparation method.
Background technology
Phenylephrine hydrochloride (Phenylephedrine Hydrochloride), has another name called neophryn or hydrochloric acid deoxygenates kidney
Upper parathyrine, for α type adrenergic receptor stimulant.It mainly increases peripheral vascular resistance, and local vascular is had contraction,
Blood pressure is made to raise；In anaesthesia process, compared with lidocaine hydrochloride, asking when can shorten induction of anesthesia, anaesthetic effect is good, consumption
Few, relative side effect just reduces；Being also used for supraventricular tachycardia and mydriasis inspection etc., this product all has relatively in these fields
Big market prospect.The bromo-3 '-methoxyacetophenone of 2-is the key intermediate preparing phenylephrine hydrochloride.In prior art
The preparation method of the bromo-3 '-methoxyacetophenone of 2-exists that productivity is low, cost is high, severe reaction conditions, environmental pollution are big, operation
Many deficiencies such as complexity.
Summary of the invention
For deficiency of the prior art, the technical problem to be solved is to provide a kind of bromo-3 '-methoxyl group of 2-
The preparation method of 1-Phenylethanone..
The technical scheme is that the preparation side of a kind of bromo-3 '-methoxyacetophenone of 2-
Method, it is characterised in that comprise the steps:
S1. nitration reaction: at-10～-5 DEG C, drops to obtain in concentrated sulphuric acid mixed solution, to described mixing by 1-Phenylethanone.
Solution drip nitrating agent and keep reaction temperature below-10 DEG C, dripping complete and fully after reaction, be stirred vigorously lower will be anti-
Answering liquid to be poured in trash ice, have solid to separate out, sucking filtration, frozen water wash, are dried, and obtain yellow crystalline powder 3-nitro-acetophenone；
S2. reduction reaction: put into by iron powder in the dilute hydrochloric acid solution that mass fraction is 4-10%, is stirred vigorously lower to above-mentioned
Putting into 3-nitro-acetophenone prepared by S1 in solution, 3-nitro-acetophenone is (0.3～0.5) with the mol ratio of iron powder: 1.6, returns
Stream stirring, is fully cooled to room temperature after reaction, filter, filtrate with ammonia regulation to neutral, filter, wash, be dried and to obtain 3-amino
1-Phenylethanone.；Wherein the mass conversion of the 3-nitro-acetophenone that the amount of the material of 3-nitro-acetophenone is prepared via S1 obtains, and i.e. makes
The intermediate product obtained during Bei is all considered to as pure substance (being can determine whether by fusing point), following during be all such.
S3. diazotising and hydrolysis: concentrated sulphuric acid dilute with water also adds 3-prepared by S2 at 45～50 DEG C in it
Aminoacetophenone, is incubated and is sufficiently stirred for and to obtain mixed liquor, drips sodium nitrite aqueous solution, dropping at 0～5 DEG C in described mixed liquor
After, adding appropriate carbamide, insulation carries out diazo-reaction 0.5-1h, its Sodium Nitrite, carbamide and 3-aminoacetophenone
Mass ratio be (70～80): (2～4): 135, after having reacted, reactant liquor is joined by dimethylbenzene, water and concentrated sulphuric acid according to
(300～400): (80～100): in the hydrolyzed solution that the mass ratio of 16 mixes, are warming up to 90 DEG C of hydrolysis carried out above,
Backflow 2～3h, hydrolysis is cooled to 10～15 DEG C after completing, be incubated and be sufficiently stirred for, and filters, washes, is dried faint yellow
Powder 3-hydroxy acetophenone；
S4. methylation reaction: add dimethyl sulfate and the 3-for preparing of S3 that mol ratio is 1.5～2:1 in the reactor
Hydroxy acetophenone, control temperature 50～60 DEG C, add alkali liquor regulation reactant liquor pH to 8～9, insulation reaction 2～3h, course of reaction
In persistently add described alkali liquor and make reactant liquor pH maintain 8～9, after having reacted, faint yellow fraction 3-methoxyl group is collected in distillation
1-Phenylethanone.；
S5. bromination reaction: the mass ratio according to 230～260:200～230:150 adds NBS, acetic acid second in reactor
3-methoxyacetophenone prepared by ester and S4 is also sufficiently mixed, room temperature reaction 3～4h, is continuously added into alkali liquor to instead in course of reaction
The hydrogen bromide that should produce absorbs, and steams ethyl acetate after completion of the reaction, adds water in remaining reactant liquor, has solid to analyse
Go out, filter, be dried, re-crystallizing in ethyl acetate, obtain the bromo-3 '-methoxyacetophenone of pale yellow powder 2-.
