CN110272351A - A kind of synthetic method of Diclofenac - Google Patents
A kind of synthetic method of Diclofenac Download PDFInfo
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- CN110272351A CN110272351A CN201910640101.8A CN201910640101A CN110272351A CN 110272351 A CN110272351 A CN 110272351A CN 201910640101 A CN201910640101 A CN 201910640101A CN 110272351 A CN110272351 A CN 110272351A
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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
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
Abstract
The present invention provides a kind of synthetic method of Diclofenac, belongs to the technical field of pharmaceutical synthesis；The specific reaction step of synthetic method of the present invention is as follows: step 1): compound (a) reacts in the presence of methanol/sodium methoxide, obtains compound (b)；Step 2): compound (b) reacts in the presence of base with compound (c), obtains compound (d)；Step 3): compound (d) reacts in organic solvent, under the action of catalyst with compound (e), obtains compound (f)；The raw material of this method is easy to get, easy to operate, and high income, cost is relatively low, and the three wastes are less, highly-safe, is suitble to industrialized production.
Description
Technical field
The invention belongs to the technical fields of pharmaceutical synthesis, are related to the synthetic method of Diclofenac；Synthetic method of the present invention is former
Material is easy to get, easy to operate, and high income, cost is relatively low, and the three wastes are less, highly-safe.
Background technique
Diclofenac belongs to non-steroidal anti-inflammatory drugs.With anti-inflammatory, analgesia and refrigeration function.For rheumatic arthritis, glue
Even pain caused by property spondylitis, non-inflammatory arthralgia, arthritis, nonarticular rheumatism, non-non-articular inflammatory, various nerves
Bitterly, fever caused by cancer pain, post-traumatic pain and various inflammation etc..It is reported that the latex of DICLOFENAC DIETHYLAMINE in 2016
Agent, annual sales amount is 1,000,000,000 or more.There was only the emulsion agent of Novartis and the gelling agent listing of Huangshi hygienic material medicine company, competition in the country
It is less.
The structure of Diclofenac is as follows:
The method of existing synthesis Diclofenac are as follows:
(1)
(2)
(3)
The product yield that method (1), method (2) and method (3) obtain is respectively 84%, 61% and 85%.
The synthetic route of method (1) and method (3) is long, and step is more.
Method (2) synthetic route is reasonable, but the yield of product is lower.
2- (methyl mercapto) chloroacetic chloride has been used in method (3), it is expensive；And the SnCl comprising heavy metal is used4, right
Water body pollutes.
Summary of the invention
The present invention provides a kind of methods of new synthesis Diclofenac, are easy to get with raw material, easy to operate, high income,
The characteristics of cost is relatively low, and the three wastes are less, highly-safe, is relatively suitble to industrial production.
The present invention to solve the above problems, provide a kind of synthetic method of Diclofenac, the technical solution adopted is as follows:
A kind of synthetic method of Diclofenac, specific reaction step are as follows:
Step 1): compound (a) reacts in the presence of methanol/sodium methoxide, obtains compound (b)；
Step 2): compound (b) reacts in the presence of base with compound (c), obtains compound (d)；
Step 3): compound (d) reacts in organic solvent, under the action of catalyst with compound (e), obtains compound
(f)。
Further, compound (a) and methanol/sodium methoxide molar ratio are 1:(0.5-1.5)；Further, compound
It (a) is 1:(0.6-1.4 with methanol/sodium methoxide molar ratio)；Preferably, compound (a) is with methanol/sodium methoxide molar ratio
1:(0.9-1.1), 1:1.05,1:1.1 or 1:1.2.
Further, compound (b) reacts in the presence of base with compound (c), and the alkali is potassium hydroxide, hydroxide
Sodium, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or saleratus.
Preferably, compound (b) reacts in the presence of base with compound (c), and the alkali is sodium carbonate.
Further, the compound (c) is slowly dropped to the tetrahydrofuran solution in 0~-78 DEG C of compound (b)
In, it is slowly increased to react at room temperature after being added dropwise to complete.
Further, the molar ratio of compound (b) and compound (c) is 1:(0.5-1.5).
Further, the molar ratio of compound (b) and compound (c) is 1:(0.6-1.4).
Further, the molar ratio of compound (b) and compound (c) is 1:(0.8-1.4).
Further, the molar ratio of compound (b) and compound (c) is 1:(0.8-1.2).
Further, the molar ratio of compound (b) and compound (c) is 1:(0.9-1.1).
Preferably, the molar ratio of compound (b) and compound (c) is 1:1.05.
Preferably, the molar ratio of compound (b) and compound (c) is 1:1.1.
Preferably, the molar ratio of compound (b) and compound (c) is 1:1.2.
Further, compound (d) is reacted with compound (e), catalyst EDC.HCl, potassium hydroxide, biphosphate
Potassium, potassium phosphate or combinations thereof etc..
Further, compound (d) is reacted with compound (e), wherein organic solvent be carbon dichloride, carbon tetrachloride,
THF, DMSO or toluene.
Preferably, compound (d) is reacted with compound (e), and wherein organic solvent is carbon dichloride.
Further, the molar ratio of compound (d) and compound (e) is 1:1~5.
Preferably, the molar ratio of compound (d) and compound (e) is 1:4.
Further, after 30~60 DEG C of reactions, addition alkali is warming up to for the compound (d), compound (e) and catalyst
80-120 DEG C of hydrolysis, obtains compound (f).
Further, the alkali is potassium hydroxide, potassium dihydrogen phosphate, potassium phosphate or combinations thereof etc..
On the other hand, the present invention provides a kind of compound, the structure being as follows:
Further, compound (d) is obtained by following reaction formula:
Wherein compound (c) reacts in the presence of base with compound (b), obtains compound (d).
Problems of the prior art:
A, the synthetic route of method (1) and method (3) is long, and step is more, is unfavorable for industrialized production.
B, the synthetic route of method (2) is reasonable, but the yield of product is lower, is unfavorable for industrialized production.
C, 2- (methyl mercapto) chloroacetic chloride has been used in method (3), it is expensive；And the SnCl comprising heavy metal is used4,
Water body is polluted.
The beneficial effects of the present invention are: compared with prior art, the present invention has synthesized a kind of new intermediate -- compound
(d), a completely new synthetic route is provided, under conditions of obtaining higher yields, synthetic route of the invention is simple.
The material that this synthetic route uses is the common raw material of organic synthesis, and raw material is simple and easy to get, at low cost；Synthesis side
Method is easy to operate, high income；The three wastes are less, highly-safe, are relatively suitble to industrial production.
Specific embodiment
The present invention is suitble to industrialized production, synthetic route is as follows using a kind of method of new synthesis Diclofenac:
Step 1): compound (a) reacts in the presence of methanol/sodium methoxide, obtains compound (b)；
Step 2): compound (b) reacts in the presence of base with compound (c), obtains compound (d)；
Step 3): compound (d) reacts in organic solvent, under the action of catalyst with compound (e), obtains compound
(f)。
Raw material is simple and easy to get, at low cost；Synthetic method is easy to operate, high income；The three wastes are less, highly-safe, relatively more suitable
Close industrial production.
Embodiment
The synthesis of 1 intermediate (d) of embodiment
2- (2- aminophenyl) acetic acid (0.79g, 5.2mmol) and sodium methoxide (0.30g, 5.5mmol) are dissolved in methanol
In (10mL), 10h is stirred at 60~70 DEG C, obtains 2- (2- aminophenyl) methyl acetate (white solid, 0.71g), yield is
82.75%.
2- (2- aminophenyl) methyl acetate (0.71g, 4.3mmol) and sodium carbonate (0.16g, 1.6mmol) are dissolved in four
In hydrogen furans (10mL), it is cooled to -78 DEG C of stirring 1h, 2- bromo propionyl chloros (0.77g, 4.5mmol) and is mixed with tetrahydrofuran (5mL)
It has been slowly added dropwise in 0.5 hour afterwards, has been added dropwise to complete and moves back to 5h is stirred at room temperature, obtained 2- (2- (2- bromine propionamide) phenyl)
Methyl acetate (white solid, 1.16g), yield 90%.
LC-MS:(M+1) m/z=286.0,287.9；
1H NMR(500MHz,CDCl3) δ ppm 7.32-7.26 (m, 3H), 7.00-6.89 (m, 1H), 5.40 (q, J=
12.4Hz, 1H), 3.69 (s, 2H), 2.11 (d, J=6.8Hz, 3H), 1.65 (d, J=6.8Hz, 3H)
Embodiment 2
By 2,6- chlorophenesic acid (0.163g, 1.0mmol), EDC.HCl (192mg, 1.0mmol) and 2- (2- (2- bromine propionyl
Amine) phenyl) methyl acetate (315mg, 1.05mmol) is dissolved in carbon dichloride (10mL), and then KOH is added in 35 DEG C of stirring 5h
Then (62mg, 1.1mmol), mixed liquor are added saturated salt solution (10mL), are cooled to room temperature, then use in 100 DEG C of heating 6h
CH2Cl2(15mL x 3) extraction, merges organic phase, and magnesium sulfate dries, filters, evaporating solvent under reduced pressure, and crude product is through column chromatography point
Analysis separation, obtains target compound Diclofenac 0.28g, yield 90%.
Embodiment 3
By 2,6- chlorophenesic acid (0.163g, 1.0mmol), KOH (56mg, 1.0mmol) and 2- (2- (2- bromine propionamide) benzene
Base) methyl acetate (315mg, 1.05mmol) is dissolved in THF (10mL), 50 DEG C of stirring 2h, be then added KOH (62mg,
1.1mmol), then mixed liquor is added saturated salt solution (10mL), is cooled to room temperature, then uses CH at 80 DEG C of heating 6h2Cl2
(15mL x 3) extraction, merges organic phase, and magnesium sulfate dries, filters, evaporating solvent under reduced pressure, and crude product is through column chromatography analysis point
From obtaining target compound Diclofenac 0.295g, yield 95%.
Embodiment 4
By 2,6- chlorophenesic acid (0.163g, 1.0mmol), KOH (56mg, 1.0mmol) and 2- (2- (2- bromine propionamide) benzene
Base) methyl acetate (315mg, 1.05mmol) is dissolved in DMSO (10mL), 60 DEG C of stirring 2h, be then added KOH (62mg,
1.1mmol), then mixed liquor is added saturated salt solution (10mL), is cooled to room temperature, then uses CH at 100 DEG C of heating 6h2Cl2
(15mL x 3) extraction, merges organic phase, and magnesium sulfate dries, filters, evaporating solvent under reduced pressure, and crude product is through column chromatography analysis point
From obtaining target compound Diclofenac 0.297g, yield 95%.
Embodiment 5
By 2,6- chlorophenesic acid (0.163g, 1.0mmol), KOH (56mg, 1.0mmol) and 2- (2- (2- bromine propionamide) benzene
Base) methyl acetate (315mg, 1.05mmol) is dissolved in toluene (10mL), 60 DEG C of stirring 2h, be then added KOH (62mg,
1.1mmol), then mixed liquor is added saturated salt solution (10mL), is cooled to room temperature, then uses CH at 80 DEG C of heating 6h2Cl2
(15mL x 3) extraction, merges organic phase, and magnesium sulfate dries, filters, evaporating solvent under reduced pressure, and crude product is through column chromatography analysis point
From obtaining target compound Diclofenac 0.28g, yield 90%.
In conclusion synthetic method of the invention, can not only guarantee the high yield of product, more conducively industrialization is big raw
It produces.
Claims (9)
1. a kind of synthetic method of Diclofenac, which is characterized in that specific reaction step is as follows:
Step 1): compound (a) reacts in the presence of methanol/sodium methoxide, obtains compound (b)；
Step 2): compound (b) reacts in the presence of base with compound (c), obtains compound (d)；
Step 3): compound (d) reacts in organic solvent, under the action of catalyst with compound (e), obtains compound (f).
2. the synthetic method of Diclofenac according to claim 1, which is characterized in that the compound (a) and methanol/first
The molar ratio of sodium alkoxide is 1:(0.5-1.5).
3. the synthetic method of Diclofenac according to claim 1, which is characterized in that the alkali is potassium hydroxide, hydrogen-oxygen
Change sodium, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or saleratus.
4. the synthetic method of Diclofenac according to claim 1, which is characterized in that the compound (c) is slowly added dropwise
Into the tetrahydrofuran solution in 0~-78 DEG C of compound (b), it is slowly increased to react at room temperature after being added dropwise to complete.
5. the synthetic method of Diclofenac according to claim 1, which is characterized in that the compound (b) and compound
(c) molar ratio is 1:(0.5-1.5).
6. the synthetic method of Diclofenac according to claim 1, which is characterized in that the catalyst is EDC.HCl, hydrogen
Potassium oxide, potassium dihydrogen phosphate, potassium phosphate or combinations thereof.
7. the synthetic method of Diclofenac according to claim 1, which is characterized in that the compound (d) and compound
(e) molar ratio is 1:1~5.
8. the synthetic method of Diclofenac according to claim 1, which is characterized in that the compound (d), compound
(e) and catalyst is after 30~60 DEG C of reactions, and addition potassium hydroxide is warming up to 80~120 DEG C of hydrolysis, obtains compound (f).
9. the synthetic method of Diclofenac according to claim 1, which is characterized in that the organic solvent is dichloride
Carbon, carbon tetrachloride, THF, DMSO or toluene.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106905178A (en) * | 2017-04-14 | 2017-06-30 | 吉林大学 | A kind of synthetic method of Dic Zn |
| CN108947861A (en) * | 2018-08-17 | 2018-12-07 | 复旦大学 | The synthetic method of C14H10Cl2NNaO2 |
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2019
- 2019-07-16 CN CN201910640101.8A patent/CN110272351A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106905178A (en) * | 2017-04-14 | 2017-06-30 | 吉林大学 | A kind of synthetic method of Dic Zn |
| CN108947861A (en) * | 2018-08-17 | 2018-12-07 | 复旦大学 | The synthetic method of C14H10Cl2NNaO2 |
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