CN113603661B - Synthesis method of (S) -5-fluoro-3-methyl isobenzofuran-3-ketone - Google Patents
Synthesis method of (S) -5-fluoro-3-methyl isobenzofuran-3-ketone Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 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 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound 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 26
- 239000000243 solution Substances 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- 238000003786 synthesis reaction Methods 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 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 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 238000007142 ring opening reaction Methods 0.000 claims 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 claims description 4
- 238000010438 heat treatment Methods 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
- 239000000203 mixture Substances 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical group [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 3
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 239000012266 salt solution Substances 0.000 claims description 2
- YNXGZAZFHFMWPY-UHFFFAOYSA-N 6-methyl-3h-2-benzofuran-1-one Chemical compound CC1=CC=C2COC(=O)C2=C1 YNXGZAZFHFMWPY-UHFFFAOYSA-N 0.000 claims 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 claims 1
- 238000001556 precipitation Methods 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 238000003747 Grignard reaction Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 238000010189 synthetic method Methods 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
- 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
- 229950001290 lorlatinib Drugs 0.000 abstract description 2
- 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 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 14
- -1 4-fluoro-2 (1-hydroxyethyl) phenylacetic acid Chemical compound 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 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 5
- KLAAXTKTDRQPOF-UHFFFAOYSA-N 4-fluoro-2-formylbenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1C=O KLAAXTKTDRQPOF-UHFFFAOYSA-N 0.000 description 5
- 239000007818 Grignard reagent Substances 0.000 description 5
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 229940122531 Anaplastic lymphoma kinase inhibitor Drugs 0.000 description 3
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-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
- 150000004795 grignard reagents Chemical class 0.000 description 3
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 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 description 2
- GZPUPDFZOLCBAD-UHFFFAOYSA-N 5-fluoro-3-methyl-3H-2-benzofuran-1-one Chemical compound FC=1C=C2C(OC(C2=CC=1)=O)C GZPUPDFZOLCBAD-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 229940008309 acetone / ethanol Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 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
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229960003088 loratadine Drugs 0.000 description 2
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical group O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 239000012027 Collins reagent Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229960001611 alectinib Drugs 0.000 description 1
- KDGFLJKFZUIJMX-UHFFFAOYSA-N alectinib Chemical compound CCC1=CC=2C(=O)C(C3=CC=C(C=C3N3)C#N)=C3C(C)(C)C=2C=C1N(CC1)CCC1N1CCOCC1 KDGFLJKFZUIJMX-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000118 hair dye Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- NPRDHMWYZHSAHR-UHFFFAOYSA-N pyridine;trioxochromium Chemical compound O=[Cr](=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 NPRDHMWYZHSAHR-UHFFFAOYSA-N 0.000 description 1
- 229910052611 pyroxene Inorganic materials 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 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 Laratinib (Lorlatinib) intermediate (S) -5-fluoro-3-methyl isobenzofuran-3-ketone, wherein 2-bromo-4-fluorobenzoic acid is used as a starting material, and the (S) -5-fluoro-3-methyl isobenzofuran-3-ketone is obtained through two-step Grignard reaction and resolution, and the total yield is more than 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, so that a novel method is provided for synthesizing the antitumor drug Laratinib.
Description
Technical Field
The invention relates to the technical field of medicines, and relates to a method for synthesizing a key intermediate (S) -5-fluoro-3-methyl isobenzofuran-3-ketone of the medicine Laratinib. 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, so that a novel method is provided for synthesizing the antitumor drug Laratinib.
Background
Latifinib (Lorlatinib) is a third generation ALK inhibitor obtained by the company of the American-type pyroxene (Pfizer) through the modification of Crizotinib (Crizotinib). The medicament enters a clinical test in 2014, is used for treating lung cancer, and mainly aims at non-small cell lung cancer patients with first generation ALK inhibitor crizotinib drug resistance and second generation ALK inhibitor Ceritinib (Ceritinib) and Ai Leti ni (Alectinib) drug resistance. Four synthetic routes to loratidine and intermediates thereof are described in WO2013132376, US8680111, JP2015510879, EP2822953, CN104169286, US2016115178, WO2014207606 in the following patent documents.
The (S) -5-fluoro-3-methyl isobenzofuran-1 (3H) -ketone is a main raw material for preparing the loratidine, is an important chemical and medical intermediate, and can be used in a plurality of fields of dyes, hair dyes, medicines, pesticide materials and the like. However, few reports have been made on the preparation of (S) -5-fluoro-3-methyl isobenzofuran-1 (3H) -one. WO2013132376 shows a synthetic method for the intermediate (S) -5-fluoro-3-methyl isobenzofuran-1 (3H) -one, but with long synthetic route, high cost, long time consumption and low yield. CN109134410a is a previous patent application by the inventor, and discloses a method for preparing 5-fluoro-3-methyl isobenzofuran-1 (3H) -one, but the method still has the problems of long synthetic route, high cost, low yield and complex treatment. CN112921057a discloses a new synthetic route of 5-fluoro-3-methyl isobenzofuran-1 (3H) -one, although the method greatly shortens the synthetic method provided by the original report, simplifies the operation and improves the yield, but the method samples biological enzyme as catalyst, thus limiting the application range of the preparation method.
Therefore, there is a need to develop a new synthesis method of an intermediate (S) -5-fluoro-3-methyl isobenzofuran-1 (3H) -one, which has the advantages of easily available raw materials, short steps, low cost and the like and is easy to industrialize.
Disclosure of Invention
The invention aims to provide a novel synthesis method of (S) -5-fluoro-3-methyl isobenzofuran-1 (3H) -ketone.
The invention is realized by the following technical scheme:
2-bromo-4-fluorobenzoic acid is used as a starting material, and (S) -5-fluoro-3-yl isobenzofuran-1 (3H) -ketone is obtained through a one-step chiral resolution reaction of two-step Grignard reaction.
The invention realizes the preparation of the key intermediate (S) -5-fluoro-3-methyl isobenzofuran-1 (3H) -ketone of the antitumor drug, the total yield can reach more than 36.5 percent, the time consumption is short, the cost is low, the industrialization is facilitated, and a novel method is provided for the synthesis of the antitumor drug of the Laratinib.
The synthesis method of the invention comprises the following steps:
the preparation method of the (S) -5-fluoro-3-methyl isobenzofuran-1 (3H) -one comprises the following steps:
(1) Reacting 2-bromo-4-fluorobenzoic acid with i-PrMgCl and DMF at low temperature to obtain 4-fluoro-2-formylbenzoic acid;
(2) Carrying out Grignard reaction on the 4-fluoro-2-formylbenzoic acid and MeMgCl at low temperature to obtain 5-fluoro-3-methyl isobenzofuran-3-ketone;
(3) Opening the ring of 5-fluoro-3-methyl isobenzofuran-3-ketone under alkaline condition, acidifying to obtain 4-fluoro-2 (1-hydroxyethyl) phenylacetic acid, salting out the 4-fluoro-2 (1-hydroxyethyl) phenylacetic acid with (S) -methylbenzylamine at low temperature to obtain amine carboxylate, recrystallizing for 3 times, dissociating under alkaline condition, and acidifying to obtain (S) -5-fluoro-3-methyl isobenzofuran-3-ketone.
The reaction scheme for preparing the compound of the invention is as follows:
in the preparation method of (S) -5-fluoro-3-methyl isobenzofuran-1 (3H) -one:
in the step (1), the 2-bromo-4-fluorobenzoic acid is prepared under the low temperature condition, the organic solvent is anhydrous tetrahydrofuran or anhydrous diethyl ether under the protection of nitrogen, the temperature for preparing the aryl grignard reagent is-30 ℃ to-35 ℃, the DMF adding temperature is-15 ℃ to-20 ℃, the DMF can be replaced by acetaldehyde, and the compound III is directly obtained, wherein the grignard reagent can be replaced by n-butyllithium, and the molar ratio of the 2-bromo-4-fluorobenzoic acid to the grignard reagent to 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-methyl isobenzofuran-3-ketone under the low temperature condition, an organic solvent is anhydrous tetrahydrofuran or anhydrous diethyl ether, nitrogen protection is used for cooling to-15 ℃, a methyl Grignard reagent is dropwise added, the Grignard reagent can be replaced by methyl magnesium bromide or methyl magnesium chloride, the dropwise addition is carried out after the dropwise addition, the dropwise addition is carried out and the room temperature is reached to prepare 4-fluoro-2 (1-hydroxyethyl) phenylacetic acid, and the post treatment is carried out under reduced pressure and distillation to prepare 5-fluoro-3-methyl isobenzofuran-3-ketone.