The concrete reaction scheme of above-mentioned preparation method is as follows:
On the basis of technique scheme, the present invention can also have the most specifically chosen following or optimized choice.
Preferably, the nitrating agent in step S1 is prepared by fully mixing according to the mass ratio of 4:3 by concentrated sulphuric acid and fuming nitric aicd.
Preferably, described nitrating agent is (350～400) with the mass ratio of described 1-Phenylethanone.: 120.
Concrete, the iron powder in step S2 is (3～4) with the mol ratio of HCl in dilute hydrochloric acid: 1.
Concrete, concentrated sulphuric acid described in step S3 is 270:(550～650 with the mass ratio of its thinned water), described 3-
Aminoacetophenone is 1:(2～3 with the mass ratio of described concentrated sulphuric acid).
Preferably, in the sodium nitrite aqueous solution described in step S3, the mass fraction of sodium nitrite is 25～35%.
Concrete, the alkali liquor in step S4 and S5 is ammonia or sodium hydrate aqueous solution.
Concrete, the mass fraction of described concentrated sulphuric acid is 98%.
Compared with prior art, the invention has the beneficial effects as follows:
(1) present invention use preparation method with 1-Phenylethanone., dimethyl sulfate and bromating agent as primary raw material, through nitrification,
Reduction, diazotising, hydrolyzing, methylate and bromination reaction prepares target product, raw material is easy to get and relative low price, respectively walks reaction
Productivity the most all more than 80%, the purity of the final bromo-3 '-methoxyacetophenone of 2-prepared can reach 99.2%, with existing
Having technology to compare, it has the advantages such as low cost, productivity is high, purity is good；
(2), in the preparation method that the present invention provides, 3-aminoacetophenone obtains 3-hydroxy benzenes through diazotising and hydrolysis
Ethyl ketone, when diazo-reaction in addition to adding sodium nitrite in aqueous solution, the most additionally adds appropriate carbamide, and it can ensure weight
Nitridation reaction carry out more quickly and thoroughly, make the productivity of 3-hydroxy acetophenone effectively improve；
(3), in the preparation method that the present invention provides, the most relatively mild and each step of the reaction condition of each step is to workman
Production operation skill set requirements the highest, the harm to environment is little, avoids using inflammable, explosive or hypertoxic chemical solution in preparation process
Agent, this preparation method is applicable to large-scale industrial production.
Detailed description of the invention
Being described in further detail the present invention below in conjunction with specific embodiment, example is served only for explaining this
Bright, it is not intended to limit the scope of the present invention.
In following embodiment, method therefor is conventional method as specified otherwise, and medicine used is as specified otherwise
Commercially available prod.
Embodiment 1
The preparation method of a kind of bromo-3 '-methoxyacetophenone of 2-, it is characterised in that comprise the steps:
S1. nitration reaction: at-10～-5 DEG C, adding 350g mass fraction in reactor is the concentrated sulphuric acid of 98%, drips
Add the 1-Phenylethanone. of 120g (1mol), nitrating agent (200g concentrated sulphuric acid and 150g fuming nitric aicd mix) is added drop-wise to lentamente
State in reactor, and keep reaction temperature below-10 DEG C, drip complete and stir 20min and make reaction complete, being stirred vigorously
Lower reactant liquor is poured in 1000g trash ice, has a large amount of solid to separate out, the washing of sucking filtration, frozen water, be dried, obtain yellow crystalline powder 3-
Nitro-acetophenone 132.3g, yield is 80.2%, and its fusing point is 76-78 DEG C after tested；
S2. reduction reaction: in the reactor, adds 90g (1.6mol) iron powder and dilute hydrochloric acid (the concentrated hydrochloric acid 50g of 37.5%
Mixing with 400g water, the mass fraction of dilute hydrochloric acid is 4.2%), it is stirred vigorously lower input 82.5g in above-mentioned solution
(0.5mol) 3-nitro-acetophenone prepared by S1, is cooled to room temperature, filtration, filtrate ammonia after return stirring, fully reaction
Regulation to neutral, filter, wash, be dried and to obtain 3-aminoacetophenone 57g, yield is 84.5%, and its fusing point is 97-99 after tested
℃；
S3. diazotising and hydrolysis: in the reactor, add 590g water, dropping 270g mass fraction be 98% dense
Sulphuric acid, controls temperature and adds 3-aminoacetophenone 135g (1mol) prepared by S2, insulated and stirred at 45～50 DEG C in it
0.5h, control temperature is at 0～5 DEG C, and (sodium nitrite 77g and 190g water are formulated, and mass fraction is for dropping sodium nitrite aqueous solution
28.8%, all drip off), after dropping, adding 2.8g carbamide, insulation carries out diazo-reaction 0.5h, will after having reacted
Reactant liquor joins (380g dimethylbenzene, 80g water and the dense sulfur of 16g in the hydrolyzed solution mixed by dimethylbenzene, water and concentrated sulphuric acid
Acid), it is warming up to 90 DEG C of reactions that are hydrolyzed, has nitrogen to release, reflux 2h, and hydrolysis is cooled to 10～15 DEG C after completing, and protects
Temperature stirring 0.5h, filters, washes, is dried to obtain pale yellow powder 3-hydroxy acetophenone 120g, and yield is 88.3%, and it melts after tested
Point is for 95-98 DEG C；
S4. methylation reaction: add 189g (1.5mol) dimethyl sulfate in the reactor and be prepared by 136g (1mol) S3
3-hydroxy acetophenone, control temperature 50～60 DEG C, add appropriate ammoniacal liquor regulation reactant liquor pH to 8～9, insulation reaction 2～3h,
Persistently adding described ammoniacal liquor in course of reaction makes reactant liquor pH maintain 8～9, and after having reacted, faint yellow fraction is collected in distillation
3-methoxyacetophenone 125.4g, standard atmosphere pressure, testing its boiling point is 240 DEG C, and yield is 83.5%；
S5. bromination reaction: in the reactor, adds 230g (1.3mol) NBS (N-bromo-succinimide), 200g acetic acid
3-methoxyacetophenone prepared by ethyl ester and 150g S4 is also sufficiently mixed, room temperature reaction 3h, the hydrogen bromide sodium hydroxide of generation
Solution absorbs, and reaction is finished, and steams ethyl acetate, is then added to the water by reactant liquor, has solid to separate out, filters, is dried slightly
Product, obtain pale yellow powder 2-bromo-3 '-methoxyacetophenone 173.1g by re-crystallizing in ethyl acetate, and yield is 75.6%, after tested
Its fusing point is 64～66 DEG C, and content is 99.2% (HPLC).
Embodiment 2
The preparation method of a kind of bromo-3 '-methoxyacetophenone of 2-, it is characterised in that comprise the steps:
S1. nitration reaction: at-10～-5 DEG C, adding 300g mass fraction in reactor is the concentrated sulphuric acid of 98%, drips
Add the 1-Phenylethanone. of 120g (1mol), nitrating agent (228g concentrated sulphuric acid and 171g fuming nitric aicd mix) is added drop-wise to lentamente
State in reactor, and keep reaction temperature below-10 DEG C, drip complete and stir 20min and make reaction complete, being stirred vigorously
Lower reactant liquor is poured in 1000g trash ice, has a large amount of solid to separate out, the washing of sucking filtration, frozen water, be dried, obtain yellow crystalline powder 3-
Nitro-acetophenone 135.5g, yield is 82.1%, and its fusing point is 76-78 DEG C after tested；
S2. reduction reaction: in the reactor, adds 90g (1.6mol) iron powder and dilute hydrochloric acid (the concentrated hydrochloric acid 80g of 37.5%
The mass fraction mixing dilute hydrochloric acid with 350g water is 7.0%), it is stirred vigorously lower input 66.1g in above-mentioned solution
(0.4mol) 3-nitro-acetophenone prepared by S1, is cooled to room temperature, filtration, filtrate ammonia after return stirring, fully reaction
Regulation to neutral, filter, wash, be dried and to obtain 3-aminoacetophenone 45g, yield is 83.2%, and its fusing point is 97-99 after tested
℃；
S3. diazotising and hydrolysis: in the reactor, add 550g water, dropping 300g mass fraction be 98% dense
