CN105601504B - A kind of preparation method of 2 (xenyl of 2 fluorine 4) propionic acid - Google Patents
A kind of preparation method of 2 (xenyl of 2 fluorine 4) propionic acid Download PDFInfo
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- CN105601504B CN105601504B CN201610192096.5A CN201610192096A CN105601504B CN 105601504 B CN105601504 B CN 105601504B CN 201610192096 A CN201610192096 A CN 201610192096A CN 105601504 B CN105601504 B CN 105601504B
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 235000019260 propionic acid Nutrition 0.000 title claims abstract description 34
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 229910052731 fluorine Inorganic materials 0.000 title abstract description 6
- 239000011737 fluorine Substances 0.000 title abstract description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 title abstract 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- OWQUYBAASOSGNO-CDNKMLFNSA-N 2-[[(Z)-N-(2-hydroxy-5-sulfoanilino)-C-phenylcarbonimidoyl]diazenyl]benzoic acid Chemical compound C1=CC=C(C=C1)/C(=N/NC2=C(C=CC(=C2)S(=O)(=O)O)O)/N=NC3=CC=CC=C3C(=O)O OWQUYBAASOSGNO-CDNKMLFNSA-N 0.000 claims abstract description 27
- 229940043798 zincon Drugs 0.000 claims abstract description 27
- 230000007062 hydrolysis Effects 0.000 claims abstract description 16
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 16
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 13
- BGJKXDPDBUTQTP-UHFFFAOYSA-N CN(C)C.[SiH4].Cl Chemical compound CN(C)C.[SiH4].Cl BGJKXDPDBUTQTP-UHFFFAOYSA-N 0.000 claims abstract description 11
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 11
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 62
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- ARFLASKVLJTEJD-UHFFFAOYSA-N ethyl 2-bromopropanoate Chemical compound CCOC(=O)C(C)Br ARFLASKVLJTEJD-UHFFFAOYSA-N 0.000 claims description 15
- 239000012074 organic phase Substances 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical group C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- 239000012298 atmosphere Substances 0.000 claims description 5
- 238000005660 chlorination reaction Methods 0.000 claims description 5
- 229910052759 nickel Inorganic materials 0.000 claims description 5
- AIVAIUMRPBQMLT-UHFFFAOYSA-N 3-acetylpentane-2,4-dione;nickel Chemical compound [Ni].CC(=O)C(C(C)=O)C(C)=O AIVAIUMRPBQMLT-UHFFFAOYSA-N 0.000 claims description 3
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical class Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- FSRXIRGQJIHEFB-UHFFFAOYSA-N diphenylphosphane;ethane Chemical compound CC.C=1C=CC=CC=1PC1=CC=CC=C1 FSRXIRGQJIHEFB-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 150000002240 furans Chemical class 0.000 claims 1
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical class CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 abstract description 48
- 238000000034 method Methods 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 8
- 230000035484 reaction time Effects 0.000 abstract description 5
- 239000003446 ligand Substances 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 3
- 239000012190 activator Substances 0.000 abstract description 2
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 238000005516 engineering process Methods 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000009434 installation Methods 0.000 abstract description 2
- 238000012805 post-processing Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 abstract 4
- 235000010290 biphenyl Nutrition 0.000 abstract 2
- 239000004305 biphenyl Substances 0.000 abstract 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract 1
- UMIVDQOVSJFWOH-UHFFFAOYSA-N C1(=CC=CC=C1)C1=CC=CC=C1.[F] Chemical group C1(=CC=CC=C1)C1=CC=CC=C1.[F] UMIVDQOVSJFWOH-UHFFFAOYSA-N 0.000 abstract 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract 1
- 229910052794 bromium Inorganic materials 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000000047 product Substances 0.000 description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 229960002390 flurbiprofen Drugs 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- MONMFXREYOKQTI-UHFFFAOYSA-N 2-bromopropanoic acid Chemical compound CC(Br)C(O)=O MONMFXREYOKQTI-UHFFFAOYSA-N 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 125000004494 ethyl ester group Chemical group 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- 230000033228 biological regulation Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- -1 corrosion inhibiter Substances 0.000 description 3
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 235000006506 Brasenia schreberi Nutrition 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 208000016247 Soft tissue disease Diseases 0.000 description 1
- 201000002661 Spondylitis Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000013563 matrix tablet Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/04—Calcium compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
The invention discloses a kind of preparation method of 2 (xenyl of 2 fluorine 4) propionic acid, belong to chemical industry synthesis and pharmaceutical technology field.The present invention prepares zincon by zinc powder activator of trimethyl ammonia chloride silane, again using the fluorine biphenyl of 4 bromine 2 as raw material, reaction obtains 2 (biphenyl of 2 fluorine 4) ethyl propionates under zincon, catalyst ligand effect, and 2 (biphenyl of 2 fluorine 4) propionic acid are obtained through hydrolysis.This method technique is simple, easy to operate, and the reaction time is short, and product yield is high, impurity is few, and post processing is simple, and utilization rate of equipment and installations is high, suitable for large-scale industrial production application.Particularly, the present invention uses metallic nickel ligand catalysis system, and catalyst activity is high, dosage is few, and can effectively improve product yield height.
