CN115925532A - Preparation method of flurbiprofen - Google Patents
Preparation method of flurbiprofen Download PDFInfo
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- CN115925532A CN115925532A CN202211466051.4A CN202211466051A CN115925532A CN 115925532 A CN115925532 A CN 115925532A CN 202211466051 A CN202211466051 A CN 202211466051A CN 115925532 A CN115925532 A CN 115925532A
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- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 229960002390 flurbiprofen Drugs 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 87
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 74
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 36
- 150000001875 compounds Chemical class 0.000 claims description 33
- 229940125782 compound 2 Drugs 0.000 claims description 30
- 229940126214 compound 3 Drugs 0.000 claims description 26
- 229940125904 compound 1 Drugs 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 20
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 239000011259 mixed solution Substances 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 8
- 229940125898 compound 5 Drugs 0.000 claims description 7
- 229910052749 magnesium Inorganic materials 0.000 claims description 6
- 239000011777 magnesium Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 4
- 239000013067 intermediate product Substances 0.000 abstract description 48
- 239000000047 product Substances 0.000 abstract description 17
- 238000009776 industrial production Methods 0.000 abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 43
- 239000012295 chemical reaction liquid Substances 0.000 description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 239000007787 solid Substances 0.000 description 30
- 238000003756 stirring Methods 0.000 description 16
- 239000007864 aqueous solution Substances 0.000 description 10
- 238000004090 dissolution Methods 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 230000001376 precipitating effect Effects 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000007086 side reaction Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000000779 smoke Substances 0.000 description 3
- SYTBZMRGLBWNTM-JTQLQIEISA-N (S)-flurbiprofen Chemical compound FC1=CC([C@@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-JTQLQIEISA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- -1 (S) -flurbiprofen Chemical compound 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- HTRNHWBOBYFTQF-UHFFFAOYSA-N 4-bromo-2-fluoro-1-phenylbenzene Chemical group FC1=CC(Br)=CC=C1C1=CC=CC=C1 HTRNHWBOBYFTQF-UHFFFAOYSA-N 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- ALIVXCSEERJYHU-UHFFFAOYSA-N Flurbiprofen axetil Chemical compound FC1=CC(C(C)C(=O)OC(OC(C)=O)C)=CC=C1C1=CC=CC=C1 ALIVXCSEERJYHU-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 208000016247 Soft tissue disease Diseases 0.000 description 1
- 208000010040 Sprains and Strains Diseases 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229950006887 esflurbiprofen Drugs 0.000 description 1
- JIYXQCWLSQSIJV-UHFFFAOYSA-N ethyl 2-(3-fluoro-4-phenylphenyl)propanoate Chemical compound FC1=CC(C(C)C(=O)OCC)=CC=C1C1=CC=CC=C1 JIYXQCWLSQSIJV-UHFFFAOYSA-N 0.000 description 1
- ARFLASKVLJTEJD-UHFFFAOYSA-N ethyl 2-bromopropanoate Chemical compound CCOC(=O)C(C)Br ARFLASKVLJTEJD-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229950005941 flurbiprofen axetil Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
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- 238000010183 spectrum analysis Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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Abstract
The invention relates to a preparation method of flurbiprofen, which has mild whole reaction conditions, directly uses the obtained intermediate product for the next reaction without treatment, has simple preparation method, high product yield of more than 90 percent, high purity of more than 99 percent, simple post-treatment and reduced cost, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of flurbiprofen.
Background
Flurbiprofen (flurbiprofen) has chemical name of (+/-) -2- (2-fluoro-4-biphenyl) -propionic acid and molecular formula of C 15 H 13 FO 2 White or off-white crystalline powders. It is easily soluble in methanol, ethanol, acetone or diethyl ether, soluble in acetonitrile, and hardly soluble in water.
Flurbiprofen is a fluorine-containing non-steroidal anti-inflammatory drug developed by the british buzz company. The composition is marketed in UK by 1976, and has analgesic, antiinflammatory and antipyretic effects due to inhibition of synthesis of cyclooxygenase by prostaglandin. Flurbiprofen axetil was jointly developed by japan scientific research pharmaceutical company and green cross pharmaceutical company, and was marketed in japan in 1992 and china in 2004. The separation and research are carried out according to the chiral structure of flurbiprofen, and the drug esflurbiprofen, namely (S) -flurbiprofen, is developed, and the drugs are further developed by taking flurbiprofen as a raw material. At present, flurbiprofen related preparations sold in the market at home and abroad comprise gel plasters, patches, tablets, injection and other formulations, are mainly clinically suitable for rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and the like, can also be used for symptomatic treatment of soft tissue diseases (such as sprains and strains), light and moderate pains (such as dysmenorrheal, postoperative pain, toothache and the like) and various cancer pains, and show wide market prospects. Flurbiprofen is a medicament, is also a base of some prodrugs and improvements, has important functions, and needs to be strictly and judiciously researched on related impurities in order to ensure the medication safety and quality of the flurbiprofen and related improved medicaments, so that the impurities are controlled within a safe and reasonable limit range.
Chinese patent CN108558651A discloses a method for preparing flurbiprofen by reacting 4-bromo-2-fluorobiphenyl with magnesium metal to generate Grignard reagent (2-fluoro- [1,1' -biphenyl)]-4-yl) magnesium bromide followed by reaction with ethyl 2-bromopropionate in TiCl 4 Carrying out coupling reaction under the catalysis of the (1), and carrying out alkaline hydrolysis, acidification and recrystallization on the prepared intermediate flurbiprofen ethyl ester to obtain the flurbiprofen. However, this method has the following drawbacks: 1) TiCl (titanium dioxide) 4 The additive has strong corrosivity, and has large corrosivity on reaction equipment and feeding equipment; 2) Is TiCl 4 High volatility, violent reaction when contacting water,in the using process, when the HCl white smoke is contacted with the atmosphere, the HCl white smoke reacts with water in the air to generate HCl white smoke with strong irritation and corrosiveness, a large amount of heat is emitted, the protection requirement on production personnel is high, a large amount of heat is emitted to increase potential safety hazards, the protection needs to be strengthened, the production cost is further increased, and the industrial production is not facilitated; 3) Is TiCl 4 The volatility is high, the feeding amount is not accurately controlled, the reaction is violent, the controllability of the reaction is poor, a large number of byproducts are generated in the preparation of the product, the difficulty of product purification and three-waste treatment is increased, the production period is prolonged, the production cost is increased, and the industrial production is not facilitated.
Therefore, the method for preparing flurbiprofen is simple and convenient to operate, safe and controllable, high in yield, high in purity, green and environment-friendly, low in production cost and easy for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of flurbiprofen based on the prior art.
The technical scheme of the invention is as follows:
a preparation method of flurbiprofen comprises the following steps:
(1) In N 2 Under the protection, the compound 1 and the solvent are mixed evenly, and CH is slowly dripped into the mixture at the temperature of minus 25 to 10 DEG C 3 Carrying out chemical reaction on a mixed solution obtained after mixing MgCl and a solvent to prepare a compound 3;
(2) In N 2 Under protection, magnesium chips, solvent and CH are added 3 I, uniformly mixing, slowly and dropwise adding a mixed solution obtained by mixing the compound 2 and a solvent at the temperature of 10-40 ℃, and carrying out chemical reaction to prepare a compound 4;
(3) Adding the reaction solution obtained in the step (1) into the reaction solution obtained in the step (2) at the temperature of 0-20 ℃ to perform chemical reaction to prepare a target product compound 5, wherein the specific synthetic route is as follows:
in step (1), from a compound1 and CH 3 When the intermediate compound 3 is prepared from MgCl, the reaction temperature needs to be strictly controlled, and is too low, so that the reaction is not thorough, the smooth proceeding of the reaction is not facilitated, and the yield of the intermediate product is low; the reaction temperature is too high, side reactions are liable to occur, and the yield and purity of the intermediate product are lowered.
For the invention, in the step (1), the reaction temperature is strictly controlled to be-25-10 ℃, but not limited to-25 ℃,20 ℃, 15 ℃, 10 ℃, 5 ℃, 0 ℃, 5 ℃ or 10 ℃, the yield and purity of the intermediate product compound 3 can be improved, the next reaction can be directly participated without post-treatment, the preparation method is simple, the efficiency of the whole reaction can be improved, the possibility of side reaction is reduced, the yield and purity of the target product flurbiprofen (compound 5) are high, the yield reaches more than 90 percent, the purity reaches more than 99 percent, the post-treatment is simple, the cost is reduced, and the method is suitable for industrial production. In a preferred embodiment, the reaction temperature is-20 to 0 ℃, and further, the reaction temperature is-15 to-10 ℃.
In step (1), from compound 1 and CH 3 When MgCl is used for preparing intermediate product compound 3, reaction raw material CH 3 The choice of MgCl is particularly important. In the course of the experiments for exploring the reaction raw materials, the invention discovers that CH is adopted 3 MgCl as reducing agent and strict control of CH 3 The addition amount of MgCl can improve the reaction efficiency and reduce the possibility of side reaction, the yield and the purity of the intermediate compound 3 are high, the intermediate compound directly participates in the next reaction, the whole reaction efficiency can be improved, the possibility of side reaction is reduced, and the yield and the purity of the target product flurbiprofen are high, the yield reaches more than 90 percent, and the purity reaches more than 99 percent. While using other analogous starting materials, e.g. CH 3 CH 2 MgCl、(CH 3 ) 2 CHMgCl, under the same reaction conditions, the yield and purity of the target product are low.
For the purposes of the present invention, in step (1), compound 1 and CH 3 The mass-to-volume ratio of MgCl is 1:3.3g/mL, 1.4 g/mL, 1.5g/mL, 1 3 The mass-to-volume ratio of MgCl is 1.0-4.5 g/mL, more preferably, compound 1 and CH 3 The mass volume ratio of MgCl is 1.
For the present invention, in step (1), the solvent is tetrahydrofuran, dichloromethane or ethanol; tetrahydrofuran is preferred.
Compared with the prior art which generally adopts the compound 2, magnesium chips and iodine particles to prepare the intermediate product compound 4, the invention selects the compound 2, the magnesium chips and CH in the step (2) 3 The I is used as a reaction raw material to prepare the intermediate compound 4, the requirement on the reaction temperature is lower, the possibility of side reaction is reduced, the yield and the purity of the intermediate compound 4 are improved, post-treatment is not needed, the intermediate compound directly participates in the next reaction, the efficiency of the whole reaction can be improved, and the yield and the purity of the target product flurbiprofen are high, the yield reaches over 90 percent, and the purity reaches over 99 percent.
In the present invention, in the step (2), the reaction temperature is 10 to 40 ℃, but not limited to 10 ℃, 15 ℃,20 ℃, 25 ℃, 30 ℃, 35 ℃ or 40 ℃, and in order to obtain a better effect, the reaction temperature is 15 to 35 ℃, and more preferably 20 to 30 ℃.
In the present invention, in step (2), compound 2, magnesium turnings and CH 3 I when compound 4 is prepared as a reaction raw material, the molar ratio of compound 2 to magnesium chips is 1.0 to 2.0, and can be, but is not limited to, 1.0, 1.
In step (2), compound 2, magnesium turnings and CH 3 When I is used as a reaction raw material to prepare an intermediate product, namely a compound 4, strict control of CH is required 3 The addition of the amount of I, which is too high or too low, is not favorable for the smooth progress of the reaction, resulting in the decrease of the yield and purity of the intermediate compound 4, and directly participating in the next reaction, resulting in the decrease of the yield and purity of the target product. In thatIn the present invention, in the step (2), the compound is reacted with CH 3 The mass-to-volume ratio of I is 1 3 The mass-volume ratio of I is 1.
For the invention, the material ratio of the compound 2 and the compound 1 has a larger influence on the yield and the purity of the target product, and the ratio is too high or too low, so that the yield and the purity of the target product are greatly reduced. In step (2), the molar ratio of compound 2 to compound 1 is 1.0 to 2.0, and can be, but is not limited to, 1.0, 1.1, 1.2, 1.3, 1.4, 1.
For the present invention, in step (2), the solvent is tetrahydrofuran, dichloromethane or ethanol; tetrahydrofuran is preferred.
For the invention, when the reaction solution obtained in the step (1) is added into the reaction solution obtained in the step (2) to carry out a chemical reaction to prepare the target product compound 5, the influence of the reaction temperature on the yield and purity of the target product cannot be ignored, and the reaction temperature is too low, so that the reaction is not thorough, the smooth proceeding of the reaction is not facilitated, and the yield of the product is low; the reaction temperature is too high, side reactions are easy to occur, and the yield and purity of the product are reduced. For the present invention, in step (3), the reaction temperature is 0 to 20 ℃, and may be, but is not limited to, 0 ℃, 5 ℃, 10 ℃, 15 ℃ or 20 ℃. In a preferable embodiment, the reaction temperature is 10 to 15 ℃, and further, the reaction temperature is 5 to 10 ℃.
By adopting the technical scheme of the invention, the advantages are as follows:
the preparation method of flurbiprofen provided by the invention has mild reaction conditions, the obtained intermediate product is directly used for the next reaction without being processed, the preparation method is simple, the yield of the product is high and reaches more than 90%, the purity is high and reaches more than 99%, the post-processing is simple, the cost is reduced, and the preparation method is suitable for industrial production.
Drawings
FIG. 1 is a photograph of the product prepared in example 1 1 H NMR and chemical shift magnification.
Fig. 2 is an HPLC spectrum of flurbiprofen prepared in example 1.
Detailed Description
The method for preparing flurbiprofen according to the present invention is further illustrated by the following examples, which are not intended to limit the present invention in any way.
EXAMPLE 1 Synthesis of flurbiprofen (Compound 5)
(1) In N 2 Under protection, 59.66g (0.39 mol) of Compound 1 and 150mL of THF are added into a 500mL dry three-necked flask, and after stirring uniformly, 200mL of CH is slowly dropped at a temperature of-15 to-10 DEG C 3 MgCl, the dropwise adding time is controlled to be 2h, and after TLC shows that the reaction is finished, reaction liquid containing an intermediate product compound 3 is obtained;
(2) At N 2 To a dry 1L four-necked flask, 8.75g (0.36 mol) of magnesium turnings, 150mL of THF, and 3mL of CH were added under protection 3 I, after uniformly stirring, slowly dropwise adding a mixed solution obtained by dissolving 75.33g (0.3 mol) of compound 2 in 150mL of THF at the temperature of 20-30 ℃, controlling the dropwise adding time to be 4h, and obtaining a reaction solution containing an intermediate product compound 4 after TLC shows that the compound 2 completely reacts;
(3) Adding the reaction liquid containing the intermediate product compound 3 obtained in the step (1) into the reaction liquid containing the intermediate product compound 4 obtained in the step (2) at the temperature of 5-10 ℃, controlling the dripping time to be 10min, adjusting the pH value of the obtained reaction liquid to 1 by using 2N hydrochloric acid after TLC shows that the reaction is finished, adding ethyl acetate for extraction, concentrating the obtained organic phase to be dry, adding 2N KOH aqueous solution for dissolution, combining the obtained water phases, adjusting the pH value to 1 by using 6N hydrochloric acid, precipitating a large amount of white solid, filtering the precipitated solid, and drying to obtain white solid flurbiprofen, wherein the yield is 96.5%, and the purity is 99.95%.
Hydrogen spectrum analysis: 1H-NMR (600MHz, DMSO-d 6) delta: 1.40 (3H, m), 3.75 (1H, m),
7.22-7.55(8H,m),12.49(1H,m)；
the single peak at a chemical shift of 1.40 is 3H on CH 3-; the doublet at chemical shift 3.75 is H on CH-; the single peak at chemical shift 12.49 is H on-COOH; the multiplet at chemical shifts 7.22-7.55 is H on the 2-fluorobenzyl group.
Example 2 Synthesis of flurbiprofen (Compound 5)
(1) In N 2 Under protection, 59.66g (0.39 mol) of Compound 1 and 150mL of THF are added into a 500mL dry three-necked flask, and after stirring uniformly, 250mL of CH is slowly added dropwise at a temperature of-15 to-10 DEG C 3 MgCl, the dropwise adding time is controlled to be 2h, and after TLC shows that the reaction is finished, reaction liquid containing an intermediate product compound 3 is obtained;
(2) At N 2 To a dry 1L four-necked flask, 8.75g (0.36 mol) of magnesium turnings, 150mL of THF, and 3mL of CH were added under protection 3 I, after uniformly stirring, slowly dropwise adding a mixed solution obtained by dissolving 75.33g (0.3 mol) of compound 2 in 150mL of THF (tetrahydrofuran) at the temperature of 20-30 ℃, controlling the dropwise adding time to be 4h, and obtaining a reaction solution containing an intermediate product compound 4 after TLC shows that the compound 2 completely reacts;
(3) Adding the reaction liquid containing the intermediate product compound 3 obtained in the step (1) into the reaction liquid containing the intermediate product compound 4 obtained in the step (2) at the temperature of 5-10 ℃, controlling the dripping time to be 10min, adjusting the pH value of the obtained reaction liquid to 1 by using 2N hydrochloric acid after TLC shows that the reaction is finished, adding ethyl acetate for extraction, concentrating the obtained organic phase to be dry, adding 2N KOH aqueous solution for dissolution, combining the obtained aqueous phases, adjusting the pH value to 1 by using 6N hydrochloric acid, precipitating a large amount of white solid, filtering the precipitated solid, and drying to obtain white solid flurbiprofen, wherein the yield is 91.8%, and the purity is 99.1%.
Example 3 Synthesis of flurbiprofen (Compound 5)
(1) In N 2 Under protection, 59.66g of the solution was added to a 500mL dry three-necked flask(0.39 mol) Compound 1 and 150mL THF, stirring well, under the temperature of-5-0 deg.C, slowly dropping 200mL CH 3 MgCl, the dropwise adding time is controlled to be 2h, and after TLC shows that the reaction is finished, reaction liquid containing an intermediate product compound 3 is obtained;
(2) At N 2 To a dry 1L four-necked flask, 8.75g (0.36 mol) of magnesium turnings, 150mL of THF, and 3mL of CH were added under protection 3 I, after uniformly stirring, slowly dropwise adding a mixed solution obtained by dissolving 75.33g (0.3 mol) of compound 2 in 150mL of THF at the temperature of 20-30 ℃, controlling the dropwise adding time to be 4h, and obtaining a reaction solution containing an intermediate product compound 4 after TLC shows that the compound 2 completely reacts;
(3) Adding the reaction liquid containing the intermediate product compound 3 obtained in the step (1) into the reaction liquid containing the intermediate product compound 4 obtained in the step (2) at the temperature of 5-10 ℃, controlling the dripping time to be 10min, adjusting the pH value of the obtained reaction liquid to 1 by using 2N hydrochloric acid after TLC shows that the reaction is finished, adding ethyl acetate for extraction, concentrating the obtained organic phase to be dry, adding 2N KOH aqueous solution for dissolution, combining the obtained aqueous phases, adjusting the pH value to 1 by using 6N hydrochloric acid, precipitating a large amount of white solid, filtering the precipitated solid, and drying to obtain white solid flurbiprofen, wherein the yield is 90.1%, and the purity is 99.3%.
Comparative example 1
(1) At N 2 Under protection, 59.66g (0.39 mol) of Compound 1 and 150mL of THF were added to a 500mL dry three-necked flask, and after stirring well, 200mL of CH was slowly dropped at 15-20 deg.C 3 MgCl, the dropwise adding time is controlled to be 2h, and after TLC shows that the reaction is finished, reaction liquid containing an intermediate product compound 3 is obtained;
(2) In N 2 To a dry 1L four-necked flask, 8.75g (0.36 mol) of magnesium turnings, 150mL of THF, and 3mL of CH were added under protection 3 I, after uniformly stirring, slowly dropwise adding a mixed solution obtained by dissolving 75.33g (0.3 mol) of compound 2 in 150mL of THF at the temperature of 20-30 ℃, controlling the dropwise adding time to be 4h, and obtaining a reaction solution containing an intermediate product compound 4 after TLC shows that the compound 2 completely reacts;
(3) Adding the reaction liquid containing the intermediate product compound 3 obtained in the step (1) into the reaction liquid containing the intermediate product compound 4 obtained in the step (2) at the temperature of 5-10 ℃, controlling the dripping time to be 10min, adjusting the pH value of the obtained reaction liquid to 1 by using 2N hydrochloric acid after TLC shows that the reaction is finished, adding ethyl acetate for extraction, concentrating the obtained organic phase to be dry, adding 2N KOH aqueous solution for dissolution, combining the obtained water phases, adjusting the pH value to 1 by using 6N hydrochloric acid, precipitating a large amount of white solid, filtering the precipitated solid, and drying to obtain white solid flurbiprofen, wherein the yield is 78.6%, and the purity is 94.3%.
Comparative example 2
(1) In N 2 Under protection, 59.66g (0.39 mol) of Compound 1 and 150mL of THF were added to a 500mL dry three-necked flask, stirred well, and 200mL of CH was slowly added dropwise at a temperature of-30 to-25 deg.C 3 MgCl, the dropwise adding time is controlled to be 2h, and after TLC shows that the reaction is finished, reaction liquid containing an intermediate product compound 3 is obtained;
(2) In N 2 To a dry 1L four-necked flask, 8.75g (0.36 mol) of magnesium turnings, 150mL of THF, and 3mL of CH were added under protection 3 I, after uniformly stirring, slowly dropwise adding a mixed solution obtained by dissolving 75.33g (0.3 mol) of compound 2 in 150mL of THF at the temperature of 20-30 ℃, controlling the dropwise adding time to be 4h, and obtaining a reaction solution containing an intermediate product compound 4 after TLC shows that the compound 2 completely reacts;
(3) Adding the reaction liquid containing the intermediate product compound 3 obtained in the step (1) into the reaction liquid containing the intermediate product compound 4 obtained in the step (2) at the temperature of 5-10 ℃, controlling the dripping time to be 10min, adjusting the pH value of the obtained reaction liquid to 1 by using 2N hydrochloric acid after TLC shows that the reaction is finished, adding ethyl acetate for extraction, concentrating the obtained organic phase to be dry, adding 2N KOH aqueous solution for dissolution, combining the obtained aqueous phases, adjusting the pH value to 1 by using 6N hydrochloric acid, precipitating a large amount of white solid, filtering the precipitated solid, and drying to obtain white solid flurbiprofen, wherein the yield is 72.5%, and the purity is 89.1%.
Comparative example 3
(1) In N 2 Under the protection of59.66g (0.39 mol) of Compound 1 and 150mL of THF were added to a 500mL dry three-necked flask, and after stirring them uniformly, 100mL of CH was slowly dropped at a temperature of-15 to-10 ℃ 3 MgCl, the dropwise adding time is controlled to be 2h, and after TLC shows that the reaction is finished, reaction liquid containing an intermediate product compound 3 is obtained;
(2) In N 2 To a dry 1L four-necked flask, 8.75g (0.36 mol) of magnesium turnings, 150mL of THF, and 3mL of CH were added under protection 3 I, after uniformly stirring, slowly dropwise adding a mixed solution obtained by dissolving 75.33g (0.3 mol) of compound 2 in 150mL of THF at the temperature of 20-30 ℃, controlling the dropwise adding time to be 4h, and obtaining a reaction solution containing an intermediate product compound 4 after TLC shows that the compound 2 completely reacts;
(3) Adding the reaction liquid containing the intermediate product compound 3 obtained in the step (1) into the reaction liquid containing the intermediate product compound 4 obtained in the step (2) at the temperature of 5-10 ℃, controlling the dripping time to be 10min, adjusting the pH value of the obtained reaction liquid to 1 by using 2N hydrochloric acid after TLC shows that the reaction is finished, adding ethyl acetate for extraction, concentrating the obtained organic phase to be dry, adding 2N KOH aqueous solution for dissolution, combining the obtained water phases, adjusting the pH value to 1 by using 6N hydrochloric acid, precipitating a large amount of white solid, filtering the precipitated solid, and drying to obtain white solid flurbiprofen, wherein the yield is 75.2%, and the purity is 92.4%.
Comparative example 4
(1) In N 2 Under protection, 100.96g (0.66 mol) of Compound 1 and 150mL of THF are added into a 500mL dry three-necked flask, and after stirring uniformly, 200mL of CH is slowly dropped at a temperature of-15 to-10 DEG C 3 MgCl, the dropwise adding time is controlled to be 2h, and after TLC shows that the reaction is finished, reaction liquid containing an intermediate product compound 3 is obtained;
(2) In N 2 To a dry 1L four-necked flask, 8.75g (0.36 mol) of magnesium turnings, 150mL of THF, and 3mL of CH were added under protection 3 I, after being uniformly stirred, slowly dropwise adding a mixed solution obtained by dissolving 75.33g (0.3 mol) of compound 2 in 150mL of THF at the temperature of 20-30 ℃, controlling the dropwise adding time to be 4h, and obtaining a compound containing an intermediate product after TLC shows that the compound 2 completely reacts4, a reaction solution;
(3) Adding the reaction liquid containing the intermediate product compound 3 obtained in the step (1) into the reaction liquid containing the intermediate product compound 4 obtained in the step (2) at the temperature of 5-10 ℃, controlling the dripping time to be 10min, adjusting the pH value of the obtained reaction liquid to 1 by using 2N hydrochloric acid after TLC shows that the reaction is finished, adding ethyl acetate for extraction, concentrating the obtained organic phase to be dry, adding 2N KOH aqueous solution for dissolution, combining the obtained water phases, adjusting the pH value to 1 by using 6N hydrochloric acid, precipitating a large amount of white solid, filtering the precipitated solid, and drying to obtain white solid flurbiprofen, wherein the yield is 85.6%, and the purity is 98.2%.
Comparative example 5
(1) In N 2 Under protection, 59.66g (0.39 mol) of Compound 1 and 150mL of THF were added to a 500mL dry three-necked flask, stirred well, and then 200mL (CH) was slowly added dropwise at a temperature of-15 to-10 deg.C 3 ) 2 CHMgCl, the dropwise adding time is controlled to be 2h, and after TLC shows that the reaction is finished, reaction liquid containing an intermediate product compound 3 is obtained;
(2) In N 2 To a dry 1L four-necked flask, 8.75g (0.36 mol) of magnesium turnings, 150mL of THF, and 3mL of CH were added under protection 3 I, after uniformly stirring, slowly dropwise adding a mixed solution obtained by dissolving 75.33g (0.3 mol) of compound 2 in 150mL of THF (tetrahydrofuran) at the temperature of 20-30 ℃, controlling the dropwise adding time to be 4h, and obtaining a reaction solution containing an intermediate product compound 4 after TLC shows that the compound 2 completely reacts;
(3) Adding the reaction liquid containing the intermediate product compound 3 obtained in the step (1) into the reaction liquid containing the intermediate product compound 4 obtained in the step (2) at the temperature of 5-10 ℃, controlling the dripping time to be 10min, adjusting the pH value of the obtained reaction liquid to 1 by using 2N hydrochloric acid after TLC shows that the reaction is finished, adding ethyl acetate for extraction, concentrating the obtained organic phase to be dry, adding 2N KOH aqueous solution for dissolution, combining the obtained water phases, adjusting the pH value to 1 by using 6N hydrochloric acid, precipitating a large amount of white solid, filtering the precipitated solid, and drying to obtain white solid flurbiprofen, wherein the yield is 83.5%, and the purity is 95.3%.
Comparative example 6
(1) In N 2 Under protection, 59.66g (0.39 mol) of Compound 1 and 150mL of THF were added to a 500mL dry three-necked flask, and after stirring uniformly, 200mL of CH was slowly added dropwise at a temperature of-15 to-10 deg.C 3 MgCl, the dropwise adding time is controlled to be 2h, and after TLC shows that the reaction is finished, reaction liquid containing an intermediate product compound 3 is obtained;
(2) In N 2 Adding 8.75g (0.36 mol) of magnesium chips, 150mL of THF and 3 particles of iodine into a dry 1L four-neck flask under protection, stirring uniformly, slowly dropwise adding a mixed solution obtained by dissolving 75.33g (0.3 mol) of compound 2 in 150mL of THF at the temperature of 20-30 ℃, controlling the dropwise adding time to be 4h, and obtaining a reaction solution containing an intermediate product compound 4 after TLC shows that the compound 2 completely reacts;
(3) Adding the reaction liquid containing the intermediate product compound 3 obtained in the step (1) into the reaction liquid containing the intermediate product compound 4 obtained in the step (2) at the temperature of 5-10 ℃, controlling the dripping time to be 10min, adjusting the pH value of the obtained reaction liquid to 1 by using 2N hydrochloric acid after TLC shows that the reaction is finished, adding ethyl acetate for extraction, concentrating the obtained organic phase to be dry, adding 2N KOH aqueous solution for dissolution, combining the obtained aqueous phases, adjusting the pH value to 1 by using 6N hydrochloric acid, precipitating a large amount of white solid, filtering the precipitated solid, and drying to obtain white solid flurbiprofen, wherein the yield is 58.1%, and the purity is 81.8%.
Comparative example 7
(1) In N 2 Under protection, 59.66g (0.39 mol) of Compound 1 and 150mL of THF are added into a 500mL dry three-necked flask, and after stirring uniformly, 200mL of CH is slowly dropped at a temperature of-15 to-10 DEG C 3 MgCl, the dropwise adding time is controlled to be 2h, and after TLC shows that the reaction is finished, reaction liquid containing an intermediate product compound 3 is obtained;
(2) At N 2 To a dry 1L four-necked flask, 8.75g (0.36 mol) of magnesium turnings, 150mL of THF, and 3mL of CH were added under protection 3 I, after being uniformly stirred, slowly dropwise adding a mixed solution obtained by dissolving 75.33g (0.3 mol) of compound 2 in 150mL of THF at the temperature of 20-30 ℃, controlling the dropwise adding time to be 4h, and waiting until TLC shows that the compound is combinedAfter the object 2 is completely reacted, reaction liquid containing an intermediate product compound 4 is obtained;
(3) Adding the reaction liquid containing the intermediate product compound 3 obtained in the step (1) into the reaction liquid containing the intermediate product compound 4 obtained in the step (2) at the temperature of 20-25 ℃, controlling the dripping time to be 10min, adjusting the pH value of the obtained reaction liquid to 1 by using 2N hydrochloric acid after TLC shows that the reaction is finished, adding ethyl acetate for extraction, concentrating the obtained organic phase to be dry, adding 2N KOH aqueous solution for dissolution, combining the obtained water phases, adjusting the pH value to 1 by using 6N hydrochloric acid, precipitating a large amount of white solid, filtering the precipitated solid, and drying to obtain white solid flurbiprofen, wherein the yield is 79.5%, and the purity is 92.4%.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: modifications of the technical solutions described in the foregoing embodiments are still possible, or some technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. The preparation method of flurbiprofen is characterized by comprising the following steps:
(1) In N 2 Under the protection, the compound 1 and the solvent are mixed evenly, and CH is slowly dripped into the mixture at the temperature of minus 25 to 10 DEG C 3 Carrying out chemical reaction on a mixed solution obtained after mixing MgCl and a solvent to prepare a compound 3;
(2) In N 2 Under protection, magnesium chips, solvent and CH are added 3 I, uniformly mixing, slowly and dropwise adding a mixed solution obtained by mixing the compound 2 and a solvent at the temperature of 10-40 ℃, and carrying out chemical reaction to prepare a compound 4;
(3) Adding the reaction solution obtained in the step (1) into the reaction solution obtained in the step (2) at the temperature of 0-20 ℃ to perform chemical reaction to prepare a target product compound 5, wherein the specific synthetic route is as follows:
2. the method for producing flurbiprofen according to claim 1, wherein the reaction temperature in step (1) is-20 to 0 ℃, preferably-15 to-10 ℃.
3. The method for producing flurbiprofen according to claim 1, wherein in step (1), compound 1 and CH are used 3 The mass volume ratio of MgCl is 1; preferably 1.0-4.5 g/mL; more preferably 1.2 to 3.5g/mL.
4. The method for producing flurbiprofen according to claim 1, wherein the reaction temperature in the step (2) is 15 to 35 ℃, preferably 20 to 30 ℃.
5. The method for producing flurbiprofen according to claim 1, wherein in step (2), the molar ratio of compound 2 to magnesium turnings is 1.0 to 2.0, preferably 1.0 to 1.5.
6. The method for producing flurbiprofen according to claim 1, wherein in the step (2), the compound is reacted with CH 3 The mass volume ratio of I is 1; preferably 1.03 to 0.05g/mL.
7. The method for producing flurbiprofen according to claim 1, wherein in step (2), the molar ratio of compound 2 to compound 1 is 1.
8. The method for producing flurbiprofen according to claim 1, wherein the reaction temperature in step (3) is 10 to 15 ℃, preferably 5 to 10 ℃.
9. The method for preparing flurbiprofen according to claim 1, wherein in the step (1), the solvent is tetrahydrofuran, dichloromethane or ethanol; tetrahydrofuran is preferred.
10. The method for preparing flurbiprofen according to claim 1, wherein in the step (2), the solvent is tetrahydrofuran, dichloromethane or ethanol; tetrahydrofuran is preferred.
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|---|---|---|---|---|
| US4144397A (en) * | 1977-02-16 | 1979-03-13 | Syntex Corporation | Preparation of 2-aryl-propionic acids by direct coupling utilizing a mixed magnesium halide complex |
| WO1987000519A1 (en) * | 1985-07-12 | 1987-01-29 | The Upjohn Company | Chemical compounds comrpising substituted phenylrings |
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| US4144397A (en) * | 1977-02-16 | 1979-03-13 | Syntex Corporation | Preparation of 2-aryl-propionic acids by direct coupling utilizing a mixed magnesium halide complex |
| WO1987000519A1 (en) * | 1985-07-12 | 1987-01-29 | The Upjohn Company | Chemical compounds comrpising substituted phenylrings |
| JPH11302220A (en) * | 1998-04-22 | 1999-11-02 | Ihara Nikkei Kagaku Kogyo Kk | Production of chloromethylphenylacetic acid |
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