Sulphuric acid, controls temperature and adds 3-aminoacetophenone 135g (1mol) prepared by S2, insulated and stirred at 45～50 DEG C in it
0.5h, control temperature is at 0～5 DEG C, and (sodium nitrite 70g and 200g water are formulated, and mass fraction is for dropping sodium nitrite aqueous solution
25.9%, all drip off), after dropping, adding 4.0g carbamide, insulation carries out diazo-reaction 0.5h, will after having reacted
Reactant liquor joins (300g dimethylbenzene, 85g water and the dense sulfur of 16g in the hydrolyzed solution mixed by dimethylbenzene, water and concentrated sulphuric acid
Acid), it is warming up to 90 DEG C of reactions that are hydrolyzed, has nitrogen to release, reflux 2h, and hydrolysis is cooled to 10～15 DEG C after completing, and protects
Temperature stirring 0.5h, filters, washes, is dried to obtain pale yellow powder 3-hydroxy acetophenone 110g, and yield is 80.9%, and it melts after tested
Point is for 95-98 DEG C；
S4. methylation reaction: add 214.2g (1.7mol) dimethyl sulfate and 136g (1mol) S3 system in the reactor
Standby 3-hydroxy acetophenone, controls temperature 50～60 DEG C, adds appropriate ammoniacal liquor regulation reactant liquor pH to 8～9, insulation reaction 2～
3h, persistently adds described ammoniacal liquor and makes reactant liquor pH maintain 8～9 in course of reaction, after having reacted, faint yellow evaporating is collected in distillation
Dividing 3-methoxyacetophenone 120.6g, standard atmosphere is depressed, and testing its boiling point is 240 DEG C, and yield is 80.3%；
S5. bromination reaction: in the reactor, adds 245g (1.4mol) NBS (N-bromo-succinimide), 215g acetic acid
3-methoxyacetophenone prepared by ethyl ester and 150g S4 is also sufficiently mixed, room temperature reaction 3h, the hydrogen bromide sodium hydroxide of generation
Solution absorbs, and reaction is finished, and steams ethyl acetate, is then added to the water by reactant liquor, has solid to separate out, filters, is dried slightly
Product, obtain pale yellow powder 2-bromo-3 '-methoxyacetophenone 182.1g by re-crystallizing in ethyl acetate, and yield is 79.5%, after tested
Its fusing point is 64～66 DEG C, and content is 99.1% (HPLC).
Embodiment 3
The preparation method of a kind of bromo-3 '-methoxyacetophenone of 2-, it is characterised in that comprise the steps:
S1. nitration reaction: at-10～-5 DEG C, adding 400g mass fraction in reactor is the concentrated sulphuric acid of 98%, drips
Add the 1-Phenylethanone. of 120g (1mol), nitrating agent (220g concentrated sulphuric acid and 165g fuming nitric aicd mix) is added drop-wise to lentamente
State in reactor, and keep reaction temperature below-10 DEG C, drip complete and stir 20min and make reaction complete, being stirred vigorously
Lower reactant liquor is poured in 1000g trash ice, has a large amount of solid to separate out, the washing of sucking filtration, frozen water, be dried, obtain yellow crystalline powder 3-
Nitro-acetophenone 133.8g, yield is 81.1%, and its fusing point is 76-78 DEG C after tested；
S2. reduction reaction: in the reactor, adds 90g (1.6mol) iron powder and dilute hydrochloric acid (the concentrated hydrochloric acid 95g of 37.5%
Mixing with 265g water, the mass fraction of dilute hydrochloric acid is 9.9%), it is stirred vigorously lower input 49.5g in above-mentioned solution
(0.3mol) 3-nitro-acetophenone prepared by S1, is cooled to room temperature, filtration, filtrate ammonia after return stirring, fully reaction
Regulation to neutral, filter, wash, be dried and to obtain 3-aminoacetophenone 34.3g, yield is 84.6%, and its fusing point is 97-99 after tested
℃；
S3. diazotising and hydrolysis: in the reactor, add 650g water, dropping 405g mass fraction be 98% dense
Sulphuric acid, controls temperature and adds 3-aminoacetophenone 135g (1mol) prepared by S2, insulated and stirred at 45～50 DEG C in it
0.5h, control temperature is at 0～5 DEG C, and (sodium nitrite 80g and 155g water are formulated, and mass fraction is for dropping sodium nitrite aqueous solution
34.1%, all drip off), after dropping, adding 2.1g carbamide, insulation carries out diazo-reaction 0.5h, will after having reacted
