CN106957237A - A kind of method for synthesizing bromfenac sodium - Google Patents
A kind of method for synthesizing bromfenac sodium Download PDFInfo
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- CN106957237A CN106957237A CN201710182240.1A CN201710182240A CN106957237A CN 106957237 A CN106957237 A CN 106957237A CN 201710182240 A CN201710182240 A CN 201710182240A CN 106957237 A CN106957237 A CN 106957237A
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- OSENYXNGRNTESR-UHFFFAOYSA-N CC(N(C(Cc1ccc2)=O)c1c2C(c(cc1)ccc1Br)=O)=O Chemical compound CC(N(C(Cc1ccc2)=O)c1c2C(c(cc1)ccc1Br)=O)=O OSENYXNGRNTESR-UHFFFAOYSA-N 0.000 description 1
- 0 CCCc1cccc(N(C(C)=O)C(C*)=O)c1C(c(cc1)ccc1Br)=O Chemical compound CCCc1cccc(N(C(C)=O)C(C*)=O)c1C(c(cc1)ccc1Br)=O 0.000 description 1
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/22—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
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- C—CHEMISTRY; METALLURGY
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- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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- C07D209/34—Oxygen atoms in position 2
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Abstract
The invention discloses a kind of method for synthesizing bromfenac sodium, including step:(1)Using 2 amino 4' bromines benzophenone as raw material, formula III is obtained through acetylization reaction:N ‑(2 ‑(4' bromophenyl acyls)Phenyl)Acetamide;(2)N ‑(2 ‑(4' bromophenyl acyls)Phenyl)Acetamide formula IV:Halogen acetylation reagent reacts to obtain formula V:N acetyl group N(2 ‑(4' bromophenyl acyls)Phenyl)2 halogen acetamides;(3)N acetyl group N(2 ‑(4' bromophenyl acyls)Phenyl)2 halogen acetamides obtain formula VI after friedel-crafts reaction:1 acetyl group 7(4 bromo-benzoyl chlorides)The ketone of indoline 2;(4)1 acetyl group 7(4 bromo-benzoyl chlorides)The ketone of indoline 2 finally hydrolyzes to obtain target product.The method of the present invention is with low cost, easy control of reaction, and post processing is simple, and overall yield is high, and there is provided a kind of new method for synthesizing bromfenac sodium the advantages of economic and environment-friendly.
Description
Technical field
The present invention relates to medication chemistry field of medicaments, specifically, invention is related to a kind of synthetic method of antalgesic, more specifically
For be it is a kind of synthesize bromfenac sodium new method.
Background technology
Bromfenac sodium (Bromfenac sodium), entitled [2- amino -3- (4- benzoyl bromides) phenyl] acetic acid of chemistry
Sodium;(2- amino -3- (4- Bromophenacyls) phenyl) sodium acetate, structure is similar with Ketoprofen and Diclofenac, can suppress epoxy conjunction
The synthesis of the prostanoid inflammatory mediator of enzyme mediation, is maximally effective cyclooxygenase-2 inhibitors, is made with strength anti-inflammatory analgesic
With.The compound be by A.H.Ro bins companies of the U.S. research and develop plan NSAIDs, after patent right is transferred into the U.S.
Wyeth-Ayers t companies, with Japanese Senju companies joint development, Senju companies of Japan in 2000 are developed as Bromfenac
Sodium eye drops, in 2 000 years in Japan's listing, in U.S.'s listing, being clinically used for treatment is used for outer eye and preceding eye within 2005
Diseases associated with inflammation symptomatic treatment:Blepharitis, conjunctivitis, strong film scorching (including upper strong film is scorching), post-operation inflammatory etc., its structural formula
It is as follows:
Patent EP221753 is disclosed with being initiation material to Brominal and indoline, in alchlor and boron chloride
Catalysis under, carry out friedel-crafts reaction, then oxidized, halogenation, sour water solution and basic hydrolysis obtain bromfenac sodium, and reaction equation is as follows:
In this method, initiation material under the catalysis of alchlor and boron chloride, is carried out to Brominal and indoline
Friedel-crafts reaction, this step reaction is high to moisture requirement, generally requires first to carry out to be reacted after point water, because boron chloride
Anti- raw explosive decomposition after water is met, its potential danger limits its application in the industrial production significantly.
