CN101701003B - Diclofenac sodium synthetic method - Google Patents
Diclofenac sodium synthetic method Download PDFInfo
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- CN101701003B CN101701003B CN 200910224071 CN200910224071A CN101701003B CN 101701003 B CN101701003 B CN 101701003B CN 200910224071 CN200910224071 CN 200910224071 CN 200910224071 A CN200910224071 A CN 200910224071A CN 101701003 B CN101701003 B CN 101701003B
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- 229960001193 diclofenac sodium Drugs 0.000 title claims abstract description 17
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 title claims abstract description 17
- 238000010189 synthetic method Methods 0.000 title claims abstract description 6
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical compound NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000006482 condensation reaction Methods 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 22
- 239000003513 alkali Substances 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- IHRGEGVVWUFMOQ-UHFFFAOYSA-N acetamide bromobenzene Chemical group C(C)(=O)N.BrC1=CC=CC=C1 IHRGEGVVWUFMOQ-UHFFFAOYSA-N 0.000 claims description 18
- 239000000843 powder Substances 0.000 claims description 18
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 17
- 239000011707 mineral Substances 0.000 claims description 17
- 235000010755 mineral Nutrition 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 229960005081 diclofenamide Drugs 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000008367 deionised water Substances 0.000 claims description 5
- 229910021641 deionized water Inorganic materials 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- KPHWPUGNDIVLNH-UHFFFAOYSA-M diclofenac sodium Chemical compound [Na+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KPHWPUGNDIVLNH-UHFFFAOYSA-M 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 2
- 229940093916 potassium phosphate Drugs 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 abstract 2
- BYABPBCYOWJRGQ-UHFFFAOYSA-N 2-(2-bromophenyl)-n,n-dimethylacetamide Chemical compound CN(C)C(=O)CC1=CC=CC=C1Br BYABPBCYOWJRGQ-UHFFFAOYSA-N 0.000 abstract 2
- JDMFXJULNGEPOI-UHFFFAOYSA-N 2,6-dichloroaniline Chemical compound NC1=C(Cl)C=CC=C1Cl JDMFXJULNGEPOI-UHFFFAOYSA-N 0.000 abstract 1
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 150000007529 inorganic bases Chemical class 0.000 abstract 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 17
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 15
- 238000000967 suction filtration Methods 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 230000006837 decompression Effects 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000011084 recovery Methods 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000010751 Ullmann type reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- HDUUZPLYVVQTKN-UHFFFAOYSA-N 2,6-dichloro-n-phenylaniline Chemical compound ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 HDUUZPLYVVQTKN-UHFFFAOYSA-N 0.000 description 1
- IUJAAIZKRJJZGQ-UHFFFAOYSA-N 2-(2-chlorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC=C1Cl IUJAAIZKRJJZGQ-UHFFFAOYSA-N 0.000 description 1
- ZNLYBPACXSOQGX-UHFFFAOYSA-N 2-[(2,6-dichlorobenzoyl)amino]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1NC(=O)C1=C(Cl)C=CC=C1Cl ZNLYBPACXSOQGX-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- ITIONVBQFUNVJV-UHFFFAOYSA-N Etomidoline Chemical compound C12=CC=CC=C2C(=O)N(CC)C1NC(C=C1)=CC=C1OCCN1CCCCC1 ITIONVBQFUNVJV-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 230000021523 carboxylation Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000005171 halobenzenes Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229940006198 sodium phenylacetate Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a diclofenac sodium synthetic method; N,N- dimethyl o-bromophenylacetamide and 2,6-dichloroaniline carry out condensation reaction in organic solvent to prepare N,N-dimethyl-2-(2,6- dichloroaniline) phenylacetamide (compound II) under the existence of Fe catalytic agent and inorganic base; hydrolysis reaction is carried out to the compound II to obtain diclofenac sodium, by calculating the N,N- dimethyl o-bromophenylacetamide, the overall yield is about 80 percent. The synthetic method has high yield and low cost and is environmental friendly, therefore, the method has good industrial prospect.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, particularly relate to a kind of non-steroidal anti-inflammatory analgesics synthetic method of sodium diclofenac.
Background technology
DICLOFENAC SODIUM BP, its chemistry 2-(2,6-dichlorobenzene amido) sodium phenylacetate by name, molecular formula: C
14H
10C
12NNaO
2, molecular weight: 318.13.Be white or off-white color crystalline powder.Structural formula is shown below:
DICLOFENAC SODIUM BP is by Switzerland vapour Ba-Jia Ji company development, and imitates anti-inflammatory analgesic by force in a kind of non-steroidal of listing in 1974, is widely used in the pain, inflammation of each rheumatoid arthritis, lupus erythematosus, neuritis and postoperative etc.Because its good effect, oral absorption is rapid, drains soon, takes no depot action for a long time, and difference between individuals is little, is one of world's situation of selling well medicine always.
It is that starting raw material makes key intermediate 2 through Ullmann condensation and decarboxylic reaction that English Patent 1132128, USP 3558690 etc. have been narrated with adjacent chlorine (bromine, iodine) phenylformic acid; The 6-dichloro diphenylamine promptly gets DICLOFENAC SODIUM BP through acidylate, pass ring, hydrolysis/salify then.Present method is that the pharmaceutical factory is used to the operational path produced the earliest, be characterized in that raw material is easy to get, but reactions step is tediously long, total recovery lower (about 15%).Japanese Patent 55108845 has been described with adjacent halobenzene formic acid and 2, and the condensation of 6-dichlorphenamide bulk powder gets 2-(2,6-dichlorobenzene amido) phenylformic acid, uses diazomethane or sodium cyanide etc. to be carbon source again, increases a carbon atom and obtains product.Owing to have complicated operation and use problem such as dangerous hypertoxic raw material, do not have industrial production to be worth.(Chinese patent, publication number: CN 1580039A) described with the pimelinketone is starting raw material to Chen Fener etc., makes DICLOFENAC SODIUM BP through chlorination, carboxylation, hydro-reduction, condensation, aromizing/salt-forming reaction.Though this method yield is higher, tediously long, used organophosphorus, the palladium catalyst of step is very big to the toxicity of environment.USP 4978773, Qin Bingchang etc. (use chemical industry, 2008,3; 275) and (Institutes Of Technology Of Taiyuan's journal, 2004,6 such as Wei Wenlong; 710) narrated with 2,6-dichloro diphenylamine and chloroacetyl chloride are main raw material, pay-the Ke alkylation through acidylate, intramolecularly; Obtain 1-(2, the 6-dichlorophenyl) Indolin-2-one, obtain product through the alkaline hydrolysis open loop.This method is the working method that generally adopts at present, but reactions step is more, and total recovery is lower.1979, Japanese Patent 72152,87748,108844 grades have disclosed NSC 4613 and 2, and the 6-dichlorphenamide bulk powder carries out Ullmann condensation reaction (Liv Ullmann condensation reaction) and goes on foot the simple and direct method of DICLOFENAC SODIUM BP that makes under the catalysis of cuprous iodide.China Zhu Shui ploughs (Chinese Journal of Pharmaceuticals, 1991,22,387), (Jiangsu chemical industry such as Gao Xueming; 1989,3,19), (Guangdong chemical industry such as Huang Qipeng; 1992,3,36) and (Chinese Journal of Pharmaceuticals, 2000 such as Fu Jianlong; 31,296) all improved the method for Japanese Patent, but yield is generally lower, and catalyzer cuprous iodide cost is higher.
Summary of the invention
The object of the invention is to overcome the deficiency of prior art, and a kind of preparation method of environmentally friendly, yield is high, cost is low DICLOFENAC SODIUM BP is provided.
Compound method of the present invention may further comprise the steps:
(1) in the presence of Fe catalyzer and mineral alkali, make N, the adjacent bromobenzene ethanamide and 2 of N-dimethyl-, the 6-dichlorphenamide bulk powder carries out condensation reaction and makes N in organic solvent, N-dimethyl--2-(2,6-dichlorobenzene amido) phenylacetamide (compound I I); Temperature of reaction is 100～200 ℃, and the reaction times is 30～90h.
(2) N that obtains of step (1), N-dimethyl--2-(2,6-dichlorobenzene amido) phenylacetamide and mineral alkali in solvent, be hydrolyzed react DICLOFENAC SODIUM BP; Temperature of reaction is 50～150 ℃, and the reaction times is 2～50h.。
By N, the adjacent bromobenzene ethanamide of N-dimethyl-calculates, and total recovery is about 80%.Wherein adopt iron catalyst to replace traditional copper catalyst, iron catalyst is compared price with copper catalyst cheaper, friendly more to environment.Mineral alkali in the reaction mainly plays the auxiliary catalysis effect.
Product meets USP, BP, Japanese officina and Chinese Pharmacopoeia each item standard, and its synthetic route is following:
Step of the present invention (1) is by N, the adjacent bromobenzene ethanamide and 2 of N-dimethyl-, and the 6-dichlorphenamide bulk powder prepares compound I I through condensation reaction, N, the adjacent bromobenzene ethanamide and 2 of N-dimethyl-, the mol ratio of 6-dichlorphenamide bulk powder is 1: 2～5.The used Fe catalyzer of condensation reaction is Fe
2O
3, Fe
3O
4Or FeCl
3, be preferably Fe
2O
3, N, adjacent bromobenzene ethanamide of N-dimethyl-and Fe
2O
3Mol ratio be 1: 0.1～0.3.The solvent that reacts used can be chlorobenzene, bromobenzene, toluene, YLENE or N, and dinethylformamide (DMF) can be a single solvent, also can be mixed solvent.The mineral alkali that reacts used is Pottasium Hydroxide, soda ash light, Anhydrous potassium carbonate, potassiumphosphate, and preferred mineral alkali is an Anhydrous potassium carbonate.N, the mol ratio of adjacent bromobenzene ethanamide of N-dimethyl-and mineral alkali is 1: 2～3.Temperature of reaction is 100～200 ℃.Reaction times is 30～90h.
The preferred reaction conditions of step (1) is: N, and the adjacent bromobenzene ethanamide and 2 of N-dimethyl-, the mol ratio of 6-dichlorphenamide bulk powder is 1: 2～3, N, adjacent bromobenzene ethanamide of N-dimethyl-and Fe
2O
3Mol ratio be 1: 0.15～0.25, reaction solvent is YLENE or N, dinethylformamide (DMF), mineral alkali are Anhydrous potassium carbonate, N, the mol ratio of adjacent bromobenzene ethanamide of N-dimethyl-and mineral alkali is 1: 2.5～3, temperature of reaction is 100～160 ℃.Reaction times is 40～60h.
Step of the present invention (2) is by compound I I (N; N-dimethyl--2-(2; 6-dichlorobenzene amido) phenylacetamide) with the mineral alkali prepared in reaction DICLOFENAC SODIUM BP that in solvent, is hydrolyzed; The mineral alkali that reacts used is Pottasium Hydroxide, Anhydrous potassium carbonate, sodium hydroxide, and preferred mineral alkali is Pottasium Hydroxide, sodium hydroxide.The mol ratio of compound I I and alkali is 1: 3～20.Solvent be water or inert organic solvents as: methyl alcohol, ethanol, propyl alcohol, dioxane can be single solvents, also can be mixed solvents.Temperature of reaction is 50～150 ℃, and the reaction times is 2～50h.
The preferred reaction conditions of step (2) is: alkali is Pottasium Hydroxide, and the mol ratio of compound I I and alkali is 1: 4～15, and solvent is an ethanol, and temperature of reaction is 60～70 ℃.Reaction times 4～20h.
The present invention has overcome many deficiencies of prior art, and yield is high, low, the environmental friendliness of cost, has excellent industrial application foreground.
Embodiment
Below in conjunction with embodiment, specific embodiments of the invention describes in further detail.Following examples are used to explain the present invention, but are not used for limiting scope of the present invention.
Embodiment 1
1) N, the preparation of N-dimethyl--2-(2,6-dichlorobenzene amido) phenylacetamide
With N, and the adjacent bromobenzene ethanamide of N-dimethyl-(5.2g, 0.0215mol), 2, the 6-dichlorphenamide bulk powder (8.5g, 0.0525mol), Fe
2O
3(0.69g, 0.0043mol), Anhydrous potassium carbonate (7.4g, 0.0538mol) and YLENE (80mL; Bp:138～141 ℃) place the exsiccant reaction flask, under nitrogen protection, stir refluxed reaction 48 hours; Temperature of reaction is 135 ℃, after reaction finishes, adds activated carbon; Suction filtration while hot, filtrate decompression is concentrated into dried.Residue is used dissolve with methanol, crystallisation by cooling in ice-water bath, suction filtration, dry incarnadine solid 5.7g (the compound I I that gets; N, N-dimethyl--2-(2,6-dichlorobenzene amido) phenylacetamide), yield 82.1%.Mp:158～160 ℃, HPLC measures content greater than 98%.
2) DICLOFENAC SODIUM BP is synthetic
Pottasium Hydroxide (2.0g), ethanol (15mL) are placed reaction flask, add compound I I (1.0g) down in stirring, 65 ℃ of reaction 6h; After reaction finished, decompression steamed solvent, residue water (10mL) heating for dissolving; Crystallisation by cooling in ice-water bath, suction filtration, the dry bullion that gets.Bullion is used the deionized water recrystallization, and decolorizing with activated carbon gets white crystalline powder 0.94g, yield 95.7%.Mp:284～285 ℃, HPLC measures content greater than 99%.
The total recovery of above-mentioned reaction is 78.6%.
Embodiment 2
1) N, the preparation of N-dimethyl--2-(2,6-dichlorobenzene amido) phenylacetamide
With N, and the adjacent bromobenzene ethanamide of N-dimethyl-(5.2g, 0.0215mol), 2, the 6-dichlorphenamide bulk powder (10.5g, 0.0645mol), Fe
2O
3(0.86g, 0.0054mol), Anhydrous potassium carbonate (7.4g, 0.0538mol) and YLENE (100mL; Bp:138～141 ℃) place the exsiccant reaction flask, under nitrogen protection, stir refluxed reaction 52 hours; Temperature of reaction is 130 ℃, after reaction finishes, adds activated carbon; Suction filtration while hot, filtrate decompression is concentrated into dried.Residue is used dissolve with methanol, crystallisation by cooling in ice-water bath, suction filtration, dry incarnadine solid 5.8g (the compound I I that gets; N, N-dimethyl--2-(2,6-dichlorobenzene amido) phenylacetamide), yield 83.6%.Mp:158～160 ℃, HPLC measures content greater than 98%.
2) DICLOFENAC SODIUM BP is synthetic
Pottasium Hydroxide (1.0g), ethanol (15mL) are placed reaction flask, add compound I I (1.0g) down in stirring, 70 ℃ of reaction 8h; After reaction finished, decompression steamed solvent, residue water (10mL) heating for dissolving; Crystallisation by cooling in ice-water bath, suction filtration, the dry bullion that gets.Bullion is used the deionized water recrystallization, and decolorizing with activated carbon gets white crystalline powder 0.93g, yield 94.7%.Mp:283～285 ℃, HPLC measures content greater than 98%.
The total recovery of above-mentioned reaction is 79.2%.
Embodiment 3
1) N, the preparation of N-dimethyl--2-(2,6-dichlorobenzene amido) phenylacetamide
With N, and the adjacent bromobenzene ethanamide of N-dimethyl-(5.2g, 0.0215mol), 2, the 6-dichlorphenamide bulk powder (8.5g, 0.0525mol), Fe
2O
3(0.69g, 0.0043mol), Anhydrous potassium carbonate (8.9g, 0.0645mol) and DMF (100mL; Bp:153 ℃) place the exsiccant reaction flask, under nitrogen protection, stir refluxed reaction 52 hours; Temperature of reaction is 140 ℃, after reaction finishes, adds activated carbon; Suction filtration while hot, filtrate decompression is concentrated into dried.Residue is used dissolve with methanol, crystallisation by cooling in ice-water bath, suction filtration, dry incarnadine solid 5.6g (the compound I I that gets; N, N-dimethyl--2-(2,6-dichlorobenzene amido) phenylacetamide), yield 80.7%.Mp:159～160 ℃, HPLC measures content greater than 98%.
2) DICLOFENAC SODIUM BP is synthetic
Pottasium Hydroxide (1.5g), ethanol (15mL) are placed reaction flask, add compound I I (1.0g) down in stirring, 60 ℃ of reaction 10h; After reaction finished, decompression steamed solvent, residue water (10mL) heating for dissolving; Crystallisation by cooling in ice-water bath, suction filtration, the dry bullion that gets.Bullion is used the deionized water recrystallization, and decolorizing with activated carbon gets white crystalline powder 0.95g, yield 96.7%.Mp:283～285 ℃, HPLC measures content greater than 98%.
The total recovery of above-mentioned reaction is 78.04%.
Embodiment 4
1) N, the preparation of N-dimethyl--2-(2,6-dichlorobenzene amido) phenylacetamide
With N, and the adjacent bromobenzene ethanamide of N-dimethyl-(5.2g, 0.0215mol), 2, the 6-dichlorphenamide bulk powder (8.5g, 0.0525mol), Fe
2O
3(0.69g, 0.0043mol), anhydrous phosphoric acid potassium (13.67g, 0.0645mol) and DMF (80mL; Bp:153 ℃) place the exsiccant reaction flask, under nitrogen protection, stir refluxed reaction 54 hours; Temperature of reaction is 135 ℃, after reaction finishes, adds activated carbon; Suction filtration while hot, filtrate decompression is concentrated into dried.Residue is used dissolve with methanol, crystallisation by cooling in ice-water bath, suction filtration, dry incarnadine solid 5.7g (the compound I I that gets; N, N-dimethyl--2-(2,6-dichlorobenzene amido) phenylacetamide), yield 82.1%.Mp:158～160 ℃, HPLC measures content greater than 98%.
2) DICLOFENAC SODIUM BP is synthetic
Sodium hydroxide (1.0g), ethanol (15mL) are placed reaction flask, add compound I I (1.0g) down in stirring, 65 ℃ of reaction 7h; After reaction finished, decompression steamed solvent, residue water (10mL) heating for dissolving; Crystallisation by cooling in ice-water bath, suction filtration, the dry bullion that gets.Bullion is used the deionized water recrystallization, and decolorizing with activated carbon gets white crystalline powder 0.95g, yield 96.7%.Mp:283～285 ℃, HPLC measures content greater than 98%.
The total recovery of above-mentioned reaction is 79.39%.
The above only is a preferred implementation of the present invention; Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from know-why of the present invention; Can also make some improvement and retouching, these improvement and retouching also should be regarded as protection scope of the present invention.
Claims (9)
1. a synthetic method of sodium diclofenac is characterized in that, may further comprise the steps:
(1) in the presence of Fe catalyzer and mineral alkali, make N, the adjacent bromobenzene ethanamide and 2 of N-dimethyl-, the 6-dichlorphenamide bulk powder carries out condensation reaction and makes N in organic solvent, N-dimethyl--2-(2,6-dichlorobenzene amido) phenylacetamide; Temperature of reaction is 100～200 ℃, and the reaction times is 30～90h;
(2) N that obtains of step (1), N-dimethyl--2-(2,6-dichlorobenzene amido) phenylacetamide and mineral alkali in solvent, be hydrolyzed react DICLOFENAC SODIUM BP; Temperature of reaction is 50～150 ℃, and the reaction times is 2～50h; The gained DICLOFENAC SODIUM BP is used the deionized water recrystallization;
Fe catalyzer in the said step (1) is Fe
2O
3, Fe
3O
4Or FeCl
3
2. compound method as claimed in claim 1 is characterized in that, N in the said step (1), and the adjacent bromobenzene ethanamide and 2 of N-dimethyl-, the mol ratio of 6-dichlorphenamide bulk powder is 1: 2～5.
3. compound method as claimed in claim 2 is characterized in that, N in the said step (1), and the adjacent bromobenzene ethanamide and 2 of N-dimethyl-, the mol ratio of 6-dichlorphenamide bulk powder is 1: 2～3.
4. compound method as claimed in claim 1 is characterized in that, N in the said step (1), adjacent bromobenzene ethanamide of N-dimethyl-and Fe
2O
3Mol ratio be 1: 0.1～0.3.
5. compound method as claimed in claim 1 is characterized in that, the mineral alkali that adopts in the said step (1) is Pottasium Hydroxide, soda ash light, Anhydrous potassium carbonate or potassiumphosphate.
6. compound method as claimed in claim 5 is characterized in that, N in the said step (1), and the mol ratio of adjacent bromobenzene ethanamide of N-dimethyl-and mineral alkali is 1: 2～3.
7. compound method as claimed in claim 1 is characterized in that, the organic solvent in the said step (1) is selected from chlorobenzene, bromobenzene, toluene, YLENE or N, one or more in the dinethylformamide.
8. compound method as claimed in claim 1 is characterized in that, the mineral alkali that adopts in the said step (2) is a sodium hydroxide; N, the mol ratio of N-dimethyl--2-(2,6-dichlorobenzene amido) phenylacetamide and mineral alkali is 1: 3～20.
9. compound method as claimed in claim 1 is characterized in that, the solvent in the said step (2) is selected from one or more in water, methyl alcohol, ethanol, propyl alcohol, the dioxane.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4283532A (en) * | 1978-08-08 | 1981-08-11 | Ikeda Mohando Co., Ltd. | Process for preparation of o-(2,6-dichloroanilino)phenylacetic acid and novel intermediate for use in preparation of the same |
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2009
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4283532A (en) * | 1978-08-08 | 1981-08-11 | Ikeda Mohando Co., Ltd. | Process for preparation of o-(2,6-dichloroanilino)phenylacetic acid and novel intermediate for use in preparation of the same |
Non-Patent Citations (5)
| Title |
|---|
| Arkaitz Correa and Carsten Bolm.Iron-Catalyzed N-Arylation of Nitrogen Nucleophiles.《Angew.Chem.Int.Ed.》.2007,第46卷(第46期),8862-8865. * |
| Arkaitz Correa,et al..Iron-catalysed carbon-heteroatom and heteroatom-heteroatom bond forming processes.《Chem.Soc.Rev.》.2008,第37卷(第6期),1108-1117. * |
| Arkaitz Correa,et al..Synthesis of Diarylamines Catalyzed by Iron Salts.《Chem.Eur.J.》.2008,第14卷(第35期),10919-10922. * |
| Carsten Bolm,et al..Iron-Catalyzed Reactions in Organic Synthesis.《Chem.Rev.》.2004,第104卷(第12期),6217-6254. * |
| JP昭55-105656A 1980.08.13 |
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