Reactant liquor joins (400g dimethylbenzene, 100g water and the dense sulfur of 16g in the hydrolyzed solution mixed by dimethylbenzene, water and concentrated sulphuric acid
Acid), it is warming up to 90 DEG C of reactions that are hydrolyzed, has nitrogen to release, reflux 2h, and hydrolysis is cooled to 10～15 DEG C after completing, and protects
Temperature stirring 0.5h, filters, washes, is dried to obtain pale yellow powder 3-hydroxy acetophenone 114g, and yield is 83.9%, and it melts after tested
Point is for 95-98 DEG C；
S4. methylation reaction: add 252.0g (2mol) dimethyl sulfate in the reactor and be prepared by 136g (1mol) S3
3-hydroxy acetophenone, control temperature 50～60 DEG C, add appropriate ammoniacal liquor regulation reactant liquor pH to 8～9, insulation reaction 2～3h,
Persistently adding described ammoniacal liquor in course of reaction makes reactant liquor pH maintain 8～9, and after having reacted, faint yellow fraction is collected in distillation
3-methoxyacetophenone 128.2g, standard atmosphere pressure, testing its boiling point is 240 DEG C, and yield is 85.3%；
S5. bromination reaction: in the reactor, adds 260g (1.5mol) NBS (N-bromo-succinimide), 230g acetic acid
3-methoxyacetophenone prepared by ethyl ester and 150g S4 is also sufficiently mixed, room temperature reaction 3h, the hydrogen bromide sodium hydroxide of generation
Solution absorbs, and reaction is finished, and steams ethyl acetate, is then added to the water by reactant liquor, has solid to separate out, filters, is dried slightly
Product, obtain pale yellow powder 2-bromo-3 '-methoxyacetophenone 185.3g by re-crystallizing in ethyl acetate, and yield is 80.9%, after tested
Its fusing point is 64～66 DEG C, and content is 99.2% (HPLC).
Comparative example 1
Drug dose and the basic operation of step each with embodiment 1 are identical, do not add during the diazo-reaction of S3 the most in steps
Entering carbamide, step S3 finally gives 3-hydroxy acetophenone 97g, and yield is 71.4%, and its fusing point is 95-98 DEG C after tested.
Comparative example 2
Drug dose and the basic operation of step each with embodiment 2 are identical, do not add during the diazo-reaction of S3 the most in steps
Entering carbamide, step S3 finally gives 3-hydroxy acetophenone 93g, and yield is 68.4%, and its fusing point is 95-98 DEG C after tested.
Comparative example 3
Drug dose and the basic operation of step each with embodiment 3 are identical, do not add during the diazo-reaction of S3 the most in steps
Entering carbamide, step S3 finally gives 3-hydroxy acetophenone 90g, and yield is 66.2%, and its fusing point is 95-98 DEG C after tested.
Can be seen that from above-described embodiment and comparative example, the preparation side of the bromo-3 '-methoxyacetophenone of 2-that the present invention provides
Method, the gentleest and each step the productivity of the reaction condition of each step is the highest, the most all more than 80%, the mesh finally given
The purity of the mark bromo-3 '-methoxyacetophenone of product 2-is high, can reach pharmaceutical grade standard；S3 diazotising in described preparation method
Step adds carbamide, can be effectively improved the productivity of this step target product 3-hydroxy acetophenone, and productivity reaches more than 80%, and shows
Have time technology only participates in reaction with sodium nitrite in aqueous solution without carbamide, productivity only about 65%, therefore what the present invention provided
Method can effectively reduce cost.
The foregoing is only presently preferred embodiments of the present invention, not in order to limit the present invention, all spirit in the present invention and
Within principle, any modification, equivalent substitution and improvement etc. made, should be included within the scope of the present invention.
Claims (8)
1. the preparation method of the bromo-3 '-methoxyacetophenone of 2-, it is characterised in that comprise the steps:
S1. nitration reaction: at-10～-5 DEG C, drops to obtain in concentrated sulphuric acid mixed solution, to described mixed solution by 1-Phenylethanone.