Document (journal of the American chemical society.1974 volumes 95 5508~5517) is carried
Supply using 2- amino -4'- bromines benzophenone and 2- first ethyl thioglycolate as raw material, carried out after being reacted with t-butyl hypochlorate
Replace cyclization, piptonychia sulfydryl, hydrolysis obtains bromfenac sodium, and reaction equation is as follows:
In this method, initiation material 2- first ethyl thioglycolates have bad smell, need to be protected when using and special
Different processing, while 2- amino -4'- bromines benzophenone and 2- first ethyl thioglycolate are replaced under t-butyl hypochlorate catalysis
Cyclization needs to carry out (be less than subzero 65 DEG C) under ultralow temperature, and follow-up piptonychia sulfydryl needs the Raney Ni in high activity, right
Safety in production has larger threat, and disadvantages described above limits the application of the route in the industrial production.
The content of the invention
The technical problem to be solved in the present invention is to overcome the defect of prior art there is provided a kind of side for synthesizing bromfenac sodium
Reagent is gentle in method, this method, and course of reaction is controllable, and post processing is simple, high income, and economic and environment-friendly.
In order to solve the above technical problems, the technical solution adopted by the present invention is:
A kind of method for synthesizing bromfenac sodium, comprises the following steps:
(1) formula II:2- amino -4'- bromines benzophenone obtains formula III through acetylization reaction;
(2) formula III and formula IV:Halogen acetylation reagent reacts to obtain formula V;
Wherein:X is selected from Cl or Br;
(3) formula V obtains formula VI after friedel-crafts reaction;
(4) bromfenac sodium is obtained after hydrolyzing.
It is preferred that, formula IV, i.e. halogen acetylation reagent are chloracetyl chloride, bromoacetyl bromide, chloroacetic anhydride, bromoacetic acid acid anhydride.
It is preferred that, in step (1):Formula II is dissolved in solvent orange 2 A, and introduces organic base A;It is preferred that, reaction temperature be 0~
90 DEG C, reaction temperature is more preferably 0~50 DEG C.It is preferred that solvent orange 2 A be selected from dichloromethane, toluene, 2- methyltetrahydrofurans
In one or more kinds of mixtures.Preferred acetylation reagent is in acetylization reaction:Chloroacetic chloride or/and acetic anhydride.
It is preferred that, formula II is 1 with the mol ratio of acetylation reagent consumption:1.01~1:1.5, more preferably 1:1.01~1:1.2.
It is preferred that organic base A be triethylamine or/and diisopropylethylamine.It is preferred that, organic base A and acetylation reagent consumption mol ratio
For 1:1~1.5:1, more preferably 1:1~1.2:1.
It is preferred that, the post-processing approach of reaction includes in step (1):Organic phase is washed with water at least once after reaction,
Then dry, concentrate.
It is preferred that, in step (2):Formula III is dissolved in solvent B, and introduces organic base B and catalyst B.It is preferred that reaction temperature
Spend for 50~120 DEG C;More preferably 70~120 DEG C.It is preferred that solvent B be toluene or/and chloroform.Formula V is rubbed with formula IV
You compare 1:1.01~1:2, more preferably 1:1.1~1:1.5.It is preferred that organic base B be triethylamine or/and diisopropyl second
Amine.It is preferred that the organic base B mol ratio of consumption and formula IV be 1:1~1.5:1, more preferably 1:1~1.2:1.Catalysis
Agent B elects DMAP as, and catalyst B and the mol ratio of formula IV preferably are 0.1:1~1:1, more preferably
0.3:1~1:1.
It is preferred that, the post-processing approach of reaction includes in step (2):Organic phase is washed with water at least once after reaction,
Then dry, concentrate.
It is preferred that, in step (3):Formula V is dissolved in solvent C, and introduces catalyst C.It is preferred that catalyst be lewis acid
Catalyst, more preferably:One or more kinds of mixtures in alchlor, ferric trichloride, zinc chloride, more enter one
Step is preferably alchlor or ferric trichloride.It is preferred that reaction temperature be 50~150 DEG C, more preferably 70~120 DEG C.It is excellent
The solvent C of choosing is chloroform or/and chlorobenzene.It is preferred that catalyst C and formula V mol ratio 1:1~3:1, more preferably 1.3:
1~2:1.
It is preferred that, the post-processing approach of reaction includes recrystallization in step (3), more preferably:Will reaction after reaction
Mixed liquor is added drop-wise in frozen water, filtering, is collected filter cake, is finally recrystallized.
