CN109553544A - A kind of synthetic method of C14H10Cl2NNaO2 - Google Patents
A kind of synthetic method of C14H10Cl2NNaO2 Download PDFInfo
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- CN109553544A CN109553544A CN201710885360.8A CN201710885360A CN109553544A CN 109553544 A CN109553544 A CN 109553544A CN 201710885360 A CN201710885360 A CN 201710885360A CN 109553544 A CN109553544 A CN 109553544A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The present invention relates to a kind of synthetic method of C14H10Cl2NNaO2, synthetic route isWherein, the X in compound A is Cl, Br or I, M Me, Et or Pro；Catalyst used in condensation reaction is CuI, CuBr, CuBr2Or CuF2；Reacting carbohydrate ligands used is D-Glucosamine Hydrochloride, glucose, chitosan, D- galactolipin and L-arabinose.The synthetic method of C14H10Cl2NNaO2 of the present invention, product purity are up to 98% or more, and two step total recoverys are up to 90% or more, high income；High using D-Glucosamine Hydrochloride fictitious hosts, the ligands such as big 8-hydroxyquinoline of environmental pollution also mitigate the pollution to environment while reducing production cost.
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a kind of conjunction of the potent anti-inflammatory analgesic C14H10Cl2NNaO2 of non-steroidal
At method.
Background technique
C14H10Cl2NNaO2, also known as diclofenac sodium, entitled 2- (2, the 6- dichloro-benzenes amino) sodium phenylacetate of chemistry, is by auspicious
Scholar's vapour Ba-Jia Ji company develops, and in a kind of potent anti-inflammatory analgesic of non-steroidal of listing in 1974, closes for each rheumatoid
Fever caused by section inflammation, lupus erythematosus, neuritis and cancer, postoperative pain and a variety of causes etc..
Its synthetic route mainly has: 1. o-Halogen benzoic acids and 2,6- dichloroaniline are condensed to obtain 2- (2,6- dichloro-benzenes amino)
Benzoic acid, then with diazomethane or Cymag etc. be carbon source, increase a carbon atom and obtain product；2. 1- (2,6- dichlorophenyl)
Indole-2,3-dione, chosen property reduction, the carbonyl of removal 3, then basic hydrolysis obtains product；3. o-halophenylacetic acid or
Its derivative obtains product 4. 2,2,6,6- tetrachloro cyclohexanone and adjacent aminobenzene through condensation with 2,6- dichloroaniline
Acid condensation forms schiff bases, through dehydrohalogenation, aromatisation, forms a variety of routes such as product.In its a variety of preparation method, by
O-chlorobenzene acetic acid and 2,6-DCA synthesis are relatively simple, but the yield of the document report route is all below 42. 5%.Just
The problem of always existing such as Ullmann reaction, the reaction time is long, and yield is low, and need to use catalyst costly and
Ligand.
Summary of the invention
The advantages that the purpose of the present invention is to provide a kind of production cost is low, and reaction yield is high, and environmental pollution is small, it is more suitable
Close the synthetic method of the C14H10Cl2NNaO2 of industrialized production.
In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical scheme:
A kind of synthetic method of C14H10Cl2NNaO2, it is characterised in that synthetic route is
Wherein, the X in compound A is Cl, Br or I, M Me, Et or Pro；Catalyst used in condensation reaction be CuI, CuBr,
CuBr2Or CuF2；React carbohydrate ligands used be D-Glucosamine Hydrochloride, glucose, chitosan, D- galactolipin and L- I
Uncle's sugar.
As a preference of the present invention, the X in compound A is I.
As a preference of the present invention, the M in the compound A is Me.
As a preference of the present invention, the catalyst is CuI.
As a preference of the present invention, reacting carbohydrate ligands used is D-Glucosamine Hydrochloride.