Middle dropping nitrating agent and keep reaction temperature below-10 DEG C, drip complete and fully reaction after, be stirred vigorously lower by reactant liquor
Being poured in trash ice, have solid to separate out, sucking filtration, frozen water wash, are dried, and obtain yellow crystalline powder 3-nitro-acetophenone；
S2. reduction reaction: put into by iron powder in the dilute hydrochloric acid solution that mass fraction is 4-10%, is stirred vigorously lower to above-mentioned solution
3-nitro-acetophenone prepared by middle input S1,3-nitro-acetophenone is (0.3～0.5) with the mol ratio of iron powder: 1.6, and backflow is stirred
Mix, fully after reaction, be cooled to room temperature, filter, filtrate with ammonia regulation to neutral, filter, wash, be dried and to obtain 3-aminobenzene second
Ketone；
S3. diazotising and hydrolysis: concentrated sulphuric acid dilute with water also adds 3-amino prepared by S2 at 45～50 DEG C in it
1-Phenylethanone., is incubated and is sufficiently stirred for and to obtain mixed liquor, drips sodium nitrite aqueous solution at 0～5 DEG C, drip complete in described mixed liquor
After, adding appropriate carbamide, insulation carries out diazo-reaction 0.5-1h, its Sodium Nitrite, carbamide and the matter of 3-aminoacetophenone
Amount is than for (70～80): (2～4): 135, is joined by reactant liquor by dimethylbenzene, water and concentrated sulphuric acid according to (300 after having reacted
～400): (80～100): in the hydrolyzed solution that the mass ratio of 16 mixes, it is warming up to 90 DEG C of hydrolysis carried out above, backflow
2～3h, hydrolysis is cooled to 10～15 DEG C after completing, be incubated and be sufficiently stirred for, and filters, washes, is dried to obtain pale yellow powder
3-hydroxy acetophenone；
S4. methylation reaction: add dimethyl sulfate and the 3-hydroxyl prepared of S3 that mol ratio is 1.5～2:1 in the reactor
1-Phenylethanone., control temperature 50～60 DEG C, add alkali liquor regulation reactant liquor pH to 8～9, insulation reaction 2～3h, course of reaction is held
Continuous add described alkali liquor and make reactant liquor pH maintain 8～9, after react, the distillation faint yellow fraction 3-methoxybenzene second of collection
Ketone；
S5. bromination reaction: the mass ratio according to 230～260:200～230:150 add in reactor NBS, ethyl acetate and
3-methoxyacetophenone prepared by S4 is also sufficiently mixed, room temperature reaction 3～4h, is continuously added into alkali liquor and produces reaction in course of reaction
Raw hydrogen bromide absorbs, and steams ethyl acetate after completion of the reaction, adds water in remaining reactant liquor, has solid to separate out, mistake
Filter, dry, re-crystallizing in ethyl acetate, obtain the bromo-3 '-methoxyacetophenone of pale yellow powder 2-.
The preparation method of a kind of bromo-3 '-methoxyacetophenone of 2-the most according to claim 1, it is characterised in that step S1
In nitrating agent be prepared by fully mixing according to the mass ratio of 4:3 by concentrated sulphuric acid and fuming nitric aicd.
The preparation method of a kind of bromo-3 '-methoxyacetophenone of 2-the most according to claim 2, it is characterised in that described nitre
Agent is (350～400) with the mass ratio of described 1-Phenylethanone.: 120.
The preparation method of a kind of bromo-3 '-methoxyacetophenone of 2-the most according to claim 1, it is characterised in that step S2
In iron powder and dilute hydrochloric acid in the mol ratio of HCl be (3～4): 1.
The preparation method of a kind of bromo-3 '-methoxyacetophenone of 2-the most according to claim 1, it is characterised in that step S3
Described in the mass ratio of concentrated sulphuric acid and its thinned water be 270:(550～650), described 3-aminoacetophenone and described concentrated sulphuric acid
Mass ratio be 1:(2～3).
The preparation method of a kind of bromo-3 '-methoxyacetophenone of 2-the most according to claim 1, it is characterised in that step S3
Described in sodium nitrite aqueous solution in the mass fraction of sodium nitrite be 25～35%.
The preparation method of a kind of bromo-3 '-methoxyacetophenone of 2-the most according to claim 1, it is characterised in that step S4
It is ammonia or sodium hydrate aqueous solution with the alkali liquor in S5.