It is preferred that, in step (4):Formula VI is dissolved in solvent D, and introduces catalyst D.It is preferred that reaction temperature be 50~100
DEG C, more preferably 70~100 DEG C.It is preferred that solvent D be selected from ethanol, isopropanol is one or more kinds of mixed in water
Compound.It is preferred that catalyst D be NaOH.It is preferred that catalyst D and formula VI mol ratio 2.1:1~10:1, it is further excellent
Elect 4 as:1~10:1.
It is preferred that, the post-processing approach of reaction includes recrystallization in step (4), more preferably:Will reaction after reaction
Mixed liquor is added drop-wise in methyl tertiary butyl ether(MTBE) (the also known as tertiary ether of first, abbreviation MTBE), and filtering is collected filter cake, finally recrystallized.
It is preferred that, bromfenac sodium includes the crystalline hydrate of type I compound or/and type I compound obtained by step (4):
Wherein, the crystalline hydrate of type I compound includes following compounds of formula VII:
The beneficial effect that the present invention is reached:
For compared with the prior art, the method for the present invention is with low cost, easy control of reaction, and post processing is simple, and overall yield is high,
Overall yield is between 46%-60%, and economic and environment-friendly there is provided a kind of new method for synthesizing bromfenac sodium.
Brief description of the drawings
Fig. 1 is the synthesis general line figure of bromfenac sodium in embodiment.
Embodiment
The invention will be further described below in conjunction with the accompanying drawings.Following examples are only used for clearly illustrating the present invention
Technical scheme, and can not be limited the scope of the invention with this.
In the present invention, if without specified otherwise, using solvent (including solvent orange 2 A, solvent B, solvent C, solvent D), reagent (bag
Include various catalyst, acetylation reagent and halogen acetylation reagent) etc. be routine business means and be commercially available, without special place
Reason.If without specified otherwise, all chemical reagent used in the present invention to its purity without particular/special requirement, chemical pure level, or purity
Higher analysis is pure, top pure grade can.But preferably purity is high.
Embodiment 1
(1) preparation of N- (2- (4'- bromophenyl acyls) phenyl) acetamide (formula III)
414g 2- amino -4'- bromines benzophenone (formula II) and 150g triethylamines are added to 2.5L 2- methyltetrahydrofurans
In, 0~20 DEG C of temperature control is added dropwise to 94g chloroacetic chlorides, and stirring is to reacting complete after addition, and organic phase washing and drying is concentrated to give N-
(2- (4'- bromophenyl acyls) phenyl) acetamide 470g, yield 98.5%.
(2) N- acetyl group-N- (2- (4'- bromophenyl acyls) phenyl) -2- acetbromamides (formula V).Wherein X be Br) system
It is standby:
Take 450gN- (2- (4'- bromophenyl acyls) phenyl) acetamide, 220g diisopropylethylamine and 22g4- dimethylamino pyrroles
Pyridine is added in 5L toluene, is added dropwise after 280g bromoacetyl bromides, completion of dropping, and 90~100 DEG C of temperature control is down to room to reacting complete
Wen Hou, organic phase is washed with water, and dries, be concentrated under reduced pressure recovery organic solvent, obtains 560g N- acetyl group-N- (2- (4'- bromobenzene acyls
Base) phenyl) -2- acetbromamides, yield 90.1%.
3) preparation of 1- acetyl group -7- (4- bromo-benzoyl chlorides) Indolin-2-ones (formula VI)
500g N- acetyl group-N- (2- (4'- bromophenyl acyls) phenyl) -2- acetbromamides are taken to be added in 2L chlorobenzene, point
Criticize and add 200g alchlors, 100~110 DEG C are warming up to after adding to reacting complete, reaction solution is added drop-wise to after reacting completely
In frozen water, filter cake is collected by filtration, filtration cakes torrefaction obtains crude product, and crude product obtains 329g1- acetyl group -7- through re-crystallizing in ethyl acetate
(4- bromo-benzoyl chlorides) Indolin-2-one, yield 80.2%.