In the step (3), the 5-fluoro-3-methyl isobenzofuran-3-ketone is subjected to ring opening under alkaline conditions, wherein 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 compound III is obtained through acidification, wherein 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; salifying the compound III with (S) -methylbenzylamine at a low temperature, wherein the molar ratio of the compound III to the (S) -methylbenzylamine is 1:0.5-1:1, and preferably 1:0.5; the salifying temperature is 0 ℃ to-15 ℃, preferably-15 ℃; the salifying solvent is tetrahydrofuran or anhydrous diethyl ether or ethyl acetate or acetonitrile, wherein tetrahydrofuran is preferred; recrystallizing the carboxylate amine salt, wherein the recrystallization solvent is selected from methanol, ethanol, acetonitrile, acetone/ethanol mixed solution, preferably acetone/ethanol mixed solution, the recrystallization temperature is not higher than 30 ℃, then the (S) -5-fluoro-3-methyl isobenzofuran-3-ketone is obtained by dissociating and acidifying 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 the acid is selected from formic acid, glacial acetic acid or hydrochloric acid; the reaction temperature is 50-70 ℃.
In step (3), resolving the remaining intermediate 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; the compound II is obtained by ring opening and oxidation, the oxidant is selected from manganese dioxide, chromium trioxide, potassium permanganate, jones reagent, collins reagent or sodium hypochlorite, the compound III is obtained by reduction, and the reducing agent is selected from NaBH 4 、LiAlH 4 And (3) diborane and aluminum isopropoxide, and resolving the obtained compound III to obtain the (S) -5-fluoro-3-methyl isobenzofuran-3-ketone.
Compared with the prior art, the method has the advantages of easily available raw materials, short steps, low cost, high yield, recycling of the product and the like, and is favorable for realizing industrialization.
Detailed Description
The invention will be further illustrated with reference to specific examples. It should be understood that the detailed description and specific examples are intended for purposes of illustration only and are not intended to limit the scope of the invention.
The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications. The reagents or equipment used were conventional products available for purchase through regular channels, with no manufacturer noted.
The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the examples described below, unless otherwise specified, are all commercially available products.
Example 1
(1) Synthesis of 4-fluoro-2-formylbenzoic acid
To a 500mL three-necked flask, 137mL (273.97 mmol) of i-PrMgCl was added under nitrogen. 20.0g (91.32 mmol) of 2-bromo-4-fluorobenzoic acid in anhydrous tetrahydrofuran (120 mL) was added dropwise to the flask at-30℃for 1h. The reaction was continued for 4h at this temperature. Heating to-15 ℃, dropwise adding 35.2mL (456.62 mmol) of anhydrous DMF solution, after the completion of dropwise adding for 0.5h, moving to room temperature for continuous reaction for 12h, and finishing the reaction. The reaction was quenched with crushed ice, concentrated under reduced pressure to remove tetrahydrofuran, and 2mol/L diluted hydrochloric acid was added under ice bath to adjust ph=1-2, and white solid was precipitated to give 13.0g of the product in 85.2% yield.
ESI-MS(m/z)：167.01[M-H] - 。 1 H 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-methyl isobenzofuran-3-one
Under the protection of nitrogen, 20.0g (119.04 mol) of 4-fluoro-2-formylbenzoic acid and anhydrous tetrahydrofuran (120 mL) are added into a 500mL three-necked flask, 60mL (357.12 mmol) of MeMgCl is added dropwise at the temperature of-15 ℃ for continuous reaction for 2 hours, and then the flask is moved to room temperature for continuous reaction for 12 hours, and the reaction is completed. Adding crushed ice into the reaction solution to quench reaction, adjusting pH to be 5-6 with acetic acid, and distilling the water layer under reduced pressure to obtain white solid. 200mL of ethyl acetate solution was added and the filter cake was removed by filtration. The filtrate was concentrated and a white solid precipitated in 86.7% yield.
ESI-MS(m/z)：167.05[M+H] + 。 1 H 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-methyl isobenzofuran-3-one
10.0g (59.52 mmol) of 5-fluoro-3-methyl isobenzofuran-3-one is dissolved in a mixed solution of methanol (50 mL) and water (20 mL), 2mol/L sodium hydroxide solution is added under stirring, the temperature is raised to 70 ℃ and reflux reaction is carried out for 0.5h, and the reaction is completed. Concentrating to remove methanol, adjusting pH to 5-6 with 2mol/L dilute hydrochloric acid under ice bath condition, extracting with tetrahydrofuran (80 mL), dropwise adding 6.8mL (59.52 mmol) of (S) -methylbenzylamine into the reaction solution at 0deg.C, stopping stirring after 10min, and standing in cold trap for 1 hr. After the reaction mixture was allowed to stand at room temperature for 12 hours, white crystals were precipitated, and 7.6g of white needle-like crystals were obtained by filtration. The mixture was recrystallized from a mixed solvent of ethanol and acetone for 2 times to obtain 6.1g of a salified product. The resulting salt-forming product was dissolved in water, 2mol/L sodium hydroxide solution was added, stirred at room temperature for 0.5h, the (S) -methylbenzylamine was extracted with diethyl ether, the aqueous layer was neutralized to ph=1-2 with 2mol/L dilute hydrochloric acid solution at room temperature, and a white solid precipitated. After filtration and concentration, 2.2g of a product was obtained. The yield thereof was found to be 83.4%.>99.9% ee (HPLC/Chiralpak IC/mobile phase: n-hexane: isopropanol: diethylamine=90:10:0.1). ESI-MS (m/z): 167.05[ M+H ]] + 。
Compared with the methods provided in the prior art documents, the reaction flow of the invention can improve the yield and save the cost.
Example 2
(1) Synthesis of 5-fluoro-3-methyl isobenzofuran-3-one
To a 500mL three-necked flask, 137mL (273.97 mmol) of i-PrMgCl was added under nitrogen. 20.0g (91.32 mmol) of 2-bromo-4-fluorobenzoic acid in anhydrous tetrahydrofuran (120 mL) was added dropwise to the flask at-30℃for 1h. The reaction was continued for 4h at this temperature. Heating to-15 ℃, dropwise adding 35.2mL (456.62 mmol) of acetaldehyde solution, after 0.5h dropwise adding, moving to room temperature for continuous reaction for 12h, after the reaction is finished, adding crushed ice for quenching reaction, adjusting pH to be=5-6 by acetic acid, and distilling a water layer under reduced pressure to obtain a white solid. 200mL of ethyl acetate solution was added and the filter cake was removed 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-methyl isobenzofuran-3-one
PF1-410.0g (60.24 mmol) was dissolved in a mixed solution of methanol (50 mL) and water (20 mL), 2.4g (60.24 mmol) of NaOH was added under stirring, and the temperature was raised to 70℃and the reaction was refluxed for 0.5h, thereby completing the reaction. The methanol was removed by concentration, the pH was adjusted to 3-4 with 2mol/L dilute hydrochloric acid under ice bath conditions, and a white solid was precipitated and filtered to give 11.0g of the ring-opened product in 99.9% yield. 10.0g (54.34 mmol) of the ring-opened product was dissolved in THF (80 mL), 3.4mL (27.72 mmol) of (S) -methylbenzylamine was added dropwise to the reaction solution at-15℃and stirring was continued for 0.5h after 10 min. Triethylamine (3.7 mL) (26.63 mmol) was added to the reaction mixture, and after 10 minutes, stirring was stopped and the mixture was allowed to stand in a cold trap for 1 hour. The reaction flask was allowed to stand at room temperature for 12 hours, and white crystals were precipitated, and the resulting white needle-like crystals were obtained by filtration in an amount of 7.6g, with a yield of 45.6%. The mixture was recrystallized from a solvent mixture of ethanol and acetone for 2 times to give 6.1g of a salt-forming product in a yield of 80.4%. The resulting salt-forming product was dissolved in water, 2mol/L sodium hydroxide solution was added, stirred at room temperature for 0.5h, the (S) -methylbenzylamine was extracted with diethyl ether, the aqueous layer was neutralized to ph=1-2 with 3mol/L dilute salt solution at room temperature, and a white solid precipitated. After filtration and concentration, 2.2g of a product was obtained, and the yield was 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
4.7g (28.31 mmol) of (R) -5-fluoro-3-methyl isobenzofuran-3-one in the mother liquor is recovered and dissolved in a mixed solution of methanol (20 mL) and water (10 mL), 2.4g (60.24 mmol) of NaOH is added under stirring, the temperature is raised to 70 ℃ and reflux reaction is carried out for 0.5h, and the reaction is completed. Concentrating to remove methanol, adjusting pH to 3-4 with 2mol/L dilute hydrochloric acid under ice bath condition, precipitating white solid, and filtering to obtain ring-opened product VIII 5.2g with 99.9% yield. 5.2g (28.31 mmol) of compound VIII is dissolved in THF (20 mL) and cooled to 0 ℃ and KBr and NaHCO are added in sequence 3 TEMPO, then slowly dropwise adding NaClO solution at 0-5 ℃ for 3 hours to obtain compound II 4.7g with the yield of 91.3%. 4.7g (25.82 mmol) of Compound II was dissolved in methanol (20 mL), cooled in an ice bath, and sodium borohydride was added thereto and reacted under stirring for 4 hours to obtain 3.85g of 4-fluoro-2 (1-hydroxyethyl) phenylacetic acid, the yield was 81.2%.
Compared with the methods provided in the prior art documents, the reaction flow of the invention can improve the yield and save the cost.
It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.
Claims (1)
1.(S) A process for the preparation of (E) -5-fluoro-3-methyl isobenzofuran-3-one, characterized in that,
(1) Synthesis of 5-fluoro-3-methyl isobenzofuran-3-one: under the protection of nitrogen, adding 137mL of i-PrMgCl, 273.97mmol and 120mL of anhydrous tetrahydrofuran with 20.0g and 91.32mmol of 2-bromo-4-fluorobenzoic acid into a 500mL three-necked flask at minus 30 ℃ and dropwise adding the solution into the reaction flask, and after 1h, continuously reacting for 4h at the temperature, heating to minus 15 ℃, and dropwise adding 35.2mL and 456 of acetaldehyde62mmol solution, after 0.5h dropwise adding, transferring to room temperature for continuous reaction for 12h, after the reaction, adding crushed ice for quenching reaction, adjusting pH to be 5-6 with acetic acid, distilling the water layer under reduced pressure to obtain white solid 5-fluoro-3-methyl isobenzofuran-3-one；
（2）(S) -synthesis of 5-fluoro-3-methyl isobenzofuran-3-one: dissolving 10.0g of 5-fluoro-3-methyl isobenzofuran-3-one and 60.24mmol of 5-fluoro-3-methyl isobenzofuran-3-one in a mixed solution of 50mL of methanol and 20mL of water, adding 2.4g of NaOH and 60.24mmol of 5-methyl isobenzofuran-3-one under stirring, heating to 70 ℃ for reflux reaction for 0.5h, concentrating to remove methanol after the reaction is finished, adjusting pH to 3-4 by using 2mol/L of dilute hydrochloric acid under ice bath condition, precipitating white solid, filtering to obtain 11.0g of ring-opened product, dissolving 10.0g of 54.34mmol of ring-opened product in 80mL of THF, and dropwise adding the ring-opened product into reaction solution at-15 DEG CS) 3.4mL of methylbenzylamine, 27.72mmol and 10min after the dropwise addition are finished, stirring is continued for 0.5h, 3.7mL of triethylamine, 26.63mmol and 10min after the dropwise addition are finished are added into the reaction solution, stirring is stopped, the reaction solution is kept stand in a cold trap for 1h, a reaction bottle is moved to room temperature and stands for 12h, white crystals are separated out, 7.6g of white needle-like crystals are obtained by filtration, ethanol and acetone mixed solvents are used for recrystallization for 2 times, a salified product 6.1g is obtained, the obtained salified product is dissolved in water, 2mol/L of sodium hydroxide solution is added, stirring is carried out for 0.5h at room temperature, and the mixture is extracted by diethyl etherS) The aqueous layer was neutralized with 3mol/L dilute salt solution at room temperature to ph=1-2 with white solid [ ]S) -5-fluoro-3-methyl isobenzofuran-3-one precipitation
，
In step (2) further comprises resolution of the remaining intermediate VII by re-ring opening under basic conditions to give compound VIII, said base being selected from sodium hydroxide; the compound II is obtained by ring opening and oxidation, the oxidant is selected from sodium hypochlorite, the compound III is obtained by reduction, and the reducing agent is selected from NaBH 4 The obtained compound III is resolved to obtain the productS) -5-fluoro-3-methyl isobenzofuran-3-Ketone
。
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