8., according to the preparation method of the bromo-3 '-methoxyacetophenone of a kind of 2-described in any one of claim 1 to 7, its feature exists
In, the mass fraction of described concentrated sulphuric acid is 98%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610616400.4A CN106242957A (en) | 2016-07-29 | 2016-07-29 | A kind of preparation method of 2 bromine 3 ' methoxyacetophenones |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610616400.4A CN106242957A (en) | 2016-07-29 | 2016-07-29 | A kind of preparation method of 2 bromine 3 ' methoxyacetophenones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106242957A true CN106242957A (en) | 2016-12-21 |
Family
ID=57605569
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610616400.4A Pending CN106242957A (en) | 2016-07-29 | 2016-07-29 | A kind of preparation method of 2 bromine 3 ' methoxyacetophenones |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106242957A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108147946A (en) * | 2017-12-04 | 2018-06-12 | 华南农业大学 | A kind of method for preparing 4- phenylphenols |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104193689A (en) * | 2014-07-23 | 2014-12-10 | 大连理工大学 | Method for synthesizing erlotinib hydrochloride |
-
2016
- 2016-07-29 CN CN201610616400.4A patent/CN106242957A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104193689A (en) * | 2014-07-23 | 2014-12-10 | 大连理工大学 | Method for synthesizing erlotinib hydrochloride |
Non-Patent Citations (4)
| Title |
|---|
| COLLINS, J. F. ET AL.: "Synthesis of 1,2,7,8-tetrahydro-3-methoxy- and 1,2,7,8-tetrahydro-3,10-dimethoxychrysene", 《JOURNAL OF THE CHEMICAL SOCIETY》 * |
| ROBERTO PERRONE ET AL.: "Oxygen Isosteric Derivatives of 3-(3-Hydroxypheny1)-N-n -propylpiperidine", 《J.MED.CHEM.》 * |
| 王超莉等: "《现代有机化学合成方法与技术研究》", 31 May 2015 * |
| 赵骏等: "《有机化学》", 28 February 2015 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108147946A (en) * | 2017-12-04 | 2018-06-12 | 华南农业大学 | A kind of method for preparing 4- phenylphenols |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104892356B (en) | The preparation method of m-trifluoromethyl phenylpropanol | |
| CN104926611B (en) | Novel process for preparing benzyl alcohol by alkali-free continuous hydrolysis of benzyl chloride | |
| CN108947875A (en) | A kind of synthetic method of 2,4- diphenyl sulfone phenol | |
| CN105753731A (en) | Preparation method of 3-amino-4-methoxybenzaniline | |
| CN106242957A (en) | A kind of preparation method of 2 bromine 3 ' methoxyacetophenones | |
| CN108191674A (en) | A kind of synthetic method of benzidine compound | |
| CN103342646B (en) | High-selectivity synthesis method of 4-nitro-ortho-xylene | |
| CN103012288B (en) | Preparation method of 6-chloro-1,3-dimethyluracil | |
| CN101348425A (en) | Method for coproduction of chrome tanning agent and menadione | |
| CN108558679A (en) | A kind of synthetic method of Parylene A presomas | |
| CN100999483B (en) | Preparation process of p-nitro phenyl hydrazine hydrochloride | |
| CN101602713B (en) | Novel method for synthesizing 2-chloronicotinic acid | |
| CN107827742A (en) | A kind of CO2The method that direct carboxylation method prepares aromatic acid | |
| WO2014121647A1 (en) | Preparation method for n-methyl sodium taurate | |
| CN103396286A (en) | Method for producing ethyl chloride by using sodium chloride and low-concentration ethanol as raw materials | |
| CN104628605B (en) | A kind of naphthalene continuous catalysis method of sulfonating and device thereof | |
| CN106748796B (en) | The method for preparing the fluoro- 2,4- dinitrobenzene of 1,5- bis- | |
| CN102627589A (en) | Method and technology for synthesizing and preparing 4-isopropylbenzenesulfonyl chloride through two steps | |
| CN102146022B (en) | Method for preparing 3-chlorine-5-bromophenol | |
| CN101698664A (en) | Preparation method of pharmaceutical intermediate 2-amine methylpyrazine hydrochloride | |
| CN114436790A (en) | Synthesis method of 6-methoxy-1-tetralone | |
| CN104672180A (en) | Chiral preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate | |
| CN103435503B (en) | Preparation process of phenylephrine key intermediate 3-hydroxyl-alpha-(methylamine ethyl)-phenylcarbinol (dextro-laevo isomer) | |
| CN104496880A (en) | N-methyl-3 phenyl succinimide compound and preparation method thereof | |
| CN106083631B (en) | A kind of preparation method of equal amido phenenyl acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20161221 |
|
| RJ01 | Rejection of invention patent application after publication |