4) preparation of bromfenac sodium
300g 1- acetyl group -7- (4- bromo-benzoyl chlorides) Indolin-2-one is taken to be added to 800mL methanol and 200ml water
In, 120g NaOH is added portionwise, 60~70 DEG C are warming up to after adding to reacting complete, reaction solution is added dropwise after reaction completely
Into the tertiary ether of 3L first, filter cake is collected by filtration, filtration cakes torrefaction obtains crude product, and crude product is received through being recrystallized to give 239.9g bromfenac sodiums
Rate 80.5%, purity 99.67%,1HNMR(d6-DMSO)δ:7.95-7.80(s,2H),7.75-7.60(d,2H,J 8Hz),
7.55-7.40 (d, 2H, J8Hz), 7.15-6.95 (dd, 2H), 6.48-6.35 (t, 1H), 3.2 (s, 2H).
Embodiment 2
(1) preparation of N- (2- (4'- bromophenyl acyls) phenyl) acetamide
700g 2- amino -4'- bromines benzophenone and 425g diisopropylethylamine are added in 5L dichloromethane, are added dropwise to
300g acetic anhydrides, stirring is to reacting complete after addition, and organic phase washing and drying is concentrated to give N- (2- (4'- bromophenyl acyls) phenyl)
Acetamide 766g, yield 95%.
(2) preparation of N- acetyl group-N- (2- (4'- bromophenyl acyls) phenyl) -2- acetbromamides
750gN- (2- (4'- bromophenyl acyls) phenyl) acetamide is taken, 357g triethylamines and 35g4- dimethylamino naphthyridines are added
Into 10L toluene, it is added dropwise after 675g bromoacetic acid acid anhydrides, completion of dropping, temperature rising reflux is down to after room temperature to reacting complete, organic
Mutually be washed with water, dry, be concentrated under reduced pressure recovery organic solvent, obtain 955g N- acetyl group-N- (2- (4'- bromophenyl acyls) phenyl)-
2- acetbromamides, yield 92.3%.
3) preparation of 1- acetyl group -7- (4- bromo-benzoyl chlorides) Indolin-2-one
900g N- acetyl group-N- (2- (4'- bromophenyl acyls) phenyl) -2- acetbromamides are taken to be added in 5L chloroform, point
Criticize and add 550g alchlors, add rear temperature rising reflux to reacting complete, reaction solution is added drop-wise in frozen water after reacting completely, mistake
Filter cake is collected in filter, and filtration cakes torrefaction obtains crude product, and crude product obtains 559g1- acetyl group -7- (4- bromobenzene first through re-crystallizing in ethyl acetate
Acyl chlorides) Indolin-2-one, yield 76.2%.
4) preparation of bromfenac sodium
300g 1- acetyl group -7- (4- bromo-benzoyl chlorides) Indolin-2-one is taken to be added to 900mL ethanol and 250ml water
In, 130g NaOH is added portionwise, 70~80 DEG C are warming up to after adding to reacting complete, reaction solution is added dropwise after reaction completely
Into the tertiary ether of 3L first, filter cake is collected by filtration, filtration cakes torrefaction obtains crude product, and crude product is received through being recrystallized to give 249.8g bromfenac sodiums
Rate 83.5%, purity 99.74%,1HNMR(d6-DMSO)δ:7.95-7.80(s,2H),7.75-7.60(d,2H,J 8Hz),
7.55-7.40 (d, 2H, J8Hz), 7.15-6.95 (dd, 2H), 6.48-6.35 (t, 1H), 3.2 (s, 2H).
Embodiment 3
(1) preparation of N- (2- (4'- bromophenyl acyls) phenyl) acetamide
500g 2- amino -4'- bromines benzophenone and 300g diisopropylethylamine are added in 5L toluene, temperature control 10~20
DEG C, 170g chloroacetic chlorides are added dropwise to, heating stirring is to reacting complete naturally after addition, and organic phase washing and drying is concentrated to give N- (2-
(4'- bromophenyl acyls) phenyl) acetamide 543g, yield 94.3%.
(2) preparation of N- acetyl group-N- (2- (4'- bromophenyl acyls) phenyl) -2- chloroacetamides
510gN- (2- (4'- bromophenyl acyls) phenyl) acetamide is taken, 320g triethylamines and 50g4- dimethylamino naphthyridines are added
Into 5L toluene, it is added dropwise after 270g chloracetyl chlorides, completion of dropping, 100~110 DEG C of temperature control is down to after room temperature to reacting complete,
Organic phase is washed with water, and dries, be concentrated under reduced pressure recovery organic solvent, obtains 552g N- acetyl group-N- (2- (4'- bromophenyl acyls) benzene
Base) -2- chloroacetamides, yield 87.5%.
3) preparation of 1- acetyl group -7- (4- bromo-benzoyl chlorides) Indolin-2-one
500g N- acetyl group-N- (2- (4'- bromophenyl acyls) phenyl) -2- chloroacetamides are taken to be added in 2L chlorobenzene, point
Criticize and add 330g alchlors, 100~110 DEG C are warming up to after adding to reacting complete, reaction solution is added drop-wise to after reacting completely
In frozen water, be collected by filtration filter cake, filtration cakes torrefaction obtains crude product, crude product through re-crystallizing in ethyl acetate obtain 343.7g1- acetyl group-
7- (4- bromo-benzoyl chlorides) Indolin-2-one, yield 76.2%.
4) preparation of bromfenac sodium
300g 1- acetyl group -7- (4- bromo-benzoyl chlorides) Indolin-2-one is taken to be added to 750mL isopropanols and 300ml
In water, 150g NaOH is added portionwise, 70~80 DEG C are warming up to after adding to reacting complete, drop will be reacted after reaction completely
Be added in the tertiary ether of 3L first, filter cake be collected by filtration, filtration cakes torrefaction obtains crude product, crude product through being recrystallized to give 257.8g bromfenac sodiums,
Yield 86.5%, purity 99.47%,1HNMR(d6-DMSO)δ:7.95-7.80(s,2H),7.75-7.60(d,2H,J 8Hz),
7.55-7.40 (d, 2H, J8Hz), 7.15-6.95 (dd, 2H), 6.48-6.35 (t, 1H), 3.2 (s, 2H).
Embodiment 4
(1) preparation of N- (2- (4'- bromophenyl acyls) phenyl) acetamide
500g 2- amino -4'- bromines benzophenone and 300g diisopropylethylamine are added in 5L toluene, temperature control 10~20
DEG C, 170g chloroacetic chlorides are added dropwise to, heating stirring is to reacting complete naturally after addition, and organic phase washing and drying is concentrated to give N- (2-
(4'- bromophenyl acyls) phenyl) acetamide 543g, yield 94.3%.
(2) preparation of N- acetyl group-N- (2- (4'- bromophenyl acyls) phenyl) -2- chloroacetamides
Take 510gN- (2- (4'- bromophenyl acyls) phenyl) acetamide, 410g diisopropylethylamine and 60g4- dimethylamino pyrroles
Pyridine is added in 5L toluene, is added dropwise after 490g chloroacetic anhydrides, completion of dropping, and 100~110 DEG C of temperature control is down to reacting complete
After room temperature, organic phase is washed with water, and dries, be concentrated under reduced pressure recovery organic solvent, obtains 526g N- acetyl group-N- (2- (4'- bromobenzenes
Acyl group) phenyl) -2- chloroacetamides, yield 83.5%.
3) preparation of 1- acetyl group -7- (4- bromo-benzoyl chlorides) Indolin-2-one
500g N- acetyl group-N- (2- (4'- bromophenyl acyls) phenyl) -2- chloroacetamides are taken to be added in 2L chlorobenzene, point
Criticize and add 350g ferric trichlorides, 100~110 DEG C are warming up to after adding to reacting complete, reaction solution is added drop-wise to after reacting completely
In frozen water, be collected by filtration filter cake, filtration cakes torrefaction obtains crude product, crude product through re-crystallizing in ethyl acetate obtain 316.7g1- acetyl group-
7- (4- bromo-benzoyl chlorides) Indolin-2-one, yield 70.2%.
4) preparation of bromfenac sodium
300g 1- acetyl group -7- (4- bromo-benzoyl chlorides) Indolin-2-one is taken to be added to 500ml methanol 500ml ethanol
In 400ml water, 180g NaOH is added portionwise, 60~70 DEG C are warming up to after adding to reacting complete, will after reaction completely
Reaction solution is added drop-wise in the tertiary ether of 3L first, and filter cake is collected by filtration, and filtration cakes torrefaction obtains crude product, and crude product is through being recrystallized to give 248.8g bromines
Fragrant acid sodium, yield 83.5%, purity 99.47%,1HNMR(d6-DMSO)δ:7.95-7.80(s,2H),7.75-7.60(d,2H,J
8Hz), 7.55-7.40 (d, 2H, J 8Hz), 7.15-6.95 (dd, 2H), 6.48-6.35 (t, 1H), 3.2 (s, 2H).