A kind of synthetic method of C14H10Cl2NNaO2, includes the following steps:
(1) in the presence of catalyst, ligand and inorganic base, so that compound A and compound B is carried out condensation reaction in a solvent and be made
Compound C；Reaction temperature is 60 ~ 140 DEG C, and the reaction time is 4 ~ 18h, after reaction, ethyl acetate is added, after centrifuge separation
Upper liquid is taken, compound C is concentrated and dried to obtain；
(2) after compound C obtained in step (1) is dissolved with solvent, NaOH aqueous solution is added, reaction, reaction temperature is hydrolyzed
It is 40 ~ 90 DEG C, the reaction time is 5 ~ 30h, and after reaction, decompression steams solvent, and residue is dissolved by heating with water, and active carbon is de-
Color filters, filtrate crystallisation by cooling in ice-water bath, filters, dry white crystalline powder C14H10Cl2NNaO2.
Solvent as described in step (1) is DMSO:H2O=1:1, DMF:H2O=1:1 or THF:H2O=1:1.
Compound used therefor A in step (1), compound B, catalyst, carbohydrate ligands and inorganic base molar ratio be 1:1:
0.02 ~ 0.2:0.02 ~ 0.2:1 ~ 3.
The molar ratio of compound used therefor C and NaOH are 1:1 ~ 5 in step (2).
In step (2), the solvent of dissolved compound C is ethyl alcohol, tetrahydrofuran, n,N-Dimethylformamide or toluene, and
The dosage of solvent is 0.5 ~ 5L/mol compound C.
The synthetic method of C14H10Cl2NNaO2 of the present invention, product purity are up to 98% or more, and two step total recoverys are up to
90% or more, high income；High using D-Glucosamine Hydrochloride fictitious hosts, the big 8-hydroxyquinoline etc. of environmental pollution is matched
Body also mitigates the pollution to environment while reducing production cost.
Specific embodiment
Below by specific embodiment, the present invention is described further.But protection scope of the present invention is not implementation
Example is limited.
Embodiment: (1) preparation of compound C
The adjacent iodobenzene methyl acetate of 27.6g (0.1mol), 16.2g (0.1mol) 2,6- dichloro-benzenes are sequentially added in three-necked flask
Amine, 1.9g (0.01mol) CuI, 2.2g (0.01mol) D-Glucosamine Hydrochloride and 65.2g (0.2mol) Cs2CO3, then
50mL DMSO and 50mL water is added, stirring is allowed to dissolve, and control reaction temperature is 100 DEG C, successive reaction 10h.Reaction terminates
Afterwards, 100mL ethyl acetate is added, takes upper liquid after centrifuge separation, is concentrated and dried to obtain compound C 29.6g, yield 95.5%,
It is 98.8% that HPLC, which measures content,.
(2) synthesis of C14H10Cl2NNaO2
25g (0.08mol) compound C, 120mLN are added in three-necked flask, dinethylformamide stirs and is warming up to 75 DEG C
The solution that is made into of 9.6g (0.24mol) NaOH and 50g water is added afterwards, the reaction was continued 20h, after reaction, decompression steams molten
Agent, residue are dissolved by heating with 200mL water, and active carbon decoloring filters, filtrate crystallisation by cooling in ice-water bath, filters, dry
White crystalline powder C14H10Cl2NNaO2 24.3g, yield 95%, it is 98.5% that HPLC, which measures content,.
The total recovery of above-mentioned reaction is 90.7%.
The synthetic method for the C14H10Cl2NNaO2 that the present embodiment uses, product purity is high, and two step total recoverys are up to 90% or more,
High income；High using D-Glucosamine Hydrochloride fictitious hosts, the ligands such as big 8-hydroxyquinoline of environmental pollution reduce
The pollution to environment is also mitigated while production cost.
Embodiment 2:(1) compound C preparation
The adjacent iodobenzene methyl acetate of 27.6g (0.1mol), 16.2g (0.1mol) 2,6- dichloro-benzenes are sequentially added in three-necked flask
Amine, 2.8g (0.015mol) CuI, 3.3g (0.015mol) D-Glucosamine Hydrochloride and 81.5g (0.25mol) Cs2CO3, so
After add 60mL DMSO and 60mL water, stirring is allowed to dissolve, and control reaction temperature is 90 DEG C, successive reaction 12h.Reaction knot
Shu Hou, be added 120mL ethyl acetate, take upper liquid after centrifuge separation, be concentrated and dried compound C 29.2g, yield are
It is 98.8% that 94.2%, HPLC, which measure content,.
