CN113603661A - Synthesis method of (S) -5-fluoro-3-methylisobenzofuran-3-one - Google Patents
Synthesis method of (S) -5-fluoro-3-methylisobenzofuran-3-one Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 13
- RRKPMLZRLKTDQV-UHFFFAOYSA-N 2-bromo-4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1Br RRKPMLZRLKTDQV-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000003747 Grignard reaction Methods 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- -1 4-fluoro-2 (1-hydroxyethyl) phenylacetic acid Chemical compound 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 12
- KLAAXTKTDRQPOF-UHFFFAOYSA-N 4-fluoro-2-formylbenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1C=O KLAAXTKTDRQPOF-UHFFFAOYSA-N 0.000 claims description 10
- 239000007818 Grignard reagent Substances 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 9
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Substances [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 9
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 6
- 150000004795 grignard reagents Chemical class 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 5
- 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 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- 229940008309 acetone / ethanol Drugs 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical group O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- 238000007142 ring opening reaction Methods 0.000 claims description 4
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- 239000012027 Collins reagent Substances 0.000 claims description 2
- 239000003810 Jones reagent Substances 0.000 claims description 2
- 229910010084 LiAlH4 Inorganic materials 0.000 claims description 2
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 229940117975 chromium trioxide Drugs 0.000 claims description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 2
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- NPRDHMWYZHSAHR-UHFFFAOYSA-N pyridine;trioxochromium Chemical compound O=[Cr](=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 NPRDHMWYZHSAHR-UHFFFAOYSA-N 0.000 claims description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 claims 2
- 239000003814 drug Substances 0.000 abstract description 7
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- IIXWYSCJSQVBQM-LLVKDONJSA-N lorlatinib Chemical compound N=1N(C)C(C#N)=C2C=1CN(C)C(=O)C1=CC=C(F)C=C1[C@@H](C)OC1=CC2=CN=C1N IIXWYSCJSQVBQM-LLVKDONJSA-N 0.000 abstract description 3
- HPMMSQUICAYILZ-UHFFFAOYSA-N 2-methyl-5-(methylaminomethyl)pyrazole-3-carbonitrile Chemical compound CNCC=1C=C(C#N)N(C)N=1 HPMMSQUICAYILZ-UHFFFAOYSA-N 0.000 abstract description 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract description 2
- 230000005494 condensation Effects 0.000 abstract description 2
- 230000008878 coupling Effects 0.000 abstract description 2
- 238000010168 coupling process Methods 0.000 abstract description 2
- 238000005859 coupling reaction Methods 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 229950001290 lorlatinib Drugs 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 238000010189 synthetic method Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- GZPUPDFZOLCBAD-YFKPBYRVSA-N (3S)-5-fluoro-3-methyl-3H-2-benzofuran-1-one Chemical compound C[C@@H]1OC(=O)c2ccc(F)cc12 GZPUPDFZOLCBAD-YFKPBYRVSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 229940122531 Anaplastic lymphoma kinase inhibitor Drugs 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 3
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229960005061 crizotinib Drugs 0.000 description 3
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229960001602 ceritinib Drugs 0.000 description 2
- VERWOWGGCGHDQE-UHFFFAOYSA-N ceritinib Chemical compound CC=1C=C(NC=2N=C(NC=3C(=CC=CC=3)S(=O)(=O)C(C)C)C(Cl)=CN=2)C(OC(C)C)=CC=1C1CCNCC1 VERWOWGGCGHDQE-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
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- 201000005202 lung cancer Diseases 0.000 description 1
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- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
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- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of medicines, and relates to a synthesis method of an antitumor drug Laolatinib (Lorlatinib) intermediate (S) -5-fluoro-3-methylisobenzofuran-3-ketone, which takes 2-bromo-4-fluorobenzoic acid as a starting material and obtains (S) -5-fluoro-3-methylisobenzofuran-3-ketone through two steps of Grignard reaction and resolution, wherein the total yield is up to over 36.5%. The synthetic method has the advantages of short route, short time consumption and low cost, and is beneficial to realizing industrialization. The intermediate and 1-methyl-3- ((methylamino) methyl) -1H-pyrazole-5-nitrile are subjected to condensation, substitution, coupling and other reaction steps to finally synthesize the Laratinib, and a new method is provided for synthesizing the anti-tumor medicine Laratinib.
Description
Technical Field
The invention relates to the technical field of medicines, and relates to a synthesis method of a medicine Laratinib key intermediate (S) -5-fluoro-3-methylisobenzofuran-3-one. The intermediate and 1-methyl-3- ((methylamino) methyl) -1H-pyrazole-5-nitrile are subjected to condensation, substitution, coupling and other reaction steps to finally synthesize the Laratinib, and a new method is provided for synthesizing the anti-tumor medicine Laratinib.
Background
Loratinib (lorelatinib) is a third-generation ALK inhibitor obtained by Pfizer, inc (Crizotinib), of Crizotinib, usa. The medicine enters clinical trials in 2014, is used for treating lung cancer and mainly aims at non-small cell lung cancer patients with drug resistance of a first generation ALK inhibitor crizotinib and drug resistance of a second generation ALK inhibitor Ceritinib (Ceritinib) and drug resistance of Aletinib (Alectininib). Four synthetic routes to loratinib and its intermediates are described in WO2013132376, US8680111, JP2015510879, EP2822953, CN 1041699286, US2016115178, WO2014207606 in the following patent documents.
(S) -5-fluoro-3-methylisobenzofuran-1 (3H) -one is a main raw material for preparing Laratinib, is an important chemical and medical intermediate, and can be used in a plurality of fields such as dyes, hair dyes, medicines, pesticide materials and the like. However, there are few reports on the preparation method of (S) -5-fluoro-3-methylisobenzofuran-1 (3H) -one. WO2013132376 shows a synthesis method for the intermediate (S) -5-fluoro-3-methylisobenzofuran-1 (3H) -one, but the synthesis route is long, the cost is high, the time consumption is long, and the yield is low. CN109134410A is a previous patent application of the inventor, and discloses a preparation method of 5-fluoro-3-methylisobenzofuran-1 (3H) -ketone, but the method still has the problems of long synthetic route, high cost, low yield and complex treatment. CN112921057A discloses a novel synthesis route of 5-fluoro-3-methyl isobenzofuran-1 (3H) -ketone, which greatly shortens the synthesis method provided by the original report, simplifies the operation and improves the yield, but the method samples biological enzyme as a catalyst, thereby limiting the application range of the preparation method.
Therefore, it is necessary to develop a new synthesis method of intermediate (S) -5-fluoro-3-methylisobenzofuran-1 (3H) -one, which has the advantages of easily available raw materials, short steps, low cost, and the like, and is easy for industrialization.
Disclosure of Invention
The invention aims to solve the technical problem of providing a novel synthesis method of (S) -5-fluoro-3-methylisobenzofuran-1 (3H) -one.
The invention is realized by the following technical scheme:
2-bromo-4-fluorobenzoic acid is taken as an initial raw material, and the (S) -5-fluoro-3-yl isobenzofuran-1 (3H) -ketone is obtained through a two-step Grignard reaction and one-step chiral resolution reaction.
The invention realizes the preparation of the antitumor drug Laratinib key intermediate (S) -5-fluoro-3-methylisobenzofuran-1 (3H) -ketone, has the total yield of over 36.5 percent, has short time consumption and low cost, is beneficial to realizing industrialization, and provides a new method for the synthesis of the antitumor drug Laratinib.
The synthesis method comprises the following steps:
the preparation method of (S) -5-fluoro-3-methylisobenzofuran-1 (3H) -one is as follows:
(1) reacting 2-bromo-4-fluorobenzoic acid with i-PrMgCl and DMF at low temperature to obtain 4-fluoro-2-formylbenzoic acid;
(2) 4-fluoro-2-formylbenzoic acid and MeMgCl are subjected to Grignard reaction at low temperature to prepare 5-fluoro-3-methylisobenzofuran-3-one;
(3) 5-fluoro-3-methylisobenzofuran-3-one is subjected to ring opening under an alkaline condition, is acidified to obtain 4-fluoro-2 (1-hydroxyethyl) phenylacetic acid, is salified with (S) -methylbenzylamine at a low temperature to separate out amine carboxylate, is subjected to recrystallization for 3 times, and is dissociated and acidified under an alkaline condition to obtain (S) -5-fluoro-3-methylisobenzofuran-3-one.
The reaction scheme for preparing the compound of the invention is as follows:
in a process for the preparation of (S) -5-fluoro-3-methylisobenzofuran-1 (3H) -one:
in the step (1), 2-bromo-4-fluorobenzoic acid is used for preparing 4-fluoro-2-formylbenzoic acid at a low temperature, an organic solvent is anhydrous tetrahydrofuran or anhydrous ether under the protection of nitrogen, the temperature for preparing the aryl Grignard reagent is-30 ℃ to-35 ℃, the temperature for adding DMF is-15 ℃ to-20 ℃, and DMF can be replaced by acetaldehyde, so that the compound III is directly obtained, the Grignard reagent can be replaced by n-butyllithium, and the molar ratio of the 2-bromo-4-fluorobenzoic acid to the Grignard reagent and the DMF is 1:3:3 to 1:3:5, preferably 1:3: 4.
In the step (2), 4-fluoro-2-formylbenzoic acid is used for preparing 5-fluoro-3-methylisobenzofuran-3-one at low temperature, an organic solvent is anhydrous tetrahydrofuran or anhydrous ether, the temperature is reduced to-15 ℃ under the protection of nitrogen, a methyl Grignard reagent is dripped, the Grignard reagent can be replaced by methyl magnesium bromide or methyl magnesium chloride, the mixture is transferred to room temperature after dripping is finished, 4-fluoro-2 (1-hydroxyethyl) phenylacetic acid is prepared, and the post-treatment is reduced pressure distillation, so that the 5-fluoro-3-methylisobenzofuran-3-one is prepared.
In the step (3), 5-fluoro-3-methyl isobenzofuran-3-one is subjected to ring opening under alkaline conditions, the alkali is selected from sodium salt organic alkali of C1-C4 alcohol or sodium hydroxide, potassium hydroxide, sodium hydride or LDA inorganic alkali, and compound III is obtained by acidification, the acid is selected from formic acid, glacial acetic acid or hydrochloric acid, and the selected solvent is a methanol/water, ethanol/water or isopropanol/water mixed system; the compound III is salified with (S) -methylbenzylamine at low temperature, and the molar ratio of the compound III to the (S) -methylbenzylamine is 1: 0.5-1: 1, preferably 1: 0.5; the salt forming temperature is 0 ℃ to-15 ℃, and is preferably-15 ℃; the salifying solvent is tetrahydrofuran or anhydrous diethyl ether or ethyl acetate or acetonitrile, wherein tetrahydrofuran is preferred; recrystallizing the carboxylic amine salt by using a recrystallization solvent selected from methanol, ethanol, acetonitrile, acetone/ethanol mixed solution, preferably acetone/ethanol mixed solution, wherein the recrystallization temperature is not higher than 30 ℃, and then the carboxylic amine salt is dissociated and acidified under the alkaline condition to obtain (S) -5-fluoro-3-methyl isobenzofuran-3-one, the alkali is selected from sodium salt organic alkali of C1-C4 alcohol or sodium hydroxide, potassium hydroxide, sodium hydride or LDA inorganic alkali, and the acid is selected from formic acid, glacial acetic acid or hydrochloric acid; the reaction temperature is 50-70 ℃.
In step (3), the remaining intermediate is resolved by re-opening the ring under basic conditions, the base being selected from the group consisting of sodium salt organic bases of C1-C4 alcohols or sodium hydroxide, potassium hydroxide, sodium hydride or LDA inorganic bases; opening the ring, oxidizing to obtain a compound II, wherein the oxidant is selected from manganese dioxide, chromium trioxide, potassium permanganate, Jones reagent, collins reagent or sodium hypochlorite, the compound II is reduced to obtain a compound III, and the reducing agent is selected from NaBH4、LiAlH4Diborane and aluminium isopropoxide, and resolving the obtained compound III to obtain the (S) -5-fluoro-3-methyl isobenzofuran-3-one.
Compared with the prior art, the method has the advantages of easily available raw materials, short steps, low cost, high yield, product recycling and the like, and is favorable for realizing industrialization.
Detailed Description
The invention is further illustrated with reference to specific examples. It should be understood that the specific embodiments described herein are illustrative only and are not limiting upon the scope of the invention.
The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products which are not known to manufacturers and are available from normal sources.
The experimental procedures in the following examples are conventional unless otherwise specified. The test materials used in the following examples are all commercially available products unless otherwise specified.
Example 1
(1) Synthesis of 4-fluoro-2-formylbenzoic acid
Under nitrogen, 137mL (273.97mmol) of i-PrMgCl was added to a 500mL three-necked flask. At-30 ℃, a solution of 20.0g (91.32mmol) of 2-bromo-4-fluorobenzoic acid in anhydrous tetrahydrofuran (120mL) is added dropwise to the reaction flask, and after 1h, the addition is complete. The reaction was continued at this temperature for 4 h. Heating to-15 ℃, dropwise adding 35.2mL (456.62mmol) of anhydrous DMF solution, after 0.5h of dropwise adding, moving to room temperature to continue reacting for 12h, and finishing the reaction. The reaction was quenched with crushed ice, concentrated under reduced pressure to remove tetrahydrofuran, and then diluted hydrochloric acid (2 mol/L) was added to adjust pH to 1-2 under ice bath to precipitate a white solid, whereby 13.0g of the product was obtained in 85.2% yield.
ESI-MS(m/z)：167.01[M-H]-。1H NMR(600MHz,DMSO-d6)δ8.29(s,1H),7.91(dd,J＝8.5,4.7Hz,1H),7.57(dd,J＝8.2,2.3Hz,1H),7.51(td,J＝9.0,2.3Hz,1H),6.65(s,1H)。
(2) Synthesis of 5-fluoro-3-methylisobenzofuran-3-one
Under the protection of nitrogen, 20.0g (119.04mol) of 4-fluoro-2-formylbenzoic acid and anhydrous tetrahydrofuran (120mL) are added into a 500mL three-necked bottle, 60mL (357.12mmol) of MeMgCl is added dropwise at-15 ℃, the temperature is kept for reaction for 2h, then the mixture is moved to room temperature for further reaction for 12h, and the reaction is finished. Crushed ice is added into the reaction liquid to quench the reaction, the pH value is adjusted to 5-6 by acetic acid, and the water layer is distilled under reduced pressure to obtain white solid. 200mL of ethyl acetate was added to dissolve the product, and the filter cake was discarded by filtration. The filtrate was concentrated, and a white solid precipitated in 86.7% yield.
ESI-MS(m/z)：167.05[M+H]+。1H NMR(600MHz,DMSO-d6)δ7.90(dd,J＝8.4,4.9Hz,1H),7.63(dd,J＝8.5,2.3Hz,1H),7.44(td,J＝8.9,2.2Hz,1H),5.69(q,J＝6.7Hz,1H),1.57(d,J＝6.7Hz,3H)。
(3) Synthesis of (S) -5-fluoro-3-methylisobenzofuran-3-one
Dissolving 10.0g (59.52mmol) of 5-fluoro-3-methylisobenzofuran-3-one in a mixed solution of methanol (50mL) and water (20mL), adding 2mol/L sodium hydroxide solution under the stirring condition, heating to 70 ℃, and carrying out reflux reaction for 0.5h to finish the reaction. The reaction mixture was concentrated to remove methanol, the pH was adjusted to 5 to 6 with 2mol/L dilute hydrochloric acid under ice bath conditions, tetrahydrofuran (80mL) was extracted, 6.8mL (59.52mmol) of (S) -methylbenzylamine was added dropwise to the reaction mixture at 0 ℃, and after 10min, stirring was stopped and the mixture was allowed to stand in a cold trap for 1 h. After the mixture was allowed to stand at room temperature for 12 hours, white crystals precipitated, and 7.6g of white needle-like crystals were obtained by filtration. Recrystallizing for 2 times by using a mixed solvent of ethanol and acetone to obtain 6.1g of salified product. Dissolving the obtained salt-forming product in water, adding 2mol/L sodium hydroxide solution, stirring at room temperature for 0.5h, extracting (S) -methylbenzylamine with diethyl ether, neutralizing the water layer with 2mol/L dilute hydrochloric acid solution at room temperature until the pH value is 1-2, and separating out white solid. After filtration and concentration, 2.2g of the product is obtained. The yield thereof was found to be 83.4%.>99.9％ee(HPLC/ChiralpakIC/mobile phase: n-hexane: isopropyl alcohol: diethylamine-90: 10: 0.1). ESI-MS (m/z): 167.05[ M + H]+。
Compared with the method provided by the prior art document, the reaction process of the invention can improve the yield and save the cost.
Example 2
(1) Synthesis of 5-fluoro-3-methylisobenzofuran-3-one
Under nitrogen, 137mL (273.97mmol) of i-PrMgCl was added to a 500mL three-necked flask. At-30 ℃, a solution of 20.0g (91.32mmol) of 2-bromo-4-fluorobenzoic acid in anhydrous tetrahydrofuran (120mL) is added dropwise to the reaction flask, and after 1h, the addition is complete. The reaction was continued at this temperature for 4 h. Heating to-15 ℃, dropwise adding 35.2mL (456.62mmol) of acetaldehyde, after 0.5h of dropwise adding, moving to room temperature to continue reacting for 12h, after the reaction is finished, adding crushed ice to quench the reaction, adjusting the pH value to 5-6 with acetic acid, and distilling the water layer under reduced pressure to obtain a white solid. 200mL of ethyl acetate was added to dissolve the product, and the filter cake was discarded by filtration. The filtrate was concentrated, and a white solid precipitated in 86.7% yield.
ESI-MS(m/z)：167.05[M+H]+。1H NMR(600MHz,DMSO-d6)δ7.90(dd,J＝8.4,4.9Hz,1H),7.63(dd,J＝8.5,2.3Hz,1H),7.44(td,J＝8.9,2.2Hz,1H),5.69(q,J＝6.7Hz,1H),1.57(d,J＝6.7Hz,3H)。
(2) Synthesis of (S) -5-fluoro-3-methylisobenzofuran-3-one
PF1-410.0g (60.24mmol) is dissolved in a mixed solution of methanol (50mL) and water (20mL), 2.4g (60.24mmol) of NaOH is added under the condition of stirring, the temperature is raised to 70 ℃, reflux reaction is carried out for 0.5h, and the reaction is finished. The mixture was concentrated to remove methanol, the pH was adjusted to 3 to 4 with 2mol/L dilute hydrochloric acid under ice-bath conditions, a white solid was precipitated, and the ring-opened product was filtered off to obtain 11.0g, with a yield of 99.9%. 10.0g (54.34mmol) of the ring-opened product was dissolved in THF (80mL), 3.4mL (27.72mmol) of (S) -methylbenzylamine was added dropwise to the reaction mixture at-15 ℃ and after 10min, stirring was continued for 0.5 h. 3.7mL (26.63mmol) of triethylamine was added to the reaction mixture, and after 10min, the dropwise addition was completed, the stirring was stopped, and the mixture was allowed to stand in a cold trap for 1 h. The reaction flask was allowed to stand at room temperature for 12 hours, and white crystals were precipitated and filtered to obtain 7.6g of white needle-like crystals with a yield of 45.6%. Recrystallizing for 2 times by using a mixed solvent of ethanol and acetone to obtain 6.1g of salified product with the yield of 80.4 percent. The obtained salt-forming product was dissolved in water, 2mol/L sodium hydroxide solution was added, stirring was carried out at room temperature for 0.5h, the (S) -methylbenzylamine was extracted with diethyl ether, and the aqueous layer was neutralized with 3mol/L dilute salt solution at room temperature to pH 1-2, and a white solid was precipitated. After filtration and concentration, 2.2g of the product was obtained with a yield of 81.6%. 99.9% ee (HPLC/Chiralpak IC/mobile phase: n-hexane: isopropanol: diethylamine ═ 90: 10: 0.1).
(3) Synthesis of 4-fluoro-2 (1-hydroxyethyl) phenylacetic acid
Recovering 4.7g (28.31mmol) of (R) -5-fluoro-3-methylisobenzofuran-3-one in the mother liquor, dissolving in a mixed solution of methanol (20mL) and water (10mL), adding 2.4g (60.24mmol) of NaOH under stirring, heating to 70 ℃, and carrying out reflux reaction for 0.5h to finish the reaction. The reaction mixture was concentrated to remove methanol, and the mixture was adjusted to pH 3-4 with 2mol/L dilute hydrochloric acid in ice bath to precipitate a white solid, which was then filtered to obtain 5.2g of ring-opened product VIII in 99.9% yield. Dissolving 5.2g (28.31mmol) of compound VIII in THF (20mL), cooling to 0 ℃, and then adding KBr and NaHCO in sequence3And TEMPO, then slowly dripping NaClO solution, wherein the temperature of the solution is 0-5 ℃, and reacting for 3 hours to obtain 4.7g of a compound II, wherein the yield is 91.3%. 4.7g (25.82mmol) of the compound II is dissolved in methanol (20mL), cooled in an ice bath, added with sodium borohydride and stirred for reaction for 4 hours to obtain 3.85g of 4-fluoro-2 (1-hydroxyethyl) phenylacetic acid with the yield of 81.2 percent.
Compared with the method provided by the prior art document, the reaction process of the invention can improve the yield and save the cost.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (5)
- A process for producing (S) -5-fluoro-3-methylisobenzofuran-3-one,(1) reacting 2-bromo-4-fluorobenzoic acid with i-PrMgCl and DMF at low temperature to obtain 4-fluoro-2-formylbenzoic acid;(2) 4-fluoro-2-formylbenzoic acid and MeMgCl are subjected to Grignard reaction at low temperature to prepare 5-fluoro-3-methylisobenzofuran-3-one;(3) 5-fluoro-3-methylisobenzofuran-3-one is subjected to ring opening under an alkaline condition, is acidified to obtain 4-fluoro-2 (1-hydroxyethyl) phenylacetic acid, then forms a salt with (S) -methylbenzylamine, and the obtained product is subjected to recrystallization for 3 times, and is dissociated and acidified under an alkaline condition to obtain (S) -5-fluoro-3-methylisobenzofuran-3-one.
- 2. The preparation method of claim 1, wherein in the step (1), the 2-bromo-4-fluorobenzoic acid is prepared into the 4-fluoro-2-formylbenzoic acid under low temperature condition, the organic solvent is anhydrous tetrahydrofuran or anhydrous ether under the protection of nitrogen, the temperature for preparing the aryl Grignard reagent is-30 ℃ to-35 ℃, the temperature for adding DMF is-15 ℃ to-20 ℃, and DMF can be replaced by acetaldehyde, so as to directly obtain the compound III, the Grignard reagent can be replaced by n-butyllithium, and the molar ratio of the 2-bromo-4-fluorobenzoic acid to the Grignard reagent and the DMF is 1:3:3 to 1:3:5, preferably 1:3:4
- 3. The preparation method according to claim 1, wherein in the step (2), the 4-fluoro-2-formylbenzoic acid is used for preparing the 5-fluoro-3-methylisobenzofuran-3-one under low temperature conditions, the organic solvent is anhydrous tetrahydrofuran or anhydrous diethyl ether, the temperature is reduced to-15 ℃ under the protection of nitrogen, a methyl Grignard reagent is added dropwise, the Grignard reagent can be replaced by methyl magnesium bromide or methyl magnesium chloride, the mixture is transferred to room temperature after dropwise addition to prepare the 4-fluoro-2 (1-hydroxyethyl) phenylacetic acid, and the post-treatment is reduced pressure distillation to prepare the 5-fluoro-3-methylisobenzofuran-3-one
- 4. The process of claim 1, wherein in step (3), 5-fluoro-3-methylisobenzofuran-3-one is ring-opened under alkaline conditions, the base is selected from sodium salt organic base of C1-C4 alcohol or sodium hydroxide, potassium hydroxide, sodium hydride or LDA inorganic base, compound III is obtained by acidification, the acid is selected from formic acid, glacial acetic acid or hydrochloric acid, and the selected solvent is methanol/water, ethanol/water, isopropanol/water mixed system; the compound III is salified with (S) -methylbenzylamine at low temperature, and the molar ratio of the compound III to the (S) -methylbenzylamine is 1: 0.5-1: 1, preferably 1: 0.5; the salt forming temperature is 0 ℃ to-15 ℃, and is preferably-15 ℃; the salifying solvent is tetrahydrofuran or anhydrous diethyl ether or ethyl acetate or acetonitrile, wherein tetrahydrofuran is preferred; recrystallizing the carboxylic amine salt by using a recrystallization solvent selected from methanol, ethanol, acetonitrile, acetone/ethanol mixed solution, preferably acetone/ethanol mixed solution, wherein the recrystallization temperature is not higher than 30 ℃, and then the carboxylic amine salt is dissociated and acidified under the alkaline condition to obtain (S) -5-fluoro-3-methyl isobenzofuran-3-one, the alkali is selected from sodium salt organic alkali of C1-C4 alcohol or sodium hydroxide, potassium hydroxide, sodium hydride or LDA inorganic alkali, and the acid is selected from formic acid, glacial acetic acid or hydrochloric acid; the reaction temperature is 50-70 DEG C
- 5. The method according to claim 1Characterised in that, in step (3), the resolution of the remaining intermediate is carried out by re-ring opening under basic conditions, the base being selected from the group consisting of sodium salt organic bases of C1-C4 alcohols or sodium hydroxide, potassium hydroxide, sodium hydride or LDA inorganic bases; opening the ring, oxidizing to obtain a compound II, wherein the oxidant is selected from manganese dioxide, chromium trioxide, potassium permanganate, Jones reagent, collins reagent or sodium hypochlorite, the compound II is reduced to obtain a compound III, and the reducing agent is selected from NaBH4、LiAlH4Diborane and aluminium isopropoxide, and the obtained compound III is subjected to the resolution to obtain (S) -5-fluoro-3-methyl isobenzofuran-3-ketone
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012058254A1 (en) * | 2010-10-29 | 2012-05-03 | Boehringer Ingelheim International Gmbh | Benzimidazole inhibitors of leukotriene production |
| CN102503919A (en) * | 2011-10-13 | 2012-06-20 | 广东中科药物研究有限公司 | Derivatives of butylphthalide and preparation method and application thereof |
| CN104058935A (en) * | 2014-06-19 | 2014-09-24 | 浙江中欣化工股份有限公司 | Preparation method of (S)-1-(2,6-dichloro-3-fluorophenyl) ethanol |
| CN109134410A (en) * | 2018-09-20 | 2019-01-04 | 沈阳药科大学 | The synthetic method of fluoro- 3- methyl isobenzofuran -1 (3H) -one of 5- |
| CN109232607A (en) * | 2018-09-20 | 2019-01-18 | 沈阳药科大学 | Laura replaces the synthetic method of Buddhist nun |
| CN112899321A (en) * | 2019-11-19 | 2021-06-04 | 上海天慈国际药业有限公司 | Preparation method of Laratinib key intermediate |
| WO2021119753A1 (en) * | 2019-12-18 | 2021-06-24 | Ctxt Pty Limited | Compounds |
-
2021
- 2021-08-11 CN CN202110919250.5A patent/CN113603661B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012058254A1 (en) * | 2010-10-29 | 2012-05-03 | Boehringer Ingelheim International Gmbh | Benzimidazole inhibitors of leukotriene production |
| CN102503919A (en) * | 2011-10-13 | 2012-06-20 | 广东中科药物研究有限公司 | Derivatives of butylphthalide and preparation method and application thereof |
| CN104058935A (en) * | 2014-06-19 | 2014-09-24 | 浙江中欣化工股份有限公司 | Preparation method of (S)-1-(2,6-dichloro-3-fluorophenyl) ethanol |
| CN109134410A (en) * | 2018-09-20 | 2019-01-04 | 沈阳药科大学 | The synthetic method of fluoro- 3- methyl isobenzofuran -1 (3H) -one of 5- |
| CN109232607A (en) * | 2018-09-20 | 2019-01-18 | 沈阳药科大学 | Laura replaces the synthetic method of Buddhist nun |
| CN112899321A (en) * | 2019-11-19 | 2021-06-04 | 上海天慈国际药业有限公司 | Preparation method of Laratinib key intermediate |
| WO2021119753A1 (en) * | 2019-12-18 | 2021-06-24 | Ctxt Pty Limited | Compounds |
Non-Patent Citations (1)
| Title |
|---|
| 方卫国;: "对乙烯基苯甲酸的合成", 浙江化工, no. 04, pages 7 - 9 * |
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