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, on the premise of the technology of the present invention principle is not departed from, some improvement and deformation can also be made, these improve and deformed
Also it should be regarded as protection scope of the present invention.
Claims (10)
1. a kind of method for synthesizing bromfenac sodium, it is characterised in that comprise the following steps:
(1) formula II:2- amino -4'- bromines benzophenone obtains formula III through acetylization reaction;
(2) formula III and formula IV:Halogen acetylation reagent reacts to obtain formula V;
Wherein:X is selected from Cl or Br;
(3) formula V obtains formula VI after friedel-crafts reaction;
(4) bromfenac sodium is obtained after hydrolyzing.
2. a kind of method for synthesizing bromfenac sodium according to claim 1, it is characterised in that in step (1):Formula II is dissolved in
In solvent orange 2 A, and introduce organic base A;In step (2):Formula III is dissolved in solvent B, and introduces organic base B and catalyst B;Step
(3) in:Formula V is dissolved in solvent C, and introduces catalyst C;In step (4):Formula VI is dissolved in solvent D, and introduces catalyst D.
3. a kind of method for synthesizing bromfenac sodium according to claim 1, it is characterised in that reaction temperature in step (1)
It it is 0~90 DEG C for reaction temperature;Reaction temperature is 50~120 DEG C in step (2);Reaction temperature is 50~150 in step (3)
DEG C, reaction temperature is 50~100 DEG C in step (4).
4. a kind of method for synthesizing bromfenac sodium according to claim 2, it is characterised in that catalyst B is:4- diformazan ammonia
Yl pyridines, catalyst C is lewis acid catalyst, and catalyst D is NaOH.
5. the method for a kind of synthesis bromfenac sodium according to claim any one of 2-4, it is characterised in that in step (1):
One or more kinds of mixtures of the solvent orange 2 A in dichloromethane, toluene, 2- methyltetrahydrofurans, acetylation reagent is
Chloroacetic chloride or/and acetic anhydride, formula II are 1 with the mol ratio of acetylation reagent consumption:1.01~1:1.5;Organic base A is triethylamine
Or/and diisopropylethylamine;Organic base A is 1 with the mol ratio of acetylation reagent consumption:1~1.5:1.
6. the method for a kind of synthesis bromfenac sodium according to claim any one of 2-4, it is characterised in that in step (2):
Solvent B is toluene or/and chloroform, the mol ratio 1 of formula V and formula IV:1.01~1:2;Organic base B is triethylamine or/and diisopropyl
Base ethamine;Organic base B consumption is 1 with the mol ratio of formula IV:1~1.5:1;Catalyst B is 0.1 with the mol ratio of formula IV:1~
1:1.
7. the method for a kind of synthesis bromfenac sodium according to claim any one of 2-4, it is characterised in that in step (3):
Solvent C is the mol ratio 1 of chloroform or/and chlorobenzene, catalyst C and formula V:1~3:1.
8. the method for a kind of synthesis bromfenac sodium according to claim any one of 2-4, it is characterised in that in step (4):
Solvent D is selected from one or more kinds of mixtures in ethanol, isopropanol, water, catalyst D and the mol ratio 2.1 of formula VI:1
~10:1.
9. the method for a kind of synthesis bromfenac sodium according to claim any one of 2-4, it is characterised in that catalyst C is selected
From alchlor, ferric trichloride, one or more kinds of mixtures in zinc chloride.
10. a kind of method for synthesizing bromfenac sodium according to claim 1, it is characterised in that Bromfenac obtained by step (4)
Sodium includes the crystalline hydrate of type I compound or/and type I compound:
。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN110885296A (en) * | 2018-09-11 | 2020-03-17 | 新发药业有限公司 | Preparation method of bromfenac sodium |
CN113698308A (en) * | 2021-08-25 | 2021-11-26 | 山东辰龙药业有限公司 | Novel synthesis method of bromfenac sodium |
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CN110885296A (en) * | 2018-09-11 | 2020-03-17 | 新发药业有限公司 | Preparation method of bromfenac sodium |
CN110885296B (en) * | 2018-09-11 | 2022-11-04 | 新发药业有限公司 | Preparation method of bromfenac sodium |
CN113698308A (en) * | 2021-08-25 | 2021-11-26 | 山东辰龙药业有限公司 | Novel synthesis method of bromfenac sodium |
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