(2) synthesis of C14H10Cl2NNaO2
25g (0.08mol) compound C, 160mLN are added in three-necked flask, dinethylformamide stirs and is warming up to 80 DEG C
The solution that 8g (0.2mol) NaOH and 35g water is made into is added afterwards, the reaction was continued for 24 hours, and after reaction, decompression steams solvent, residual
Object 200mL water is stayed to dissolve by heating, active carbon decoloring filters, filtrate crystallisation by cooling in ice-water bath, filters, whitely dry
Crystalline powder C14H10Cl2NNaO2 24.6g, yield 96.1%, it is 98.2% that HPLC, which measures content,.
The total recovery of above-mentioned reaction is 90.5%.
Embodiment 3
(1) preparation of compound C
The adjacent iodobenzene methyl acetate of 27.6g (0.1mol), 16.2g (0.1mol) 2,6- dichloro-benzenes are sequentially added in three-necked flask
Amine, 3.8g (0.02mol) CuI, 4.4g (0.02mol) D-Glucosamine Hydrochloride and 97.8g (0.3mol) Cs2CO3, then
80mL DMSO and 80mL water is added, stirring is allowed to dissolve, and control reaction temperature is 110 DEG C, successive reaction 8h.Reaction terminates
Afterwards, 160mL ethyl acetate is added, takes upper liquid after centrifuge separation, is concentrated and dried to obtain compound C 29.8g, yield 96.1%,
It is 98.7% that HPLC, which measures content,.
(2) synthesis of C14H10Cl2NNaO2
25g (0.08mol) compound C, 180mLN are added in three-necked flask, dinethylformamide stirs and is warming up to 85 DEG C
The solution that 12g (0.3mol) NaOH and 55g water is made into is added afterwards, the reaction was continued, and 18h is depressurized after reaction and is steamed solvent,
Residue is dissolved by heating with 200mL water, active carbon decoloring, is filtered, filtrate crystallisation by cooling in ice-water bath, is filtered, whitely dry
Color crystalline powder C14H10Cl2NNaO2 24.2g, yield 94.5%, it is 98.2% that HPLC, which measures content,.
The total recovery of above-mentioned reaction is 90.8%.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modifications, equivalent replacements, and improvements etc. within mind and principle should all include within protection scope of the present invention.
Claims (10)
1. a kind of synthetic method of C14H10Cl2NNaO2, it is characterised in that synthetic route is
Wherein, the X in compound A is Cl, Br or I, M Me, Et or Pro；Catalyst used in condensation reaction be CuI, CuBr,
CuBr2Or CuF2；React carbohydrate ligands used be D-Glucosamine Hydrochloride, glucose, chitosan, D- galactolipin and L- I
Uncle's sugar.
2. a kind of synthetic method of C14H10Cl2NNaO2 according to claim 1, it is characterised in that the X in compound A is I.
3. a kind of synthetic method of C14H10Cl2NNaO2 according to claim 1, it is characterised in that in the compound A
M is Me.
4. a kind of synthetic method of C14H10Cl2NNaO2 according to claim 1, it is characterised in that the catalyst is
CuI。
5. a kind of synthetic method of C14H10Cl2NNaO2 according to claim 1, it is characterised in that reacting carbohydrate ligands used is
D-Glucosamine Hydrochloride.
6. the synthetic method of C14H10Cl2NNaO2 according to claim 1, it is characterised in that include the following steps:
(1) in the presence of catalyst, ligand and inorganic base, so that compound A and compound B is carried out condensation reaction in a solvent and be made
Compound C；Reaction temperature is 60 ~ 140 DEG C, and the reaction time is 4 ~ 18h, after reaction, ethyl acetate is added, after centrifuge separation
Upper liquid is taken, compound C is concentrated and dried to obtain；
(2) after compound C obtained in step (1) is dissolved with solvent, NaOH aqueous solution is added, reaction, reaction temperature is hydrolyzed
It is 40 ~ 90 DEG C, the reaction time is 5 ~ 30h, and after reaction, decompression steams solvent, and residue is dissolved by heating with water, and active carbon is de-
Color filters, filtrate crystallisation by cooling in ice-water bath, filters, dry white crystalline powder C14H10Cl2NNaO2.
7. a kind of synthetic method of C14H10Cl2NNaO2 according to claim 6, it is characterised in that as described in step (1) molten
Agent is DMSO:H2O=1:1, DMF:H2O=1:1 or THF:H2O=1:1.
8. a kind of synthetic method of C14H10Cl2NNaO2 according to claim 6, it is characterised in that used in the step (1)
Compound A, compound B, catalyst, carbohydrate ligands and inorganic base molar ratio be 1:1:0.02 ~ 0.2:0.02 ~ 0.2:1 ~ 3.
9. a kind of synthetic method of C14H10Cl2NNaO2 according to claim 6, it is characterised in that chemical combination used in step (2)
The molar ratio of object C and NaOH are 1:1 ~ 5.
10. a kind of synthetic method of C14H10Cl2NNaO2 according to claim 6, it is characterised in that in the step (2),
The solvent of dissolved compound C is ethyl alcohol, tetrahydrofuran, n,N-Dimethylformamide or toluene, and the dosage of solvent is 0.5 ~ 5L/
Mol compound C.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710885360.8A CN109553544B (en) | 2017-09-27 | 2017-09-27 | Method for synthesizing diclofenac sodium |
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| CN201710885360.8A CN109553544B (en) | 2017-09-27 | 2017-09-27 | Method for synthesizing diclofenac sodium |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3778470A (en) * | 1972-08-23 | 1973-12-11 | A Sallman | Chemical intermediates for the production of substituted 2-anilinophenylacetic acids and esters |
| JPS537641A (en) * | 1976-07-09 | 1978-01-24 | Teikoku Hormone Mfg Co Ltd | Diphenylamine derivatives |
| JPS537640A (en) * | 1976-07-09 | 1978-01-24 | Teikoku Hormone Mfg Co Ltd | Synthesis of diphenylamine derivatives |
| CN1580039A (en) * | 2004-05-20 | 2005-02-16 | 复旦大学 | Method for synthesizing dichlofenac sodium |
| CN101701003A (en) * | 2009-12-04 | 2010-05-05 | 蚌埠丰原涂山制药有限公司 | Diclofenac sodium synthetic method |
| CN101993446A (en) * | 2009-08-13 | 2011-03-30 | 中国科学院上海药物研究所 | Novel benzanthracene cyclic compounds and preparation method and use thereof |
| CN105949128A (en) * | 2016-05-27 | 2016-09-21 | 浙江汇能生物股份有限公司 | Preparation method of nilotinib intermediate-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline |
-
2017
- 2017-09-27 CN CN201710885360.8A patent/CN109553544B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3778470A (en) * | 1972-08-23 | 1973-12-11 | A Sallman | Chemical intermediates for the production of substituted 2-anilinophenylacetic acids and esters |
| JPS537641A (en) * | 1976-07-09 | 1978-01-24 | Teikoku Hormone Mfg Co Ltd | Diphenylamine derivatives |
| JPS537640A (en) * | 1976-07-09 | 1978-01-24 | Teikoku Hormone Mfg Co Ltd | Synthesis of diphenylamine derivatives |
| CN1580039A (en) * | 2004-05-20 | 2005-02-16 | 复旦大学 | Method for synthesizing dichlofenac sodium |
| CN101993446A (en) * | 2009-08-13 | 2011-03-30 | 中国科学院上海药物研究所 | Novel benzanthracene cyclic compounds and preparation method and use thereof |
| CN101701003A (en) * | 2009-12-04 | 2010-05-05 | 蚌埠丰原涂山制药有限公司 | Diclofenac sodium synthetic method |
| CN105949128A (en) * | 2016-05-27 | 2016-09-21 | 浙江汇能生物股份有限公司 | Preparation method of nilotinib intermediate-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline |
Non-Patent Citations (1)
| Title |
|---|
| YOSHIHIRO HORIO等: "A synthesis of carbon-14-labeled sodium 2-[o[(2,6-dichlorophenyl)amino]phenyl]acetate ([14C]diclofenac sodium)", 《CHEMICAL & PHARMACEUTICAL BULLETIN》 * |
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