CN104974057B - The preparation method and important intermediate of a kind of bromfenac sodium - Google Patents
The preparation method and important intermediate of a kind of bromfenac sodium Download PDFInfo
- Publication number
- CN104974057B CN104974057B CN201410138392.8A CN201410138392A CN104974057B CN 104974057 B CN104974057 B CN 104974057B CN 201410138392 A CN201410138392 A CN 201410138392A CN 104974057 B CN104974057 B CN 104974057B
- Authority
- CN
- China
- Prior art keywords
- bromfenac sodium
- preparation
- reaction
- acid
- reaction temperature
- 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.)
- Active
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A kind of reaction condition of present invention offer is mild, easy to operate, products obtained therefrom purity is high, yield is high, at low cost, is easy to preparation and the process for purification of the bromfenac sodium of industrialized production.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, it is related to new method prepared by a kind of non-steroidal anti-inflammatory drugs bromfenac sodium and its again
Want intermediate.
Background technology
Bromfenac sodium（Bromfenac sodium, chemical name：2- amino -3-（4- benzoyl bromides）Sodium）,
It is the non-steroidal anti-inflammatory drugs of Wyeth-Ayerst companies exploitation, there is powerful pain-stopping effect, listed, be used in the U.S. in 1997
Sharp pain is treated, without additive.It is then listed by the exploitation of thousand longevity company of Japan for eye drops, for the inflammation of outer eye and preceding eye
The symptomatic treatment of property disease：Blepharitis, conjunctivitis, strong film are scorching（It is scorching including upper strong film）, post-operation inflammatory etc..The medicine is postoperative to eyes
The therapeutic effect of inflammation protrudes, better tolerance, and on intraocular pressure without influence, ocular side effect incidence is low.
Research at present on bromfenac sodium synthetic method is few, it has been disclosed that synthetic method mainly have it is following two.
Method one, United States Patent (USP) US4126635 and US4182774 disclose the synthetic method of bromfenac sodium first, specifically
Be using aryl amine derivatives as starting material, with methylmercaptan ethyl acid esters under the catalysis of pivaloyl chloride cyclization synthesis of indole ketone, then pass through
Catalytic hydrogenation hydrolyzes to obtain product.Although this method reaction step is less, starting material need to be synthesized through multistep and is made, technique
It is complex, and annulation need to carry out at -70 DEG C, condition is more harsh.
Method two, document J Med Chem1984,27 (11):1379-1388 and European patent EP 0221753 provide one
Kind synthesis bromfenac sodium new method, this method using to bromobenzylcyanide and indoline as raw material, with alchlor and boron trifluoride
Carry out Fu Ke acylations for catalyst, then aoxidize through activated manganese dioxide, NCS chloros, acidolysis, basic hydrolysis generation bromfenac sodium.
This method starting material is cheap and easy to get, but there are complicated for operation, part steps yield is relatively low, is unfavorable for industrial metaplasia
The shortcomings of production.Therefore find that a kind of reaction condition is mild, and easy to operate, being easy to the process route of industrialized production seems especially heavy
It will.
In addition, the report refined at present on bromfenac sodium is less, the method for having document report is to use 1,2- diformazans
Oxygroup ethane is as refined solvent.1,2- dimethoxy-ethane is two class solvents as defined in ICH, and toxicity is larger, is used for limitation
Solvent, bromfenac sodium finished product residual can to human body generate harm, so as to influence the therapeutic effect of product.Therefore find
A kind of efficient process for purification no less important of low toxicity.
The content of the invention
The object of the present invention is to provide a kind of reaction condition is mild, easy to operate, products obtained therefrom purity is high, yield is high, into
This is low, is easy to the new preparation of bromfenac sodium and the process for purification of industrialized production.
The present invention relates to a kind of preparation method of bromfenac sodium, it is characterized in that reaction scheme is as follows：
Step 1：Intermediate II is obtained by the reaction under Louis acid catalysis with chloroacetonitrile in starting material I；Step 2：Intermediate
Intermediate III is obtained by the reaction with parabromobenzoyl chloride in II under Louis acid catalysis；Step 3：Intermediate III and acidic aqueous solution
Be obtained by the reaction intermediate IV, the acidic aqueous solution for the hydrochloric acid of content more than 30%, sulfuric acid or phosphoric acid aqueous solution；Step
Four：Intermediate IV obtains bromfenac sodium with NaOH reactant aqueous solutions.
