CN108516928A - A kind of preparation process of 1- (2,3- difluorophenyls) -2- methyl-1s-acetone - Google Patents
A kind of preparation process of 1- (2,3- difluorophenyls) -2- methyl-1s-acetone Download PDFInfo
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- difluorophenyl
- acetone
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- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- -1 2,3 difluorophenyl Chemical group 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical compound FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 claims abstract description 13
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000012043 crude product Substances 0.000 claims abstract description 9
- 150000007530 organic bases Chemical class 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 7
- 238000000746 purification Methods 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 239000012467 final product Substances 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 3
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 10
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 3
- 238000004817 gas chromatography Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000012263 liquid product Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000005292 vacuum distillation Methods 0.000 description 4
- 238000007689 inspection Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 125000006202 diisopropylaminoethyl group Chemical group [H]C([H])([H])C([H])(N(C([H])([H])C([H])([H])*)C([H])(C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- 241000254173 Coleoptera Species 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- CATSNJVOTSVZJV-UHFFFAOYSA-N heptan-2-one Chemical compound CCCCCC(C)=O CATSNJVOTSVZJV-UHFFFAOYSA-N 0.000 description 1
- IUYHWZFSGMZEOG-UHFFFAOYSA-M isopropylmagnesium chloride Substances [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- HINICOSKCHKZOG-UHFFFAOYSA-N lithium;1,2-difluorobenzene-6-ide Chemical compound [Li+].FC1=CC=C[C-]=C1F HINICOSKCHKZOG-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
-
- 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
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/02—Lithium compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides a kind of preparation process of 1 acetone of 1 (2,3 difluorophenyl) 2 methyl, and in particular to technical field of medicine synthesis specifically includes under cryogenic, and 1,2 difluorobenzene reacts in a solvent with organic base, generates 2,3 difluorophenyl lithiums；Then the crude product in solution that isobutyryl chloride obtains 1 acetone of final product 1 (2,3 difluorophenyl) 2 methyl is added, then pH to 35 is adjusted with acid, last extracted, concentration, purification process generates 1 (2,3 difluorophenyl) 2 methyl, 1 acetone of high-purity.Present invention process is novel, and reaction condition is mild, and by-product is few, and purification process is simple, high income, of low cost compared with existing synthesis technology, easy to operate, is convenient for large-scale production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of 1- (2,3- difluorophenyl) -2- methyl-1s-acetone
Preparation process.
Background technology
1- (2,3- difluorophenyl) -2- methyl-1s-acetone is a kind of important bulk pharmaceutical chemicals intermediate, is synthesized in many new drugs
In often occur, prior art discloses following synthetic routes
The route with 2,3- difluorobenzonilyiles be starting material, with grignard reagent isopropylmagnesium chloride pyroreaction, rear low temperature
It is lower to use hydrochloric acid, extraction, concentration and purifying, 1- (2,3- difluorophenyl) -2- methyl-1s-acetone is prepared.The technique is former
Expect of high cost, side reaction is more, to heat up and cool down repeatedly in reaction, cumbersome, is unfavorable for large-scale production.
It is therefore desirable to the synthetic methods to 1- (2,3- difluorophenyl) -2- methyl-1s-acetone to be studied, and be grasped with simplifying
Make, reduce cost, improves yield, adapt to the requirement of large-scale production.
Invention content
The object of the present invention is to provide a kind of preparation processes of 1- (2,3- difluorophenyl) -2- methyl-1s-acetone, solve existing
It is some there are the problem of include cost of material height, side reaction is more, to heat up and cool down repeatedly in reaction, cumbersome, is unfavorable for
Large-scale production.
The present invention provides the following technical solutions：
A kind of preparation process of 1- (2,3- difluorophenyl) -2- methyl-1s-acetone, is as follows：
S1：Under cryogenic, 1,2- difluorobenzenes (alias o-difluoro-benzene) react in a solvent with organic base, generate 2,3-
Difluorophenyl lithium；
S2, under cryogenic, isobutyryl chloride is added in 2, the 3- difluorophenyl lithium solution obtained in step S1, is obtained
Obtain the crude product in solution of final product 1- (2,3- difluorophenyls) -2- methyl-1s-acetone；
S3, with acid by the crude product of the final product 1- obtained in step S2 (2,3- difluorophenyls) -2- methyl-1s-acetone
Solution tune pH to 3-5, then extracted, concentration, purification process generate 1- (2,3- difluorophenyl) -2- methyl-1s-the third of high-purity
Ketone.
Preferably, the organic base in step S1 is n-BuLi, s-butyl lithium, tert-butyl lithium, diisopropylaminoethyl
One kind in lithium or bis- (trimethyl silicon substrate) lithium amides.Specifically reaction equation is：
Wherein R1 is normal-butyl, sec-butyl, tertiary butyl, the one of diisopropylaminoethyl or bis- (trimethyl silicon substrate) amino
Kind.
Preferably, the cryogenic conditions in step S1 are -30~-80 DEG C.
Preferably, the cryogenic conditions in step S2 are less than -30 DEG C.
Preferably, the molar ratio of 1, the 2- difluorobenzenes in step S1 and the organic base is 1：0.9~1：1.2.
Preferably, in step sl reaction dissolvent and organic base solvent is anhydrous ether, anhydrous tetrahydro furan, without water beetle
Any one in base tertbutyl ether, isopropyl ether, dry toluene, anhydrous n-hexane, anhydrous normal heptane and hexamethylene or two kinds.
Preferably, the molar ratio of 1, the 2- difluorobenzenes and the dosage of the isobutyryl chloride is 1：0.9~1：1.2.
Preferably, solvent used in the extraction in step S3 and purification process is methyl tertiary butyl ether(MTBE), n-hexane, positive heptan
One kind in alkane, ethyl acetate, ethylene-propylene ether, petroleum ether, toluene or dichloromethane.
Preferably, the acid in step S3 is one kind in hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid or aqueous formic acid.
Preferably, a concentration of 1-3M of the acid in step S3.
The beneficial effects of the invention are as follows：The new technology, reaction condition is mild, and by-product is few, and purification process is simple, yield
Height, it is of low cost compared with existing synthesis technology, it is easy to operate, it is convenient for large-scale production.
Specific implementation mode
Example one
O-difluoro-benzene (100g, 0.877mol), anhydrous tetrahydro furan are sequentially added into three mouthfuls of reaction bulbs of 2.0L
(1.0L), stirring to system are clarified, and are cooled to -80 DEG C.N-BuLi is added dropwise at -30~-80 DEG C in control system temperature
(315ml, 2.5M cyclohexane solution) after being added dropwise, continues to stir 1-2.0h.Isobutyryl chloride is added dropwise into reaction system
(84g, 0.788mol), control system temperature are added dropwise at -30~-80 DEG C, continue to be stirred to react 2.0h.Holding system temperature
Degree is less than -30 DEG C, with 3M hydrochloric acid solution regulation systems pH in 3-5.
Reaction system is filtered, filtrate is extracted with ethyl acetate for several times, and organic phase concentration obtains 1- (2,3- difluorobenzenes
Base) -2- methyl-1s-acetone crude product, vacuum distillation purifying obtains colorless liquid product 148g, and purity is more than 98%, and purity is same
When by three kinds of methods of HPLC (high performance liquid chromatography), GC (gas chromatography) and HNMR (hydrogen in nuclear magnetic resonance technique is composed) into
Row detection, yield 92%, sample collection of illustrative plates are consistent with standard diagram comparison.
Example two
O-difluoro-benzene (100g, 0.877mol) is sequentially added into three mouthfuls of reaction bulbs of 2.0L, anhydrous ether (1.0L) stirs
It mixes to system and clarifies, be cooled to -80 DEG C.S-butyl lithium (555ml, 1.5M hexamethylene is added dropwise at -30~-80 DEG C in control system temperature
Alkane solution), after being added dropwise, continue to stir 1-2.0h.Isobutyryl chloride (84g, 0.788mol), control are added dropwise into reaction system
System temperature is added dropwise at -30~-80 DEG C, continues to be stirred to react 2.0h.System temperature is kept to be less than -30 DEG C, with 3M hydrochloric acid
PH is in 3-5 for solution regulation system.
Reaction system is filtered, filtrate is extracted with ethyl acetate for several times, and organic phase concentration obtains 1- (2,3- difluorobenzenes
Base) -2- methyl-1s-acetone crude product, vacuum distillation purifying obtains colorless liquid product 145g, and purity is more than 98%, and purity is same
When pass through three kinds of methods inspections of HPLC (high performance liquid chromatography), GC (gas chromatography) and HNMR (the hydrogen spectrum in nuclear magnetic resonance technique)
It surveys, yield 90%, sample collection of illustrative plates is consistent with standard diagram comparison.
Example three
O-difluoro-benzene (100g, 0.877mol) is sequentially added into three mouthfuls of reaction bulbs of 2.0L, anhydrous ether (1.0L) stirs
It mixes to system and clarifies, be cooled to -80 DEG C.Control system temperature at -30~-80 DEG C, be added dropwise lithium diisopropyl amido (315ml,
2.5M tetrahydrofuran solutions), after being added dropwise, continue to stir 1-2.0h.Into reaction system be added dropwise isobutyryl chloride (84g,
0.788mol), control system temperature is added dropwise at -30~-80 DEG C, continues to be stirred to react 2.0h.Keep system temperature small
In -30 DEG C, with 3M hydrochloric acid solution regulation systems pH in 3-5.
Reaction system is filtered, filtrate is extracted with ethyl acetate for several times, and organic phase concentration obtains 1- (2,3- difluorobenzenes
Base) -2- methyl-1s-acetone crude product, vacuum distillation purifying obtains colorless liquid product 148g, and purity is more than 98%, and purity is same
When pass through three kinds of methods inspections of HPLC (high performance liquid chromatography), GC (gas chromatography) and HNMR (the hydrogen spectrum in nuclear magnetic resonance technique)
It surveys, yield 92%, sample collection of illustrative plates is consistent with standard diagram comparison.
Example four
O-difluoro-benzene (100g, 0.877mol) is sequentially added into three mouthfuls of reaction bulbs of 2.0L, anhydrous ether (1.0L) stirs
It mixes to system and clarifies, be cooled to -80 DEG C.Lithium hexamethyldisilazide is added dropwise at -30~-80 DEG C in control system temperature
(315ml, 2.5M tetrahydrofuran solution) after being added dropwise, continues to stir 1-2.0h.Isobutyryl chloride is added dropwise into reaction system
(84g, 0.788mol), control system temperature are added dropwise at -30~-80 DEG C, continue to be stirred to react 2.0h.Holding system temperature
Degree is less than -30 DEG C, with 3M hydrochloric acid solution regulation systems pH in 3-5.
Reaction system is filtered, filtrate is extracted with ethyl acetate for several times, and organic phase concentration obtains 1- (2,3- difluorobenzenes
Base) -2- methyl-1s-acetone crude product, vacuum distillation purifying obtains colorless liquid product 143g, and purity is more than 98%, and purity is same
When pass through three kinds of methods inspections of HPLC (high performance liquid chromatography), GC (gas chromatography) and HNMR (the hydrogen spectrum in nuclear magnetic resonance technique)
It surveys, yield 89%, sample collection of illustrative plates is consistent with standard diagram comparison.
It these are only the preferred embodiment of the present invention, be not intended to restrict the invention, although with reference to the foregoing embodiments
Invention is explained in detail, for those skilled in the art, still can be to foregoing embodiments institute
The technical solution of record is modified or equivalent replacement of some of the technical features.It is all the present invention spirit and
Within principle, any modification, equivalent replacement, improvement and so on should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of preparation process of 1- (2,3- difluorophenyl) -2- methyl-1s-acetone, which is characterized in that be as follows：
S1：Under cryogenic, 1,2- difluorobenzenes react in a solvent with organic base, generate 2,3- difluorophenyl lithiums；
S2, under cryogenic, isobutyryl chloride is added in 2, the 3- difluorophenyl lithium solution obtained in step S1, is obtained most
The crude product in solution of final product 1- (2,3- difluorophenyls) -2- methyl-1s-acetone；
S3, with acid by the crude product in solution of the final product 1- obtained in step S2 (2,3- difluorophenyls) -2- methyl-1s-acetone
PH to 3-5, then extracted, concentration, purification process is adjusted to generate 1- (2,3- difluorophenyl) -2- methyl-1s-acetone of high-purity.
2. the preparation process of 1- (2,3- difluorophenyl) -2- methyl-1s-acetone according to claim 1, which is characterized in that
The organic base in step S1 is n-BuLi, s-butyl lithium, tert-butyl lithium, lithium diisopropylamine or bis- (trimethyl silicanes
Base) one kind in lithium amide.
3. the preparation process of 1- (2,3- difluorophenyl) -2- methyl-1s-acetone according to claim 1, which is characterized in that
The cryogenic conditions in step S1 are -30~-80 DEG C.
4. the preparation process of 1- (2,3- difluorophenyl) -2- methyl-1s-acetone according to claim 1, which is characterized in that
The cryogenic conditions in step S2 are less than -30 DEG C.
5. the preparation process of 1- (2,3- difluorophenyl) -2- methyl-1s-acetone according to any one of claims 1-4,
It is characterized in that, the molar ratio of 1, the 2- difluorobenzenes and the organic base in step S1 is 1：0.9~1：1.2.
6. the preparation process of 1- (2,3- difluorophenyl) -2- methyl-1s-acetone according to claim 1, which is characterized in that
Reaction dissolvent and organic base solvent in step sl is anhydrous ether, anhydrous tetrahydro furan, anhydrous methyl tertbutyl ether, isopropyl
Any one in base ether, dry toluene, anhydrous n-hexane, anhydrous normal heptane and hexamethylene or two kinds.
7. the preparation process of 1- (2,3- difluorophenyl) -2- methyl-1s-acetone according to claim 1, which is characterized in that
The molar ratio of 1, the 2- difluorobenzenes and the dosage of the isobutyryl chloride is 1：0.9~1：1.2.
8. the preparation process of 1- (2,3- difluorophenyl) -2- methyl-1s-acetone according to claim 1, which is characterized in that
Solvent used in extraction and purification process in step S3 is methyl tertiary butyl ether(MTBE), n-hexane, normal heptane, ethyl acetate, second
One kind in propyl ether, petroleum ether, toluene or dichloromethane.
9. requiring the preparation process of the 1- (2,3- difluorophenyl) -2- methyl-1s-acetone according to right 1, which is characterized in that
The acid in step S3 is one kind in hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid or aqueous formic acid.
10. the preparation process of 1- (2,3- difluorophenyl) -2- methyl-1s-acetone according to claim 9, feature exist
In a concentration of 1-3M of the acid in step S3.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005042516A2 (en) * | 2003-10-22 | 2005-05-12 | Neurocrine Biosciences, Inc. | Ligands of melanocortin receptors and compositions and methods related thereto |
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| WO2005042516A2 (en) * | 2003-10-22 | 2005-05-12 | Neurocrine Biosciences, Inc. | Ligands of melanocortin receptors and compositions and methods related thereto |
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