Description
Technical field
The present invention relates to a kind of preparation method of 2- (the fluoro- 4- xenyls of 2-) propionic acid, belong to chemical industry synthesis and medical science
Field.
Background technology
2- (the fluoro- 4- xenyls of 2-) propionic acid also known as Flurbiprofen, Flurbiprofen, molecular formula C15H13FO2, molecular weight
244.3, white crystalline powder, micro- smelly and pungent, 114.5~115.5 DEG C of fusing point, be soluble in ethanol, ether, acetone,
Chloroform, it is practically insoluble in water.Flurbiprofen is a kind of potent phenylpropionic acid antipyretic and anti-inflammatory antalgesic, and its mechanism of action is to pass through suppression
The synthesis of Cycloxygenase hindrance blocks prostaglandin processed, mitigate pain, heating and inflammation.Carboxyl and benzene in Flurbiprofen molecule
At a distance of a carbon atom between ring, there is a methyl in the α positions of carboxyl, rotating freely for carboxyl can be limited, make it keep being adapted to
The conformation combined with acceptor or enzyme, to strengthen its anti-inflammatory analgesic action.The meta of phenyl ring has an electron withdraw group fluorine, fluorine atom
Electronegativity it is extremely strong, the affinity between carbon atom can be strengthened, shadow is produced to compound activity by electrical effect and mimic effect
Ring.In addition, fluorinated organic compound has higher hydrophobicity and fat-soluble, can improve the transmission of compound in vivo and
Absorption rate, strengthen anti-inflammatory activity.At present, Flurbiprofen is mainly used in treating rheumatoid arthritis, osteoarthritis, tatanic ridge
Post inflammation, trauma pain, Curved spondylitis, and soft tissue disease are such as sprained, pulled, while to dysmenorrhoea and postoperative pain
There is good efficacy.Compared with other same type medicines, Flurbiprofen has that curative effect is high, rapid-action, dosage is low, Small side effects, stomach
Intestines react the advantage such as slight, and oral effectively tolerance is preferable, and long-term use also will not promote or suppress own metabolism.
Flurbiprofen listed in 1976 in Britain, had been included in English, U.S. pharmacopeia, in recent years the at home and abroad sales volume in market
Progressively rise, market development has a extensive future, existing tablet, corrosion inhibiter, suppository, solid dispersion, hydrogel matrix tablet, joint
A variety of formulations such as chamber microsphere for injection, its active compound synthesis technique is also more by the extensive concern of researcher.At present, Traditional Method closes
Into Flurbiprofen generally existing complex process, the reaction time is long, yield is low, accessory substance is more the shortcomings of, be unfavorable for industrial extension
Production.A kind of method for preparing Flurbiprofen, utilizes improvement as disclosed in publication No. CN101585760A patent of invention
Gomberg-bachmann reacts, and using natrium nitrosum or isoamyl nitrite as diazo reagent, silica gel is dehydrating agent, makes 2-
With benzene coupling reaction occurs for (4- amino -3- fluorophenyls) ethyl propionate, 2- (the fluoro- 4- xenyls of 2-) ethyl propionate is generated, through water
Target product Flurbiprofen is obtained after solution, this method is easy to operate, and production cost is low, but the reaction time is longer, product yield
It is low, and high toxicity solvent is used in reacting, environmental safety is poor.
The content of the invention
It is an object of the invention to provide 2- (the fluoro- 4- connection of 2- that a kind of operating procedure is few, the reaction time is short, product yield is high
Phenyl) propionic acid preparation method.
In order to realize the above object the technical solution adopted in the present invention is：
A kind of preparation method of 2- (the fluoro- 4- xenyls of 2-) propionic acid, comprises the following steps：
1) preparation of zincon
In inert atmosphere, zinc powder, trimethyl ammonia chloride silane and tetrahydrofuran are taken, is heated to flowing back after mixing, add 2- bromines
Ethyl propionate, 1~4h of back flow reaction at 65~70 DEG C of temperature, obtains zincon；
2) synthesis of 2- (the fluoro- 4- xenyls of 2-) propionic acid
In inert atmosphere, zincon is added in the mixed liquor of the bromo- 2- fluorine biphenyl of 4-, catalyst, part and tetrahydrofuran,
3~8h of back flow reaction at 60~70 DEG C of temperature, terminating reaction, solvent is removed after isolating organic phase, is hydrolyzed, is produced.
Step 1), 2) in inert atmosphere nitrogen etc. can be used to protect gas.
Zinc powder, trimethyl ammonia chloride silane, the mass ratio of tetrahydrofuran are 1 in step 1):0.1~0.5:1~2.
The mass ratio of zinc powder and 2 bromopropionic acid ethyl ester is 1 in step 1):2~3.Before 2 bromopropionic acid ethyl ester is added, elder generation is needed
Diluted with tetrahydrofuran, prepare the mass ratio of the tetrahydrofuran solution of 2 bromopropionic acid ethyl ester, 2 bromopropionic acid ethyl ester and tetrahydrofuran
For 1:1.5~3.When adding the tetrahydrofuran solution of 2 bromopropionic acid ethyl ester, should control add speed keep the temperature at 65~
70 DEG C, adding excessive velocities can cause that exothermic heat of reaction is serious, and temperature drastically raises.
The bromo- 2- fluorine biphenyl of 4-, catalyst, part, the mass ratio of tetrahydrofuran are 1 in step 2):0.01~0.03:0.02
~0.06:3~6.
The addition of zincon is 3~5 times of the bromo- 2- fluorine biphenyl quality of 4- in step 2).
Catalyst is 1,2- double (diphenylphosphine) ethane chlorination nickel, diacetyl acetone nickel or nickel chlorides in step 2).
Part is triphenylphosphine or terpyridyl in step 2).
Back flow reaction terminates in step 2), and system is placed in ice bath and cooled, and adds hydrochloric acid solution (1mol/L) termination
Reaction.After reaction terminating, organic phase is first separated, aqueous phase is extracted with appropriate ethyl acetate, and organic phase is merged after extraction, then depressurizes steaming
Except solvent.
Hydrolysis can be in acid (such as hydrochloric acid, sulfuric acid) or alkaline (such as sodium hydroxide, potassium hydroxide, hydroxide in step 2)
Lithium etc.) under the conditions of carry out, after hydrolysis refine, can obtain high-purity 2- (the fluoro- 4- xenyls of 2-) propionic acid product.
Beneficial effects of the present invention：
The present invention prepares zincon by zinc powder activator of trimethyl ammonia chloride silane, then using the bromo- 2- fluorine biphenyl of 4- as raw material,
Reaction obtains 2- (the fluoro- 4- biphenyl of 2-) ethyl propionate under zincon, catalyst-ligand effect, and obtaining 2- through hydrolysis, (2- is fluoro-
4- biphenyl) propionic acid.This method technique is simple, easy to operate, and the reaction time is short, and product yield is high, impurity is few, and post processing is simple,
Utilization rate of equipment and installations is high, suitable for large-scale industrial production application.Particularly, the present invention uses metallic nickel-ligand catalysis system, urges
Agent activity is high, dosage is few, and can effectively improve product yield height.
Embodiment
Following embodiments are only described in further detail to the present invention, but do not form any limitation of the invention.
Embodiment 1
The preparation process of 2- (the fluoro- 4- xenyls of 2-) propionic acid is as follows：
1) preparation of zincon
Under nitrogen protection, zinc powder 100g, trimethyl ammonia chloride silane 20g, tetrahydrofuran 100g are sequentially added in reaction bulb,
15min is stirred at room temperature, is heated to flowing back (65 DEG C of temperature), the tetrahydrofuran solution 500g of 2 bromopropionic acid ethyl ester is slowly added dropwise
(ethyl ester containing 2 bromopropionic acid 200g, 2h drip off), 65 DEG C of back flow reaction 3.5h, it is standby to obtain zincon；Reaction equation is as follows：
2) synthesis of 2- (the fluoro- 4- xenyls of 2-) ethyl propionate
The bromo- 2- fluorine biphenyl 206g of 4-, diacetyl acetone nickel 3.1g, triphenylphosphine 7.2g, four are sequentially added in reaction bulb
Hydrogen furans 731g, is stirred and evenly mixed at room temperature, and above-mentioned zincon (2h is dripped off) is slowly added dropwise under nitrogen protection, is heated to reflux at 65 DEG C
3h is reacted, reaction is finished, cooled down in ice-water bath, and adds 1L 1mol/L hydrochloric acid solution terminating reactions, after reaction terminating, first
Organic phase is separated, aqueous phase is extracted with 1L ethyl acetate, and solvent (tetrahydrofuran and ethyl acetate) is removed under reduced pressure after merging organic phase,
Obtain 2- (the fluoro- 4- xenyls of 2-) ethyl propionate 223g；Reaction equation is as follows：
3) hydrolysis of 2- (the fluoro- 4- xenyls of 2-) ethyl propionate and product is refined
2230g 10%NaOH are added in above-mentioned 2- (the fluoro- 4- xenyls of 2-) ethyl propionate, are warming up to 90 DEG C of hydrolysis,
TLC detections reaction is cooled to less than 25 DEG C, filtered completely after (about 3h), and filtrate is with 30% sulfuric acid solution regulation pH value to being less than
4, through suction filtration, rejection filter, obtain 2- (the fluoro- 4- xenyls of 2-) propionic acid crude product；
The mixed solvent 1.7L of ethyl acetate and petroleum ether is added in 2- (the fluoro- 4- xenyls of 2-) propionic acid crude product (with body
Product is than meter, ethyl acetate:Petroleum ether=1:7), being heated to 60 DEG C makes its dissolving, and heat filter, crystallization are (cold after activated carbon decolorizing
But), filter, dry (60 DEG C), obtain 2- (the fluoro- 4- xenyls of 2-) propionic acid sterling 143g (yield 71.5%, purity 99.5%)；
Reaction equation is as follows：
Embodiment 2
The preparation process of 2- (the fluoro- 4- xenyls of 2-) propionic acid is as follows：
1) preparation of zincon
Under nitrogen protection, zinc powder 200g, trimethyl ammonia chloride silane 60g, tetrahydrofuran 400g are sequentially added in reaction bulb,
15min is stirred at room temperature, is heated to flowing back (66 DEG C of temperature), the tetrahydrofuran solution 1100g of 2 bromopropionic acid ethyl ester is slowly added dropwise
(ethyl ester containing 2 bromopropionic acid 500g, 2.5h drip off), 66 DEG C of back flow reaction 4h, it is standby to obtain zincon；
2) synthesis of 2- (the fluoro- 4- xenyls of 2-) ethyl propionate
The bromo- 2- fluorine biphenyl 440g of 4-, nickel chloride 11g, terpyridyl 22g, tetrahydrofuran are sequentially added in reaction bulb
1980g, stir and evenly mix at room temperature, above-mentioned zincon (2.5h is dripped off) is slowly added dropwise under nitrogen protection, be heated to reflux at 60 DEG C anti-
4h is answered, reaction finishes, and is cooled down in ice-water bath, and adds 2L 1mol/L hydrochloric acid solution terminating reactions, after reaction terminating, first divides
Go out organic phase, aqueous phase is extracted with 2L ethyl acetate, is removed solvent (tetrahydrofuran and ethyl acetate) under reduced pressure after merging organic phase, is obtained
To 2- (the fluoro- 4- xenyls of 2-) ethyl propionate 477g；
3) hydrolysis of 2- (the fluoro- 4- xenyls of 2-) ethyl propionate and product is refined
4770g 10%NaOH are added in above-mentioned 2- (the fluoro- 4- xenyls of 2-) ethyl propionate, are warming up to 95 DEG C of hydrolysis,
TLC detections reaction is cooled to less than 25 DEG C, filtered completely after (about 3h), and filtrate is with 30% sulfuric acid solution regulation pH value to being less than
4, through suction filtration, rejection filter, obtain 2- (the fluoro- 4- xenyls of 2-) propionic acid crude product；
The mixed solvent 3.4L of ethyl acetate and petroleum ether is added in 2- (the fluoro- 4- xenyls of 2-) propionic acid crude product (with body
Product is than meter, ethyl acetate:Petroleum ether=1:7), being heated to 62 DEG C makes its dissolving, and heat filter, crystallization are (cold after activated carbon decolorizing
But), filter, dry (60 DEG C), obtain 2- (the fluoro- 4- xenyls of 2-) propionic acid sterling 300g (yield 70.1%, purity 99.3%).
Embodiment 3
The preparation process of 2- (the fluoro- 4- xenyls of 2-) propionic acid is as follows：
1) preparation of zincon
Under nitrogen protection, zinc powder 350g, trimethyl ammonia chloride silane 35g, tetrahydrofuran 500g are sequentially added in reaction bulb,
20min is stirred at room temperature, is heated to flowing back (temperature 70 C), the tetrahydrofuran solution 1950g of 2 bromopropionic acid ethyl ester is slowly added dropwise
(ethyl ester containing 2 bromopropionic acid 1050g, 3h drip off), 70 DEG C of back flow reaction 3h, it is standby to obtain zincon；
2) synthesis of 2- (the fluoro- 4- xenyls of 2-) ethyl propionate
Sequentially added in reaction bulb double (diphenylphosphine) the ethane chlorination nickel 21.6g of 4- bromo- 2- fluorine biphenyl 720g, 1,2-,
Triphenylphosphine 43.2g, tetrahydrofuran 4200g, are stirred and evenly mixed at room temperature, and above-mentioned zincon (3h drops are slowly added dropwise under nitrogen protection
It is complete), heating reflux reaction 5h at 65 DEG C, reaction is finished, cooled down in ice-water bath, and adds 2.5L 1mol/L hydrochloric acid solutions end
Only react, after reaction terminating, first separate organic phase, aqueous phase is extracted with 2.5L ethyl acetate, is removed under reduced pressure after merging organic phase molten
Agent (tetrahydrofuran and ethyl acetate), obtain 2- (the fluoro- 4- xenyls of 2-) ethyl propionate 781g；
3) hydrolysis of 2- (the fluoro- 4- xenyls of 2-) ethyl propionate and product is refined
7810g 10%NaOH are added in above-mentioned 2- (the fluoro- 4- xenyls of 2-) ethyl propionate, are warming up to 100 DEG C of hydrolysis,
TLC detections reaction is cooled to less than 25 DEG C, filtered completely after (about 3h), and filtrate is with 30% sulfuric acid solution regulation pH value to being less than
4, through suction filtration, rejection filter, obtain 2- (the fluoro- 4- xenyls of 2-) propionic acid crude product；
The mixed solvent 6.0L of ethyl acetate and petroleum ether is added in 2- (the fluoro- 4- xenyls of 2-) propionic acid crude product (with body
Product is than meter, ethyl acetate:Petroleum ether=1:7), being heated to 63 DEG C makes its dissolving, and heat filter, crystallization are (cold after activated carbon decolorizing
But), filter, dry (60 DEG C), obtain 2- (the fluoro- 4- xenyls of 2-) propionic acid sterling 488g (yield 69.7%, purity 99.6%).
Embodiment 4
The preparation process of 2- (the fluoro- 4- xenyls of 2-) propionic acid is as follows：
1) preparation of zincon
Under nitrogen protection, zinc powder 450g, trimethyl ammonia chloride silane 157g, tetrahydrofuran are sequentially added in reaction bulb
700g, 20min is stirred at room temperature, be heated to flowing back (68 DEG C of temperature), the tetrahydrofuran solution of 2 bromopropionic acid ethyl ester is slowly added dropwise
2855g (ethyl ester containing 2 bromopropionic acid 1080g, 3.5h drip off), 68 DEG C of back flow reaction 3.5h, it is standby to obtain zincon；
2) synthesis of 2- (the fluoro- 4- xenyls of 2-) ethyl propionate
Sequentially added in reaction bulb double (diphenylphosphine) the ethane chlorination nickel 18.5g of 4- bromo- 2- fluorine biphenyl 925g, 1,2-,
Terpyridyl 32.4g, tetrahydrofuran 3700g, are stirred and evenly mixed at room temperature, and above-mentioned zincon (3h drops are slowly added dropwise under nitrogen protection
It is complete), heating reflux reaction 6h at 68 DEG C, reaction is finished, cooled down in ice-water bath, and adds the termination of 3L 1mol/L hydrochloric acid solutions
React, after reaction terminating, first separate organic phase, aqueous phase is extracted with 3L ethyl acetate, and solvent (four is removed under reduced pressure after merging organic phase
Hydrogen furans and ethyl acetate), obtain 2- (the fluoro- 4- xenyls of 2-) ethyl propionate 1000g；
3) hydrolysis of 2- (the fluoro- 4- xenyls of 2-) ethyl propionate and product is refined
10kg 10%NaOH are added in above-mentioned 2- (the fluoro- 4- xenyls of 2-) ethyl propionate, are warming up to 95 DEG C of hydrolysis, TLC
After (about 3h) completely is reacted in detection, less than 25 DEG C are cooled to, is filtered, filtrate adjusts pH value to less than 4 with 30% sulfuric acid solution, passes through
Filter, rejection filter, obtain 2- (the fluoro- 4- xenyls of 2-) propionic acid crude product；
The mixed solvent 7.65L of ethyl acetate and petroleum ether is added in 2- (the fluoro- 4- xenyls of 2-) propionic acid crude product (with body
Product is than meter, ethyl acetate:Petroleum ether=1:7), being heated to 64.5 DEG C makes its dissolving, and heat filter, crystallization are (cold after activated carbon decolorizing
But), filter, dry (60 DEG C), obtain 2- (the fluoro- 4- xenyls of 2-) propionic acid sterling 648g (yield 72.0%, purity 99.6%).
Embodiment 5
The preparation process of 2- (the fluoro- 4- xenyls of 2-) propionic acid is as follows：
1) preparation of zincon
Under nitrogen protection, zinc powder 500g, trimethyl ammonia chloride silane 125g, tetrahydrofuran are sequentially added in reaction bulb
750g, 20min is stirred at room temperature, be heated to flowing back (temperature 70 C), the tetrahydrofuran solution of 2 bromopropionic acid ethyl ester is slowly added dropwise
2900g (ethyl ester containing 2 bromopropionic acid 1400g, 4h drip off), 70 DEG C of back flow reaction 4h, it is standby to obtain zincon；
2) synthesis of 2- (the fluoro- 4- xenyls of 2-) ethyl propionate
Sequentially added in reaction bulb double (diphenylphosphine) the ethane chlorination nickel 8.55g of 4- bromo- 2- fluorine biphenyl 855g, 1,2-,
Terpyridyl 17.1g, tetrahydrofuran 2565g, are stirred and evenly mixed at room temperature, and above-mentioned zincon (3h drops are slowly added dropwise under nitrogen protection
It is complete), heating reflux reaction 6.5h at 70 DEG C, reaction is finished, cooled down in ice-water bath, and adds 5L 1mol/L hydrochloric acid solutions end
Only react, after reaction terminating, first separate organic phase, aqueous phase is extracted with 4L ethyl acetate, and solvent is removed under reduced pressure after merging organic phase
(tetrahydrofuran and ethyl acetate), obtain 2- (the fluoro- 4- xenyls of 2-) ethyl propionate 944g；
3) hydrolysis of 2- (the fluoro- 4- xenyls of 2-) ethyl propionate and product is refined
9.44kg 10%NaOH are added in above-mentioned 2- (the fluoro- 4- xenyls of 2-) ethyl propionate, are warming up to 95 DEG C of hydrolysis,
TLC detections reaction is cooled to less than 25 DEG C, filtered completely after (about 3h), and filtrate is with 30% sulfuric acid solution regulation pH value to being less than
4, through suction filtration, rejection filter, obtain 2- (the fluoro- 4- xenyls of 2-) propionic acid crude product；
The mixed solvent 8.5L of ethyl acetate and petroleum ether is added in 2- (the fluoro- 4- xenyls of 2-) propionic acid crude product (with body
Product is than meter, ethyl acetate:Petroleum ether=1:7), being heated to 65 DEG C makes its dissolving, and heat filter, crystallization are (cold after activated carbon decolorizing
But), filter, dry (60 DEG C), obtain 2- (the fluoro- 4- xenyls of 2-) propionic acid sterling 601g (yield 72.2%, purity
99.65%).
Claims (6)
- A kind of 1. preparation method of 2- (the fluoro- 4- xenyls of 2-) propionic acid, it is characterised in that：Comprise the following steps：1）The preparation of zinconIn inert atmosphere, zinc powder, trimethyl ammonia chloride silane and tetrahydrofuran are taken, is heated to flowing back after mixing, add 2 bromopropionic acid Ethyl ester, 1 ~ 4h of back flow reaction at 65 ~ 70 DEG C of temperature, obtains zincon；2）The synthesis of 2- (the fluoro- 4- xenyls of 2-) propionic acidIn inert atmosphere, zincon is added in the mixed liquor of the bromo- 2- fluorine biphenyl of 4-, catalyst, part and tetrahydrofuran, in temperature 3 ~ 8h of back flow reaction at 60 ~ 70 DEG C of degree, terminating reaction, solvent is removed after isolating organic phase, is hydrolyzed, is produced；Step 2）The bromo- 2- fluorine biphenyl of middle 4-, catalyst, part, the mass ratio of tetrahydrofuran are 1:0.01~0.03:0.02~ 0.06:3~6；Step 2）The addition of middle zincon is 3 ~ 5 times of the bromo- 2- fluorine biphenyl quality of 4-；Step 2）Middle catalyst is 1,2- double (diphenylphosphine) ethane chlorination nickel, diacetyl acetone nickel or nickel chlorides；Step 2）Middle part is triphenylphosphine or terpyridyl.
- 2. preparation method according to claim 1, it is characterised in that：Step 1）Middle zinc powder, trimethyl ammonia chloride silane, tetrahydrochysene The mass ratio of furans is 1:0.1~0.5:1~2.
- 3. preparation method according to claim 1 or 2, it is characterised in that：Step 1）Middle zinc powder and 2 bromopropionic acid ethyl ester Mass ratio is 1:2~3.
- 4. preparation method according to claim 1, it is characterised in that：Step 1）Before 2 bromopropionic acid ethyl ester is added, first make The mass ratio of the tetrahydrofuran solution of standby 2 bromopropionic acid ethyl ester, 2 bromopropionic acid ethyl ester and tetrahydrofuran is 1:1.5~3.
- 5. preparation method according to claim 1, it is characterised in that：Step 2）Middle back flow reaction terminates, and system is placed in Cool in ice bath, and add hydrochloric acid solution terminating reaction.
- 6. preparation method according to claim 1, it is characterised in that：Step 2）Middle hydrolysis is entered under acid or alkaline conditions OK, refined after hydrolysis, produce 2- (the fluoro- 4- xenyls of 2-) propionic acid sterling.
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Address after: No. 6, No. 4, No. 52, No. 4, Huang Yang Street, high tech Industrial Development Zone, Zhengzhou City, Henan Province, 41 Patentee after: Zhengzhou principle Biological Technology Co., Ltd. Address before: No. 41, No. 4, No. 4, phase 2, long Ding enterprise center of electronic and electrical appliances Industrial Park, Henan Province Patentee before: Zhengzhou Sigma Chemical Co., Ltd. |