A kind of preparation method of the bromfenac sodium, it is characterized in that：Lewis acid described in step 1 is selected from borontrifluoride
Boron, boron chloride, zinc chloride, ferric trichloride, butter of tin or titanium tetrachloride, reaction temperature are 40~80 DEG C；Step 2 institute
The lewis acid stated is selected from alchlor, boron trifluoride, boron chloride, zinc chloride, ferric trichloride, butter of tin or four chlorinations
Titanium, reaction temperature are 20~80 DEG C；Acidic aqueous solution described in step 3 is selected from 30%~38% aqueous hydrochloric acid solution, 60%~80%
Aqueous sulfuric acid or 80~98% phosphate aqueous solution, reaction temperature be 30~120 DEG C；The reaction temperature of step 4 for 50~
100℃。
A kind of preparation method of the bromfenac sodium, it is characterized in that：Lewis acid described in step 1 is selected from zinc chloride
Or titanium tetrachloride；Lewis acid described in step 2 is selected from alchlor or titanium tetrachloride；Acidic aqueous solution described in step 3
For 60%~80% aqueous sulfuric acid；The concentration of NaOH aqueous solutions described in step 4 is 20%~50%.
A kind of preparation method of the bromfenac sodium, it is characterized in that：The reaction temperature of step 1 is 60~70 DEG C；Step
Two reaction temperature is 60~70 DEG C；The reaction temperature of step 3 is 80~90 DEG C；The reaction temperature of step 4 is 60~65 DEG C.
A kind of preparation method of the bromfenac sodium, it is characterized in that：It feeds intake in step 1 to starting material I and chloroacetonitrile
Molar ratio is 1:1-1.5；The molar ratio of intermediate II and parabromobenzoyl chloride is 1 in step 2:1-3；It is sour in step 3
It is 1 with III molar ratio of intermediate:0.1-1；The molar ratio of NaOH and intermediate IV is 1 in step 4：0.5-1.
A kind of preparation method of the bromfenac sodium, it is characterized in that：Reaction dissolvent is selected from the alkane of C6~C8 in step 1
Hydrocarbon, dichloromethane, chloroform, carbon tetrachloride or 1,2- dichloroethanes；In step 2 reaction dissolvent be selected from C6~C8 alkane,
Dichloromethane, chloroform, carbon tetrachloride or 1,2- dichloroethanes；In step 4 reaction dissolvent be selected from C1~C4 fatty alcohol,
One or more in the alkane of C6~C8, tetrahydrofuran, dioxane, benzene, toluene or dimethylbenzene.
A kind of preparation method of the bromfenac sodium, it is characterized in that：Lewis acid described in step 1 is with starting material I's
Molar ratio is 1:2-10；Lewis acid described in step 2 and the molar ratio of intermediate II are 1:1-10；Step 3
Middle acid is 1 with III molar ratio of intermediate:0.2-0.5.
The preparation method of a kind of bromfenac sodium, it is characterized in that further including following purification step：It is molten using mixing
Agent A recrystallizes bromfenac sodium, isopropyl ethers of the mixed solvent A by 40%~50% parts by volume, 40%~45% parts by volume
Ethyl alcohol and excess water composition.
Compound II, structure are shown below：
Compound III, structure are shown below：
The new method of synthesis bromfenac sodium provided by the invention, the advantage is that not only agents useful for same is cheap and easy to get, and right
Environmental pollution is small.Each step operation is simple, is easy to purify, and yield is higher, and target product purity is higher, and process for purification is simple,
It is very suitable for industrialized production.
Specific embodiment
Below will by embodiment, the invention will be further described, these description be not present invention is made into
The restriction of one step.It should be understood by those skilled in the art that the equivalent substitution made of technical characteristic to the present invention or changing accordingly
Into still falling within protection scope of the present invention.
Embodiment 1
Embodiment 1-1
Under nitrogen protection, 107g N-acetylsulfanilic acids are added in 1L reaction bulbs, add in the dissolving of 537ml dichloromethane,
41.5g chloroacetonitriles are added in, 13.6g zinc chloride are added portionwise, are heated to 40 DEG C, back flow reaction 2h, TLC detection is after the reaction was complete,
It is cooled to room temperature.3ml water is slowly added dropwise into reaction solution, ice salt bath temperature control is less than 20 DEG C.It is filtered to remove insoluble matter, filtrate washing
It is concentrated under reduced pressure into after to neutrality near dry.Gained crude product obtains white solid 94g, yield 74% with re-crystallizing in ethyl acetate.
Embodiment 1-2~1-24 starting materials inventory, operating procedure reference implementation example 1-1, other conditions refer to following table, real
Test that the results are shown in table below：
Compound II：m/e:254.04(100.0%)；Elemental analysis：C,47.20;H,3.99;N,11.05;O,25.20;
S,12.56
C13NMR:
Embodiment 2
Embodiment 2-1
Under nitrogen protection, 76g formulas are added in 1L reaction bulbs（Ⅱ）Compound and 79g parabromobenzoyl chlorides add in 381ml bis-
Chloromethanes dissolves, and 16g alchlors are added portionwise in 30min, and ice salt bath temperature control is less than 20 DEG C.After alchlor adds, slowly
It is warming up to reflux, back flow reaction 4h.TLC detections are cooled to room temperature, 2ml water, ice are slowly added dropwise into reaction solution after the reaction was complete
Salt bath temperature control is less than 20 DEG C.Insoluble matter is filtered to remove, filtrate is concentrated under reduced pressure near do after being washed to neutrality.Gained crude product acetic acid second
Ester recrystallizes to obtain yellow solid 107g, yield 82%.
Embodiment 2-2~2-24 starting materials inventory, operating procedure reference implementation example 2-1, other conditions refer to following table, real
Test that the results are shown in table below：
Compound III：m/e:437.97(100.0%)；Elemental analysis：C,46.55;H,3.04;Br,18.22;N,6.45;
O,18.32;S,7.42
C13NMR:
Embodiment 3
Embodiment 3-1
87g formulas are added in 500ml reaction bulbs（Ⅲ）Compound adds in the hydrochloric acid of 105ml contents 30%, is heated to 80-90
DEG C, it is stirred to react, reaction solution is poured into 5L ice water, a large amount of yellow-brown solids are precipitated after the reaction was complete by TLC detections, is filtered, filter
Cake is washed to neutrality, obtains yellow-brown solid 53.6g, yield 85%.
Embodiment 3-2~3-17 starting materials inventory, operating procedure reference implementation example 3-1, other conditions refer to following table, real
Test that the results are shown in table below：
Embodiment 4
Embodiment 4-1 is by 50g formulas（Ⅳ）Compound is added in 200ml toluene and 100ml alcohol mixed solutions, and stirring is next
Secondary property adds in 25% aqueous solution of 9.5g NaOH, reacts 1.5h at 60-65 DEG C, and TLC detections are cooled to room temperature after the reaction was complete,
700ml isopropyl ethers are added in, after 2h is stirred at room temperature, filter to obtain bromfenac sodium crude product 54g, yield 96%, content 95%.
Embodiment 4-2~4-14 starting materials, inventory operating procedure reference implementation example 4-1, other conditions refer to following table, real
Test that the results are shown in table below：
Embodiment 5
Embodiment 5-1
The heating of 95% bromfenac sodium crude product of 50g contents is dissolved in the mixed of the water composition of the ethyl alcohol of 700ml40%/isopropyl ether/40%/20%
In bonding solvent, heat filtering removes insoluble matter, stirs lower slow cooling to 5 DEG C, filters to obtain bromfenac sodium fine work 45g, yield 90%,
Content 99.2%.
Embodiment 5-2
The heating of 95% bromfenac sodium crude product of 50g contents is dissolved in the mixed of the water composition of the ethyl alcohol of 700ml40% isopropyl ethers/45%/15%
In bonding solvent, heat filtering removes insoluble matter, stirs lower slow cooling to 15 DEG C, filters to obtain bromfenac sodium fine work 46g, yield 92%,
Content 99.0%.
Embodiment 5-3
The heating of 95% bromfenac sodium crude product of 50g contents is dissolved in the mixed of the water composition of the ethyl alcohol of 800ml50% isopropyl ethers/40%/10%
In bonding solvent, heat filtering removes insoluble matter, stirs lower slow cooling to room temperature, filters to obtain bromfenac sodium fine work 46.5g, yield
93%, content 98.7%.
Embodiment 5-4
The heating of the bromfenac sodium crude products of 50g contents 95% is dissolved in the water composition of the ethyl alcohol of 1600ml50% isopropyl ethers/45%/5%
In the mixed solvent, heat filtering remove insoluble matter, stir lower slow cooling to room temperature, filter to obtain bromfenac sodium fine work 47.5g, yield
94%, content 98.6%.
Claims (10)
1. a kind of preparation method of bromfenac sodium, it is characterized in that reaction scheme is as follows：
Step 1：Intermediate II is obtained by the reaction under Louis acid catalysis with chloroacetonitrile in starting material I；
Step 2：Intermediate III is obtained by the reaction with parabromobenzoyl chloride in intermediate II under Louis acid catalysis；
Step 3：Intermediate III and acidic aqueous solution are obtained by the reaction intermediate IV, the acidic aqueous solution for content 30% with
On hydrochloric acid, the aqueous solution of sulfuric acid or phosphoric acid；
Step 4：Intermediate IV obtains bromfenac sodium with NaOH reactant aqueous solutions.
2. a kind of preparation method of bromfenac sodium as described in claim 1, it is characterized in that：
Lewis acid described in step 1 is selected from boron trifluoride, boron chloride, zinc chloride, ferric trichloride, butter of tin or four
Titanium chloride, reaction temperature are 40~80 DEG C；
Lewis acid described in step 2 is selected from alchlor, boron trifluoride, boron chloride, zinc chloride, ferric trichloride, four chlorinations
Tin or titanium tetrachloride, reaction temperature are 20~80 DEG C；
Acidic aqueous solution described in step 3 is selected from 30%~38% aqueous hydrochloric acid solution, 60%~80% aqueous sulfuric acid
Or 80~98% phosphate aqueous solution, reaction temperature be 30~120 DEG C；
The reaction temperature of step 4 is 50~100 DEG C.
3. a kind of preparation method of bromfenac sodium as described in claim 2, it is characterized in that：
Lewis acid described in step 1 is selected from zinc chloride or titanium tetrachloride；
Lewis acid described in step 2 is selected from alchlor or titanium tetrachloride；
The aqueous sulfuric acid that acidic aqueous solution described in step 3 is 60%~80%；
The concentration of NaOH aqueous solutions described in step 4 is 20%~50%.
4. a kind of preparation method of bromfenac sodium as described in claim 3, it is characterized in that：
The reaction temperature of step 1 is 60~70 DEG C；
The reaction temperature of step 2 is 60~70 DEG C；
The reaction temperature of step 3 is 80~90 DEG C；
The reaction temperature of step 4 is 60~65 DEG C.
5. a kind of preparation method of bromfenac sodium as described in claim 4, it is characterized in that：
The molar ratio of starting material I and chloroacetonitrile is 1 in step 1:1-1.5 ；
The molar ratio of intermediate II and parabromobenzoyl chloride is 1 in step 2:1-3 ；
Acid and III molar ratio of intermediate are 1 in step 3:0.1-1 ；
The molar ratio of NaOH and intermediate IV is 1 in step 4：0.5-1.
6. a kind of preparation method of bromfenac sodium as described in claim 1-5 is any, it is characterized in that：
Reaction dissolvent is selected from alkane, dichloromethane, chloroform, carbon tetrachloride or the 1,2- dichloros of C6~C8 in step 1
Ethane；
Reaction dissolvent is selected from alkane, dichloromethane, chloroform, carbon tetrachloride or the 1,2- dichloros of C6~C8 in step 2
Ethane；
In step 4 reaction dissolvent be selected from the fatty alcohol of C1~C4, the alkane of C6~C8, tetrahydrofuran, dioxane,
One or more in benzene, toluene or dimethylbenzene.
7. a kind of preparation method of bromfenac sodium as described in claim 6, it is characterized in that：
The molar ratio of lewis acid described in step 1 and starting material I are 1:2-10 ；
Lewis acid described in step 2 and the molar ratio of intermediate II are 1:1-10 ；
Acid and III molar ratio of intermediate are 1 in step 3:0.2-0.5.
8. a kind of preparation method of bromfenac sodium as described in claim 1~5 is any, it is characterized in that further including following
Essence
Step processed：Bromfenac sodium is recrystallized using mixed solvent A, the mixed solvent A is by 40%~50% volume
The isopropyl ether of part, the ethyl alcohol of 40%~45% parts by volume and excess water composition.
9. compound II, structure are shown below：
。
10. compound III, structure are shown below：
。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410138392.8A CN104974057B (en) | 2014-04-08 | 2014-04-08 | The preparation method and important intermediate of a kind of bromfenac sodium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410138392.8A CN104974057B (en) | 2014-04-08 | 2014-04-08 | The preparation method and important intermediate of a kind of bromfenac sodium |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104974057A CN104974057A (en) | 2015-10-14 |
| CN104974057B true CN104974057B (en) | 2018-05-18 |
Family
ID=54271075
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410138392.8A Active CN104974057B (en) | 2014-04-08 | 2014-04-08 | The preparation method and important intermediate of a kind of bromfenac sodium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104974057B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107573311A (en) * | 2017-08-09 | 2018-01-12 | 江苏工程职业技术学院 | A kind of synthetic method of Dapagliflozin |
| CN110885296B (en) * | 2018-09-11 | 2022-11-04 | 新发药业有限公司 | Preparation method of bromfenac sodium |
| CN111848410A (en) * | 2020-07-13 | 2020-10-30 | 上海万巷制药有限公司 | Preparation method of 2-nitro-aniline |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4126635A (en) * | 1975-08-13 | 1978-11-21 | A. H. Robins Company, Incorporated | 2-amino-3-(5- and 6-)benzoylphenylacetic acids, esters and metal salts thereof |
-
2014
- 2014-04-08 CN CN201410138392.8A patent/CN104974057B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4126635A (en) * | 1975-08-13 | 1978-11-21 | A. H. Robins Company, Incorporated | 2-amino-3-(5- and 6-)benzoylphenylacetic acids, esters and metal salts thereof |
Non-Patent Citations (2)
| Title |
|---|
| Antiinflammatory Agents. 3.l Synthesis and Pharmacological Evaluation of 2-Amino-3-benzoylphenylacetic Acid and Analogues;David A. Walsh et al.;《journal of medicinal chemistry》;19841130;1379-1388 * |
| 溴芬酸钠的合成;夏泽宽等;《中国医药大学学报》;20031231;405-406 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104974057A (en) | 2015-10-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106256824B (en) | Preparation method of high-purity delafloxacin meglumine salt | |
| CN100491339C (en) | Technique for synthesizing antineoplastic melphalan | |
| CN104974057B (en) | The preparation method and important intermediate of a kind of bromfenac sodium | |
| CN105732622A (en) | Preparation method of apixaban | |
| CN102558005A (en) | Environmentally-friendly method for synthesizing selenomethionine | |
| CN104058954B (en) | A kind of friendly process preparing keto-leucine calcium in aqueous phase | |
| CN102367260A (en) | Synthesis method of 2-aminopyrimidine-5-boric acid | |
| CN102731605B (en) | A kind of purification process of Abiraterone acetate | |
| CN105198718A (en) | Preparation method for buparvaquone | |
| CA2368815A1 (en) | Novel synthesis and crystallization of piperazine ring-containing compounds | |
| CN104844593A (en) | Synthetic method for Apixaban drug intermediate | |
| CN102146079A (en) | Preparation method of scopolamine butylbromide | |
| CN110305067A (en) | A kind of optimum synthesis technique of anticancer drug Dacarbazine | |
| CN101565428B (en) | Preparation method of prulifloxacin | |
| CN103665084A (en) | Method for preparing abiraterone acetate | |
| CN102558069A (en) | Method for preparing intermediate in process of preparing bendamustine hydrochloride | |
| CN106957237B (en) | A method of synthesis bromfenac sodium | |
| CN102485722B (en) | Aliskiren, its intermediates and medicinal salt, as well as preparation method thereof | |
| CN102464699A (en) | Method for preparing carbenoxolone sodium | |
| CN111747879B (en) | Large-process synthesis method of erexib | |
| CN102633594A (en) | Method for synthesizing triphenylchloromethane by using triphenylmethyl alkyl ether | |
| CN106748884B (en) | Preparation method of bicalutamide intermediate | |
| CN106117200B (en) | Prevention or the preparation method for the treatment of joint replacement phlebothrombosis medicine Eliquis | |
| CN102363611A (en) | Method for producing pharmaceutical grade dibenzothiazyl disulfide (DM) by using sodium nitrite as oxidant | |
| CN102180864A (en) | Preparation method of strontium ranelate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |