CN114230598B - Process method for synthesizing 2-substituted thiazole-4-boric acid pinacol ester - Google Patents
Process method for synthesizing 2-substituted thiazole-4-boric acid pinacol ester Download PDFInfo
- Publication number
- CN114230598B CN114230598B CN202111651761.XA CN202111651761A CN114230598B CN 114230598 B CN114230598 B CN 114230598B CN 202111651761 A CN202111651761 A CN 202111651761A CN 114230598 B CN114230598 B CN 114230598B
- Authority
- CN
- China
- Prior art keywords
- substituted
- reaction
- bromothiazole
- thiazole
- temperature
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 23
- 230000008569 process Effects 0.000 title claims abstract description 12
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 25
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims abstract description 22
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims abstract description 20
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 239000005051 trimethylchlorosilane Substances 0.000 claims abstract description 11
- MKEJZKKVVUZXIS-UHFFFAOYSA-N 2,4-dibromo-1,3-thiazole Chemical compound BrC1=CSC(Br)=N1 MKEJZKKVVUZXIS-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- -1 2-substituted-4-bromothiazole Chemical class 0.000 claims description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 13
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 11
- 229910052751 metal Inorganic materials 0.000 claims description 11
- 239000002184 metal Substances 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 238000004821 distillation Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 6
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 238000005885 boration reaction Methods 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- 125000001979 organolithium group Chemical group 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- CCZVEWRRAVASGL-UHFFFAOYSA-N lithium;2-methanidylpropane Chemical compound [Li+].CC(C)[CH2-] CCZVEWRRAVASGL-UHFFFAOYSA-N 0.000 claims description 3
- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 claims description 3
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 claims description 3
- XGITVAYMIKUXIN-UHFFFAOYSA-M magnesium;propane;iodide Chemical compound [Mg+2].[I-].C[CH-]C XGITVAYMIKUXIN-UHFFFAOYSA-M 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims 2
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 abstract description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 8
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 4
- 239000001257 hydrogen Substances 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 3
- 229910052763 palladium Inorganic materials 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 abstract 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract 1
- 229910052794 bromium Inorganic materials 0.000 abstract 1
- 238000013341 scale-up Methods 0.000 abstract 1
- 239000012071 phase Substances 0.000 description 17
- 239000007789 gas Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 230000001276 controlling effect Effects 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000006069 Suzuki reaction reaction Methods 0.000 description 5
- 230000000171 quenching effect Effects 0.000 description 5
- WLQGXFSBIGJXDA-UHFFFAOYSA-N (4-bromo-1,3-thiazol-2-yl)-trimethylsilane Chemical compound C[Si](C)(C)C1=NC(Br)=CS1 WLQGXFSBIGJXDA-UHFFFAOYSA-N 0.000 description 4
- IUHVEWBGPBCWTQ-UHFFFAOYSA-N 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CSC=N1 IUHVEWBGPBCWTQ-UHFFFAOYSA-N 0.000 description 4
- XGBWZNGTYRKKFE-UHFFFAOYSA-N 4-bromo-2-phenyl-1,3-thiazole Chemical compound BrC1=CSC(C=2C=CC=CC=2)=N1 XGBWZNGTYRKKFE-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- OZROWEIIPIELCJ-UHFFFAOYSA-N 4-bromo-2-methoxy-1,3-thiazole Chemical compound COC1=NC(Br)=CS1 OZROWEIIPIELCJ-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 150000003557 thiazoles Chemical class 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- LEKSIJZGSFETSJ-UHFFFAOYSA-N cyclohexane;lithium Chemical compound [Li]C1CCCCC1 LEKSIJZGSFETSJ-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000001465 metallisation Methods 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of organic chemistry, and relates to a method for preparing 2-substituted thiazole-4-boric acid pinacol ester. A process for synthesizing 2-substituted thiazole-4-pinacol borate uses 2, 4-dibromothiazole as initial raw material, and includes such steps as modifying 2 position, converting 5-hydrogen of thiazole to trimethyl silicon by isopropyl magnesium chloride and trimethyl chlorosilane, and converting 4-bromine to pinacol borate by metal-organic reagent. The method avoids using expensive palladium catalyst, has simple and convenient post-treatment, and is suitable for industrial scale-up production.
Description
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a method for preparing 2-substituted thiazole-4-boric acid pinacol ester.
Background
The thiazole ring is an important aromatic five-membered heterocyclic ring, and the thiazole ring can be obtained by replacing the 3-position carbon atom of the thiophene ring with a nitrogen atom. The heterocyclic ring contains nitrogen and sulfur hetero atoms, and has the physicochemical properties of rich electrons, easiness in forming hydrogen bonds, capability of coordinating with nonmetallic ions, pi-pi accumulation, generation of electrostatic and hydrophobic interaction and the like [1]. The various physicochemical properties determine that the thiazole ring has wide application prospect in the fields of chemistry, pharmacy, biology, materials science and the like, so that the thiazole ring is also widely paid attention to. In the medical field, thiazoles and their derivatives have various biological and pharmacological activities such as antibacterial, antimalarial, anticancer, antimitotic, antihypertensive, anti-inflammatory and anti-HIV [2] among them, there is no lack of drugs requiring modification at the 4-position of thiazole, and among them, suzuki coupling is one of the most commonly used methods when it is required to introduce aromatic ring compounds at the 4-position of thiazole. Modification of the thiazole 4 position using a Suzuki coupling inevitably leads to the use of 2-substituted thiazole-4-boronic acid pinacol esters.
Because the hydrogens at the 2-and 5-positions of the thiazole ring have stronger acidity, pure thiazole-4-boronic acid pinacol ester is difficult to obtain by utilizing a metal organic reagent and a boronate boronation reaction even if the 2-position is occupied by an inert substituent. Although thiazole-4-boronic acid pinacol ester [3] can be obtained by using the Suzuki coupling method, the use of an expensive palladium catalyst greatly increases the production cost, and is unfavorable for large-scale production.
Disclosure of Invention
The invention aims to solve the problem of abnormal high cost of the existing synthesis of 2-substituted-thiazole-4-boric acid pinacol ester, and provides a process method for synthesizing 2-substituted-thiazole-4-boric acid pinacol ester, which still prepares 2-substituted-thiazole-4-boric acid pinacol ester by a metal organic reagent and boric acid ester boronation reaction. However, before the metal organic reagent and the borate are subjected to the boronation reaction, the trimethylsilyl group is used for replacing the hydrogen at the 5-position of thiazole with the trimethylsilyl group, so that after the protection, the 2-substituted-thiazole-4-boric acid can be successfully obtained through the metal organic reagent and the borate boronation reaction, and then pinacol is added for esterification, so that the 2-substituted-thiazole-4-boric acid pinacol ester is obtained.
The invention adopts the technical proposal for realizing the aim that: a process method for synthesizing 2-substituted-thiazole-4-boric acid pinacol ester comprises the following steps:
step one: 2, 4-dibromothiazole is used as an initial raw material to prepare 2-substituted-4-bromothiazole for standby;
step two: 2-substituted-4-bromothiazole is dissolved in tetrahydrofuran, tetrahydrofuran solution of isopropyl magnesium chloride is dripped at the temperature of 0 to minus 50 ℃, trimethylchlorosilane is dripped at the temperature of minus 20 to 0 ℃ after the reaction is completed, saturated brine is dripped for quenching reaction after the reaction is completed, the reaction solution is filtered, the filtrate is evaporated to dryness, methyl tertiary butyl ether is used for redissolution, insoluble matters are filtered, the obtained filtrate is evaporated to dryness, and then the 2-substituted-5- (trimethylsilyl) -4-bromothiazole is obtained through distillation and purification;
step three: boration reaction of a metal organic reagent with a borate: dissolving 2-substituted-5- (trimethylsilyl) -4-bromothiazole in tetrahydrofuran, controlling the temperature to minus 75 ℃ to minus 85 ℃, dripping an organic lithium reagent, after the dripping, dripping trimethyl borate at minus 60 ℃ to minus 80 ℃, controlling the temperature to minus 20 ℃ to 0 ℃, dripping hydrochloric acid to adjust the pH value to 2-3, adjusting the pH value to 6-7 with 2-3N sodium hydroxide, adding pinacol and ethyl acetate for extraction, separating the liquid, drying the organic phase, concentrating at least a certain amount of solvent under reduced pressure, and recrystallizing to obtain the 2-substituted thiazole-4-boric acid pinacol.
Further, the 2-position substituents include, but are not limited to: and non-reactive substituents such as phenyl, trimethylsilyl, and alkoxy.
Further, the second capture proton reagent includes, but is not limited to: metal organic strong bases such as isopropyl magnesium chloride, isopropyl magnesium bromide and isopropyl magnesium iodide.
Further, the organolithium reagents used in step three include, but are not limited to: alkyl lithium reagents such as n-butyl lithium, n-hexyl lithium, cyclohexyl lithium and isobutyl lithium.
Further, the ratio of the 2-substituted 4-bromothiazole, the taken proton reagent and the trimethylchlorosilane in the second step is as follows: 1: 1.1-1.5:1.1-1.5.
Further, the ratio of the 2-substituted 5- (trimethylsilyl) -4-bromothiazole, the organolithium reagent, the trimethyl borate and the pinacol in the step three is as follows: 1: 1.1-1.5:1.2-1.6:0.6-1.2.
Further, the concentration of the hydrochloric acid is 5-15%.
The invention takes 2, 4-dibromothiazole as an initial raw material, carries out modification on the 2-position of the 2-dibromothiazole, then carries out trimethyl silicon protection on carbon at the 5-position, and finally carries out boronation reaction between a metal organic reagent and borate to obtain the target compound 2-substituted-thiazole-4-borate pinacol ester.
The mechanism of the invention is as follows:
The invention adopts a strategy of introducing trimethylsilyl group to protect carbon containing stronger acid hydrogen, innovates two steps to prepare 2-substituted thiazole-4-boric acid pinacol ester, wherein isopropyl magnesium chloride, trimethylchlorosilane, n-butyllithium, trimethyl borate and pinacol are commodity, the raw materials are cheap and easy to obtain, the 2, 4-dibromothiazole is used as the initial raw materials to prepare 2-substituted 4-bromothiazole, for example, the 2- (trimethylsilyl) -4-bromothiazole is prepared by respectively carrying out metallization with a format reagent and then reacting with trimethylchlorosilane, suzuki coupling is carried out with phenylboronic acid to prepare 2-phenyl-4-bromothiazole, and nucleophilic substitution is carried out with sodium methoxide to prepare 2-methoxy-4-bromothiazole. The 2-substituted 4-bromothiazole is the same as the starting material used for the Suzuki coupling, and avoids the use of an expensive palladium catalyst (Pd (dppf) Cl 2/100000/kg) as a whole, and has relatively low cost. And the heavy metal is not used, so that the heavy metal residue in the product is relatively less.
Detailed Description
The following describes the present invention in detail with reference to specific embodiments, but the present invention is not limited to the specific embodiments, and all technical solutions within the scope of the present invention are within the scope of protection of the present invention.
Example 1
A process for synthesizing 2-substituted thiazole-4-boric acid pinacol ester comprises the following steps,
Step one, preparing 2- (trimethylsilyl) -4-bromothiazole:
150g of 2, 4-dibromothiazole is weighed and dissolved in 650mL of tetrahydrofuran, the temperature is controlled to be-10-0 ℃, 264g of self-made tetrahydrofuran solution of 2.57mol/kg of isopropyl magnesium chloride is dripped, the temperature is kept for 1h after the dripping is finished, the reaction of raw materials in a gas phase is controlled to be complete, the temperature is controlled to be-10-0 ℃, 73.8g of trimethylchlorosilane is dripped, the temperature is kept for 4h after the dripping is finished, the weather is controlled to be complete, the temperature is controlled to be-10-0 ℃, 50mL of saturated salt water quenching reaction is dripped, the stirring reaction is carried out for 10 minutes after the dripping is finished, the filtration is carried out, the filtrate is concentrated to be not dripped, the reduced pressure distillation and purification are carried out, and 89.4g of 2- (trimethylsilyl) -4-bromothiazole is obtained, the gas phase content is 97.8%, and the yield is 55%.
Step two, trimethyl silicon is used for protecting 5-carbon:
80g of 2- (trimethylsilyl) -4-bromothiazole is weighed and dissolved in 350mL of tetrahydrofuran, the temperature is controlled to be-10-0 ℃, 145g of self-made tetrahydrofuran solution of 2.57mol/kg of isopropyl magnesium chloride is dripped, the reaction is kept for 1h after the dripping is finished, the reaction of the raw materials controlled in the gas phase is complete, the temperature is controlled to be-10-0 ℃, 40.5g of trimethylchlorosilane is dripped, the reaction is kept for 4h after the dripping is finished, the meteorological intermediate is controlled to be complete, the temperature is controlled to be-10-0 ℃,20 mL of saturated salt water quenching reaction is dripped, the reaction is stirred for 10 minutes after the dripping is finished, the filtration is carried out, the filtrate is concentrated to be not dripped, the distillation and purification are carried out under reduced pressure, and the 2, 5-bis (trimethylsilyl) -4-bromothiazole is obtained, the gas phase content is 96.5%, and the yield is 43%.
Step three, preparing borate by a boration reaction of a metal organic reagent and borate:
Weighing 44g of 2, 5-bis (trimethylsilyl) -4-bromothiazole, dissolving in 150mL of tetrahydrofuran, controlling the temperature to minus 75 to minus 85 ℃, dripping 63mL of 2.5N-butyllithium hexane solution, keeping the temperature for reaction for 1H after dripping, keeping the temperature for controlling the disappearance of raw materials in gas phase, dripping 17.8g of trimethyl borate at the temperature to minus 60 to minus 80 ℃, keeping the temperature for reaction for 30 min after dripping, naturally heating to room temperature for reaction overnight, controlling the temperature to minus 20 to 0 ℃, dripping 10% hydrochloric acid for regulating the pH value to 2 to 3, stirring for 1H at 0 to 5 ℃, regulating the pH value to 6 to 6.5 with 2N sodium hydroxide, adding 15.1g of pinacol and 150mL of ethyl acetate for extraction, separating liquid, extracting water phase with 50mL of ethyl acetate for 3 times, merging organic phases, concentrating at least a certain amount of solvent to remain under reduced pressure, and then recrystallizing with N-heptane to obtain 15.7g of thiazole-4-boric acid pinacol ester which is white-like solid, the gas phase content is 97.7%,1H NMR (400 MHz, d 6-delta 9.19.7H) and 1H (1.27 s) 1H (12H) and 1.27 s (12H)
Example 2:
A process for synthesizing 2-phenyl-thiazole-4-pinacol borate comprises the following steps,
Step one, preparing 2-phenyl-4-bromothiazole:
200g of 2, 4-dibromothiazole, 110.42g of phenylboronic acid and 525.7g of potassium phosphate are weighed into a four-mouth bottle filled with 2.2L of tetrahydrofuran, nitrogen is introduced for protection, 11.96g g Xanyphos and 4.62g Pd (OAc) 2 are added, the mixture is heated to 60 ℃ for reaction for 8 to 14 hours, filtration is carried out, the filtrate is concentrated to be non-dripping, and ethyl acetate is used for preparing the mixture: the chromatography liquid of n-heptane=1:10 was passed through a silica gel column to obtain 134.5g of 2-phenyl-4-bromothiazole, the GC purity was 98.2%, and the yield was 68%. [4]
Step two, trimethyl silicon is used for protecting 5-carbon:
100g of 2-phenyl-4-bromothiazole is weighed and dissolved in 410mL of tetrahydrofuran, the temperature is controlled to be-10-0 ℃, 178g of self-made tetrahydrofuran solution of 2.57mol/kg of isopropyl magnesium chloride is dripped, the reaction is carried out for 1h after the dripping is finished, the temperature is controlled to be-10-0 ℃, 49.8g of trimethylchlorosilane is dripped, the reaction is carried out for 4h after the dripping is finished, the weather is controlled, the intermediate is completely converted, the temperature is controlled to be-10-0 ℃, 20mL of saturated salt water quenching reaction is dripped, the reaction is carried out for 10min after the dripping is finished, the filtration is carried out, the filtrate is concentrated to be not dripped, the reduced pressure distillation and purification are carried out, and 62.2g of 4-bromo-2- (phenyl) -5-trimethylsilyl) thiazole is obtained, the gas phase content is 97.1%, and the yield is 48%.
Step three, preparing borate by a boration reaction of a metal organic reagent and borate:
62.2g of 4-bromo-2- (phenyl) -5-trimethylsilyl) thiazole are weighed and dissolved in 200mL of tetrahydrofuran, 88mL of 2.5N N-butyllithium hexane solution is dripped at the temperature of minus 75 to minus 85 ℃, the reaction is carried out for 1H after the dripping is finished, the gas phase central control raw material disappears, then 24.9g of trimethyl borate is dripped at the temperature of minus 60 to minus 80 ℃, the reaction is carried out for 30 minutes after the dripping is finished, the reaction is naturally carried out to room temperature overnight, the temperature of minus 20 to 0 ℃, 10% hydrochloric acid is dripped to adjust the pH value to 2 to 3, the reaction is carried out for 1H at 0 to 5 ℃, 2N sodium hydroxide is used for adjusting the pH value to 6 to 6.5, 21.2g of pinacol and 200mL of ethyl acetate are added, the reaction is carried out for 3 times by 50mL of ethyl acetate, the water phase is separated, the reaction is carried out, anhydrous magnesium sulfate is added into the mixture, at least a reduced pressure concentration is carried out, at least a residual solvent is left, then 15.7g of thiazole-4-boric acid pinacol ester is obtained by recrystallization by N-heptane, the gas phase content is white solid, the gas phase content is 97.4%,1H (CD3 MHz=12.7.7.7.7 m (8-7.7.7H), 1.7.7.7H (8.7.7 m, 7.7.7.7H, 8 (8-7.7 m) 7.7.7H) 7.7 (8 m) H) 2)
Example 3:
A process for synthesizing 2-methoxythiazole-4-boric acid pinacol ester comprises the following steps,
Step one, preparing 2-substituted-4-bromothiazole:
250g of 2, 4-dibromothiazole is weighed and dissolved in 2.5L of methanol, 166.8g of sodium methoxide is added for reaction for 14-16 hours at 20-30 ℃, reduced pressure and concentration are carried out until no drop is caused, 1.5L of methyl tertiary butyl ether and 1.5L of water are added for extraction, liquid separation is carried out, 800mL of methyl tertiary butyl ether is used for carrying out two-time extraction on water phase, the organic phases are combined, reduced pressure concentration is carried out until no drop is caused, reduced pressure distillation and purification are carried out, 149.8g of light yellow oily matter is obtained, the GC purity is 98.1%, and the yield is 75.1%; [5]
Step two, trimethyl silicon is used for protecting 5-carbon:
100g of 4-bromo-2- (methoxy) thiazole is weighed and dissolved in 410mL of tetrahydrofuran, the temperature is controlled to be-10-0 ℃, 220g of self-made tetrahydrofuran solution of 2.57mol/kg of isopropyl magnesium chloride is dripped, the reaction is carried out for 1h after the dripping is finished, the temperature is controlled to be-10-0 ℃, 61.6g of trimethylchlorosilane is dripped, the reaction is carried out for 4h after the dripping is finished, the meteorological center is controlled, the intermediate is completely converted, the temperature is controlled to be-10-0 ℃, 20mL of saturated salt water quenching reaction is dripped, the reaction is carried out for 10 min after the dripping is finished, the filtration is carried out, the filtrate is concentrated to be not dripped, the distillation and purification are carried out under reduced pressure, and 54.9g of 4-bromo-2- (methoxy) -5- (trimethylsilyl) thiazole are obtained, the gas phase content is 96.8%, and the yield is 40%.
Step three, preparing borate by a boration reaction of a metal organic reagent and borate:
Weighing 54.9g of 4-bromo-2- (methoxy) -5- (trimethylsilyl) thiazole, dissolving in 210mL of tetrahydrofuran, dropwise adding 91mL of 2.5N N-butyllithium hexane solution at the temperature of-75 to-85 ℃, keeping the temperature for 1h after the dropwise adding is finished, keeping the temperature for 1h, enabling the gas phase central control raw materials to disappear, then dropwise adding 25.7g of trimethyl borate at the temperature of-60 to-80 ℃, keeping the temperature for 30min after the dropwise adding, naturally heating to room temperature for reaction overnight, controlling the temperature to-20 to 0 ℃, dropwise adding 10% hydrochloric acid to adjust the pH to 2 to 3, stirring for 1h at 0 to 5 ℃, adjusting the pH to 6.5 to 7.0 with 2N sodium hydroxide, adding 17.61g of pinacol and 200mL of ethyl acetate for extraction, separating the liquid, extracting the water phase with 50mL of ethyl acetate for 3 times, merging the organic phase, adding anhydrous magnesium sulfate for drying, concentrating at least a quantity of solvent under reduced pressure, and then using N-heptane: recrystallisation of the acetone 5:1 solution gives 15.7g of 2- (methoxy) thiazole-4-boronic acid pinacol ester as an off-white solid with a gas phase content of 97.4%,1H NMR (CDCl 3,200 MHz): 7.38 (s, 1H), 4.14 (s, 3H), 8.01-8.11 (m, 2H), 1.35 (s, 12H).
In the above examples, the same effect was obtained by changing the isopropyl magnesium chloride in the second step to isopropyl magnesium bromide, ethyl magnesium bromide, or the like in the experiment with the same effect as the organometallic strong base.
In the above examples, the same effect was obtained by changing n-butyllithium to an alkyllithium reagent such as n-hexyllithium, cyclohexyllithium, or isobutyllithium in the third step.
Reference to the literature
[1]Y.Wang.,et al.Recent advances inapplication of thiazole compounds.Science China Press,2012,42(8):1105-1131.
[2]A.Rouf,C.Tanyeli.Bioactive thiazole and benzothiazole derivatives.European Journal of Medicinal Chemistry,2015(97):911-927.
[3][ACS Medicinal Chemistry Letters,2021,vol.12,#4,p.563-571][4][Bulletin of the Chemical Society of Japan,2019,vol.92,#12,p.2030-2037]
[5][Bioorganic and Medicinal Chemistry,1999,vol.7,#5,p.665-697]
Claims (4)
1. A process method for synthesizing 2-substituted thiazole-4-boric acid pinacol ester is characterized by comprising the following steps:
step one: 2, 4-dibromothiazole is used as an initial raw material to prepare 2-substituted-4-bromothiazole for standby;
Step two: the method for protecting the 5-carbon by using the trimethylsilyl comprises the steps of dissolving 2-substituted-4-bromothiazole in tetrahydrofuran, dropwise adding tetrahydrofuran solution of a proton grabbing reagent at the temperature of 0 to 50 ℃ below zero, wherein the 2-substituent is selected from the group consisting of: phenyl, trimethylsilyl; the proton capturing reagent is selected from the group consisting of: isopropyl magnesium chloride, isopropyl magnesium bromide and isopropyl magnesium iodide; after the reaction is completed, dropwise adding trimethylchlorosilane at the temperature of minus 20-0 ℃, after the reaction is completed, dropwise adding saturated salt water to quench the reaction, filtering the reaction liquid, evaporating filtrate to dryness, redissolving the filtrate by methyl tertiary butyl ether, filtering insoluble substances, evaporating the obtained filtrate to dryness, and then purifying by distillation to obtain 2-substituted-5- (trimethylsilyl) -4-bromothiazole;
Step three: boration reaction of a metal organic reagent with a borate: dissolving 2-substituted-5- (trimethylsilyl) -4-bromothiazole in tetrahydrofuran, and dropwise adding an organolithium reagent at a temperature of-75 to-85 ℃, wherein the organolithium reagent is selected from the group consisting of: n-butyllithium, n-hexyllithium, cyclohexyllithium, and isobutyllithium; and (3) dropwise adding trimethyl borate at the temperature of minus 60 to minus 80 ℃ after complete conversion, controlling the temperature of minus 20 to 0 ℃ after complete conversion, dropwise adding hydrochloric acid to adjust the pH to 2 to 3, then adjusting the pH to 6 to 7 with 2 to 3N sodium hydroxide, adding pinacol and ethyl acetate for extraction, separating liquid, drying an organic phase, concentrating at least a certain amount of solvent under reduced pressure, and then recrystallizing to obtain the 2-substituted thiazole-4-pinacol borate.
2. The process for synthesizing 2-substituted thiazole-4-boronic acid pinacol ester according to claim 1, wherein the molar ratio of the 2-substituted-4-bromothiazole, the proton capturing reagent and the trimethylchlorosilane in the step two is as follows: 1: 1.1-1.5:1.1-1.5.
3. The process for synthesizing 2-substituted thiazole-4-boronic acid pinacol ester according to claim 1, wherein the molar ratio of the 2-substituted-5- (trimethylsilyl) -4-bromothiazole, the organolithium reagent, the trimethyl borate and the pinacol in the step three is as follows: 1: 1.1-1.5:1.2-1.6:0.6-1.2.
4. The process for synthesizing 2-substituted thiazole-4-boronic acid pinacol ester according to claim 1, wherein the hydrochloric acid is 5% -15% hydrochloric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111651761.XA CN114230598B (en) | 2021-12-30 | 2021-12-30 | Process method for synthesizing 2-substituted thiazole-4-boric acid pinacol ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111651761.XA CN114230598B (en) | 2021-12-30 | 2021-12-30 | Process method for synthesizing 2-substituted thiazole-4-boric acid pinacol ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114230598A CN114230598A (en) | 2022-03-25 |
| CN114230598B true CN114230598B (en) | 2024-07-26 |
Family
ID=80744754
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111651761.XA Active CN114230598B (en) | 2021-12-30 | 2021-12-30 | Process method for synthesizing 2-substituted thiazole-4-boric acid pinacol ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114230598B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105481790A (en) * | 2014-09-19 | 2016-04-13 | 中国科学院上海药物研究所 | A class of sulfonamide-containing dihydrothiazolone compounds and their pharmaceutical compositions and uses |
| WO2020038394A1 (en) * | 2018-08-21 | 2020-02-27 | 南京明德新药研发有限公司 | Pyrazolopyrimidine derivative and use thereof as pi3k inhibitor |
-
2021
- 2021-12-30 CN CN202111651761.XA patent/CN114230598B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105481790A (en) * | 2014-09-19 | 2016-04-13 | 中国科学院上海药物研究所 | A class of sulfonamide-containing dihydrothiazolone compounds and their pharmaceutical compositions and uses |
| WO2020038394A1 (en) * | 2018-08-21 | 2020-02-27 | 南京明德新药研发有限公司 | Pyrazolopyrimidine derivative and use thereof as pi3k inhibitor |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114230598A (en) | 2022-03-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Yamaguchi et al. | A ring opening reaction of oxetanes with lithium acetylides promoted by boron trifluoride etherate | |
| Cossu et al. | Synthesis of structurally modified atropisomeric biaryl dithiols. Observations on the Newman-Kwart rearrangement | |
| EP4186915A1 (en) | Method for synthesizing c-nucleoside compound | |
| AU3593193A (en) | Enantioselective oxazaborolidine catalysts | |
| CN114230598B (en) | Process method for synthesizing 2-substituted thiazole-4-boric acid pinacol ester | |
| CN101863912A (en) | Preparation method of cyclopropylboronic acid | |
| CN104860980A (en) | Ezetimibe synthesis intermediate and preparation method and application thereof | |
| Björk et al. | Improved syntheses of thieno [2, 3‐b]‐and [3, 2‐b]‐fused naphthyridines | |
| CN111217847B (en) | A kind of thiosilane ligand, its preparation method and application in aryl boronation catalytic reaction | |
| Mortier et al. | First synthesis and crystal structures of chiral 1, 3-dienylborates | |
| Mirzayans et al. | Synthesis of cis-vinyltrimethylstannanes and cis-vinylpinacolboronates in a two-step highly regio and stereoselective process | |
| CN102432594B (en) | Method for preparing 1-(3-hydroxymethylpyridine-2-yl)-2-phenyl-4-methyl piperazine serving as medicinal intermediate | |
| JP4994772B2 (en) | Method for producing piperidin-4-one derivative using bisaminol ether compound | |
| CN114891046A (en) | Triplecene metallocene catalyst and application thereof | |
| CN102656177B (en) | The preparation method of spiroketal derivative | |
| Goto et al. | Syntheses and structural characterizations of a novel bowl-type germanol and its derivatives | |
| CN109265385B (en) | Synthesis process of chiral catalyst | |
| CN112159424A (en) | Synthesis process of trimethylsilylacetylene | |
| CN107304194A (en) | The method for preparing Dapagliflozin | |
| CN112341433A (en) | A kind of preparation method of loratadine | |
| CN110016030B (en) | Preparation method of 5-fluoro-1H-pyrrole- [2,3-b ] pyridine-4-formaldehyde | |
| CN115703806B (en) | Phosphine ligand of pyrazole-amide framework, and preparation method and application thereof | |
| CN111423354B (en) | Synthesis method of 1H-3-pyrrolidone compound | |
| US4772751A (en) | Process for lithium mono- and diorganylborohydrides | |
| CN103145613B (en) | Method for synthesizing (E)-3-[2-cyclopropyl-4-(4-fluorophenyl) quinolinyl-2-propenal |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |