CN110407683A - A kind of preparation method of celecoxib diketone intermediate - Google Patents
A kind of preparation method of celecoxib diketone intermediate Download PDFInfo
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- CN110407683A CN110407683A CN201910264603.5A CN201910264603A CN110407683A CN 110407683 A CN110407683 A CN 110407683A CN 201910264603 A CN201910264603 A CN 201910264603A CN 110407683 A CN110407683 A CN 110407683A
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- preparation
- melilotal
- ethyl ester
- celecoxib
- trifluoroacetic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
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- Crystallography & Structural Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The preparation method of present invention offer celecoxib diketone intermediate, wherein react melilotal and Trifluoroacetic Acid Ethyl Ester in the presence of sodium methoxide, it is characterised in that: use toluene as solvent, reaction temperature is 20-40 DEG C；After completion of the reaction, it is quenched with hydrochloric acid solution, then purifies water washing, standing separates water phase；Organic phase cooling crystallization, obtains faint yellow solid product.The safety of industrialized production celecoxib diketone intermediate can be improved in method of the invention, and technique is very convenient, while not reducing the purity and yield of product.
Description
Technical field
The present invention relates to the synthesis fields of small molecule compound, and in particular to the synthesis side of a kind of drug and its intermediate
Method.
Background technique
Celecoxib, entitled 4- [5- (4- aminomethyl phenyl) -3- (the trifluoromethyl) -1H- pyrazol-1-yl] benzene sulfonyl of chemistry
Amine (its structural formula sees below Formulas I) is a species specificity 2 type ring oxygenase (COX-2) inhibitor, it is strong to the selectivity of COX-2
Degree is 375 times of COX-1, is mainly used for the treatment of osteoarthritis and rheumatoid arthritis, has very high anti-inflammatory activity, and
And almost without stomach and intestine side reaction.
The synthetic route of celecoxib is fairly simple, can be obtained by the synthesis of two steps, is melilotal warp first
It crosses Claisen condensation and obtains beta-diketon intermediate, celecoxib is made with to Hydrazinobenzenesulfonamide cyclization again in the latter.
CN103724268B discloses a kind of method for synthesizing celecoxib:, will be right under the action of Cymag or potassium cyanide
Methyl acetophenone and Trifluoroacetic Acid Ethyl Ester are in methanol and methyl tertiary butyl ether(MTBE) in the mixed solvent, -5-100 DEG C of back flow reactions, reaction
Afterwards with 10% hydrochloric acid, ethyl acetate extraction, anhydrous magnesium sulfate is dry, and concentrate is direct plungeed into and is reacted in next step.The party
Method is reacted at a reflux temperature using low boiling point solvent, used in alkali also height is active, industrial safety compared with
Low, Yi Yinfa is fired, and the volatilization of organic solvent is also unfavorable to environmental protection.In addition, the total recovery of this method production celecoxib
Also to be improved.
It is disclosed in CN103242233A and alkali is done with sodium methoxide, n-hexane is solvent, reacts at 60~80 DEG C, uses after reaction
5N hydrochloric acid, n-hexane extract, and anhydrous sodium sulfate is dry, are concentrated to get celecoxib diones intermediate, yield 94%-
99%, purity 99%-100%.Use n-hexane as solvent at such a temperature, be highly dangerous in industrial production, just oneself
69 DEG C of alkane boiling point, it is very high to fire risk by explosion limit 1.0-8.1%.
CN103951549A disclosure adds to melilotal, Trifluoroacetic Acid Ethyl Ester and Ultra-fine anhydrous carbonate
In organic solvent, -20~180 DEG C are reacted obtained celecoxib diones intermediate, yield 83%-99%.But Ultra-fine
Carbonate is difficult to obtain, and because dosage is big, can generate a large amount of solid wastes, causes huge environmental protection pressure to industrialized production.
Therefore, seek a kind of celecoxib easy to operate, highly-safe, not reducing generation purity and yield again simultaneously
The production method of intermediate is that this field is desired.
Summary of the invention
The object of the present invention is to provide the preparation methods of celecoxib diketone intermediate, to improve the peace of industrialized production
Quan Xing, and the very succinct purity and yield for not reducing product simultaneously of technique.
A kind of preparation method of celecoxib diketone intermediate, makes melilotal and Trifluoroacetic Acid Ethyl Ester in methanol
It is reacted in the presence of sodium, it is characterised in that: use toluene as solvent, reaction temperature is 20-40 DEG C；After completion of the reaction, hydrochloric acid is used
Solution is quenched, and then purifies water washing, and standing separates water phase；Organic phase cooling crystallization, obtains faint yellow solid product.
Specific embodiment
Synthesis technology of the present invention to celecoxib intermediate 4,4,4- tri- fluoro- 1- (4- aminomethyl phenyl) -1,3- diacetyl
It is optimized.This method are as follows: by the melilotal (I) of corresponding amount and Trifluoroacetic Acid Ethyl Ester (II) depositing in sodium methoxide
It under, is reacted in toluene solvant, carries out reaction between 20-40 DEG C.After completion of the reaction, it is quenched with 10% dilute hydrochloric acid solution
It goes out, purifies water washing, standing separates water phase；Organic phase cooling crystallization, filtration drying obtain faint yellow solid product (III).
Reaction equation is as follows:
The present invention is found surprisingly that based on inventor one: the reaction, at room temperature can be smooth in toluene solvant
It carries out, moreover, toluene solvant can almost dissolve melilotal and Trifluoroacetic Acid Ethyl Ester well at room temperature, and
Interesting show then is presented to the dissolubility of reaction product 4,4,4- tri- fluoro- 1- (4- aminomethyl phenyl) -1,3- diacetyl of the two
As, it is fine at 20-40 DEG C, but as temperature declines, solubility property sharply declines, at -10~-5 DEG C, almost all
It is precipitated from toluene.
The reaction system proposed according to the present invention as a result, mild condition do not need high temperature reflux, will not lead to solvent
Volatilization (boiling point of toluene is at 111 DEG C or more), post-process it is very simple.
In a preferred manner, melilotal and sodium methoxide are dissolved in toluene, trifluoro is slowly added dropwise while stirring
Ethyl acetate, in the process, control temperature are being no more than 40 DEG C of range, and preferably not less than 20 DEG C.It, can in actual production
To carry out at atmospheric temperature, typically in 25~35 DEG C of range.The speed of dropwise addition is not significantly risen with temperature as original
Then, temperature rises above 5 DEG C such as in 1 minute, preferably rises above 3 DEG C.By controlling charging rate, so that instead
It should mildly, smoothly carry out, side reaction does not occur substantially.Due to taking the reason of this mode, trifluoroacetic acid second in the present invention
Ester without a large amount of excessive, input melilotal, Trifluoroacetic Acid Ethyl Ester and sodium methoxide molar ratio can for 1:(1~
1.2): (1~1.2), preferably 1:1.1:1.2.
After detecting that melilotal is totally consumed, hydrochloric acid solution is added into reaction solution, is quenched therein
Highly basic.The hydrochloric acid solution that mass concentration is 10-18% or equivalent concentration is 3~5N can be used.This process turns sodium methoxide
It turns to methanol and sodium chloride enters water phase, and the excessive Trifluoroacetic Acid Ethyl Ester in part can be dissolved.
Next toluene solution is washed, the purifying water washing of 0.5-1 times of volume can be used, is preferably washed twice,
The process can further desalination and hydrochloric acid.
After washing, toluene solution is crystallized at low temperature, crystallization temperature can be at -10~0 DEG C, more preferably -10
~-5 DEG C of range.
Embodiment 1
In 1000ml reaction flask, 500.0g toluene, 187.9g (1.40mol) melilotal, 94.1g methanol is added
Sodium (1.68mol) is slowly added dropwise in 238.8g Trifluoroacetic Acid Ethyl Ester (1.54mol) and drips off, and keeps the temperature 20~30 DEG C, is added dropwise
The reaction was continued afterwards 5h, is adjusted to 2 for pH value with configured 5N hydrochloric acid solution, then washed twice with 500g purified water；After washing
For organic phase slow cooling to -10 DEG C~-5 DEG C, crystallization 2h, filtration drying obtains the faint yellow solid of 305.5g, molar yield
94.8%, purity 99.8%.
Embodiment 2
In 1000ml reaction flask, 500.0g toluene, 187.9g (1.40mol) melilotal, 94.1g methanol is added
Sodium (1.68) is slowly added dropwise in 238.8g Trifluoroacetic Acid Ethyl Ester (1.68mol) and drips off, and keeps the temperature 20~30 DEG C, is added dropwise subsequent
Continuous reaction 5h, is adjusted to 2 for pH value with configured 5N hydrochloric acid solution, then washed twice with 500g purified water；It is organic after washing
For phase slow cooling to -10 DEG C 0~-5 DEG C, crystallization 2h, filtration drying obtains the faint yellow solid of 307.1g, molar yield
94.8%, purity 99.3%.
The present embodiment uses different molar ratios, and compared with embodiment 1, yield is slightly improved, but product purity is omited
Micro- decline.
Comparative example 1
200ml toluene, 200mmol (26.8ml) melilotal, 300mmol are added in 500ml single port bottle
(36ml) Trifluoroacetic Acid Ethyl Ester, 360mmol partial size are the Anhydrous potassium carbonate of 200nm, and 85 DEG C are reacted 24 hours.Filter recycling nothing
Machine salt.Toluene solvant and unreacted raw material are recycled in mother liquor rectifying, isometric water are added into distillation residual liquid, with 10%
PH value is adjusted to 6 by hydrochloric acid solution, and chloroform extracts 6 times, each 70ml, is merged, and concentration, freeze-drying obtain the pale yellow colored solid of 46.0g
Body, molar yield 54%, purity 98.3%.
The present embodiment uses toluene solvant, due to using different alkali, does not show such as the conversion in preceding embodiment
Rate, this method post-processing is comparatively laborious, and uses this kind of high toxicity solvent of chloroform.And traditional post-processing approach is used,
The purity of product is declined.
Claims (8)
1. a kind of preparation method of celecoxib diketone intermediate, makes melilotal and Trifluoroacetic Acid Ethyl Ester in sodium methoxide
In the presence of react, it is characterised in that: use toluene as solvent, reaction temperature is 20-40 DEG C；After completion of the reaction, hydrochloric acid solution is used
It is quenched, then purifies water washing, standing separates water phase；Organic phase cooling crystallization, obtains faint yellow solid product.
2. preparation method according to claim 1, which is characterized in that melilotal and sodium methoxide are dissolved in first first
In benzene, Trifluoroacetic Acid Ethyl Ester is inwardly then added dropwise under stirring.
3. preparation method according to claim 2, which is characterized in that control heating rate, temperature rises not in 1 minute
More than 5 DEG C, 3 DEG C are preferably risen above.
4. preparation method according to claim 1, which is characterized in that melilotal, Trifluoroacetic Acid Ethyl Ester and methanol
The molar ratio of sodium is 1:(1~1.2): (1~1.2).
5. preparation method according to claim 1, which is characterized in that melilotal, Trifluoroacetic Acid Ethyl Ester and methanol
The molar ratio of sodium is 1:1.1:1.2.
6. preparation method according to claim 1, which is characterized in that the mass concentration of the hydrochloric acid solution is 10-18%.
7. preparation method according to claim 1, which is characterized in that crystallization temperature is at -10~0 DEG C.
8. preparation method according to claim 7, which is characterized in that range of the crystallization temperature at -10~-5 DEG C.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996037476A1 (en) * | 1995-05-25 | 1996-11-28 | G.D. Searle & Co. | Method of preparing 3-haloalkyl-1h-pyrazoles |
| US20080234491A1 (en) * | 2007-03-19 | 2008-09-25 | Raghupathi Reddy Anumula | Process for preparation of celecoxib |
| CN102391184A (en) * | 2011-10-17 | 2012-03-28 | 江西同和药业有限责任公司 | Synthesis method of celecoxib |
| CN103102306A (en) * | 2013-02-06 | 2013-05-15 | 河南东泰制药有限公司 | Preparation method for celecoxib |
| CN103242233A (en) * | 2012-02-08 | 2013-08-14 | 黄华 | Novel method for preparing celecoxib |
| CN103923011A (en) * | 2014-05-04 | 2014-07-16 | 苏州天马精细化学品股份有限公司 | Synthetic method of celecoxib |
-
2019
- 2019-04-03 CN CN201910264603.5A patent/CN110407683A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996037476A1 (en) * | 1995-05-25 | 1996-11-28 | G.D. Searle & Co. | Method of preparing 3-haloalkyl-1h-pyrazoles |
| US20080234491A1 (en) * | 2007-03-19 | 2008-09-25 | Raghupathi Reddy Anumula | Process for preparation of celecoxib |
| CN102391184A (en) * | 2011-10-17 | 2012-03-28 | 江西同和药业有限责任公司 | Synthesis method of celecoxib |
| CN103242233A (en) * | 2012-02-08 | 2013-08-14 | 黄华 | Novel method for preparing celecoxib |
| CN103102306A (en) * | 2013-02-06 | 2013-05-15 | 河南东泰制药有限公司 | Preparation method for celecoxib |
| CN103923011A (en) * | 2014-05-04 | 2014-07-16 | 苏州天马精细化学品股份有限公司 | Synthetic method of celecoxib |
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