CN114805019B - Method for synthesizing 2-aryl-1-cyclohexanol based on continuous flow reaction technology - Google Patents
Method for synthesizing 2-aryl-1-cyclohexanol based on continuous flow reaction technology Download PDFInfo
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- 238000006243 chemical reaction Methods 0.000 title claims abstract description 69
- 238000000034 method Methods 0.000 title claims abstract description 35
- 230000002194 synthesizing effect Effects 0.000 title claims description 11
- 238000005516 engineering process Methods 0.000 title abstract description 10
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 24
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 21
- ZWAJLVLEBYIOTI-UHFFFAOYSA-N cyclohexene oxide Chemical compound C1CCCC2OC21 ZWAJLVLEBYIOTI-UHFFFAOYSA-N 0.000 claims abstract description 13
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohexene oxide Natural products O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 12
- 238000005086 pumping Methods 0.000 claims abstract description 12
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 10
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- 239000000463 material Substances 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- 238000002474 experimental method Methods 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 239000012074 organic phase Substances 0.000 claims description 6
- 150000007517 lewis acids Chemical group 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 5
- 230000000087 stabilizing effect Effects 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 239000004809 Teflon Substances 0.000 claims description 2
- 229920006362 Teflon® Polymers 0.000 claims description 2
- 238000010924 continuous production Methods 0.000 claims description 2
- 238000007599 discharging Methods 0.000 claims description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 claims description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 229910001220 stainless steel Inorganic materials 0.000 claims description 2
- 239000010935 stainless steel Substances 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims 2
- 125000001979 organolithium group Chemical group 0.000 claims 1
- 238000012805 post-processing Methods 0.000 claims 1
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 abstract description 16
- 230000000694 effects Effects 0.000 abstract description 7
- 238000005265 energy consumption Methods 0.000 abstract description 5
- 230000003321 amplification Effects 0.000 abstract description 4
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 4
- 238000005112 continuous flow technique Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- 239000000047 product Substances 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 12
- -1 aryl bromine Chemical compound 0.000 description 8
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 239000004593 Epoxy Substances 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QBELEDRHMPMKHP-UHFFFAOYSA-N 1-bromo-2-chlorobenzene Chemical compound ClC1=CC=CC=C1Br QBELEDRHMPMKHP-UHFFFAOYSA-N 0.000 description 2
- IPWBFGUBXWMIPR-UHFFFAOYSA-N 1-bromo-2-fluorobenzene Chemical compound FC1=CC=CC=C1Br IPWBFGUBXWMIPR-UHFFFAOYSA-N 0.000 description 2
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical compound CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 2
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000003193 general anesthetic agent Substances 0.000 description 2
- 229960003299 ketamine Drugs 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- QDFKKJYEIFBEFC-UHFFFAOYSA-N 1-bromo-3-fluorobenzene Chemical compound FC1=CC=CC(Br)=C1 QDFKKJYEIFBEFC-UHFFFAOYSA-N 0.000 description 1
- WJIFKOVZNJTSGO-UHFFFAOYSA-N 1-bromo-3-methylbenzene Chemical compound CC1=CC=CC(Br)=C1 WJIFKOVZNJTSGO-UHFFFAOYSA-N 0.000 description 1
- PKJBWOWQJHHAHG-UHFFFAOYSA-N 1-bromo-4-phenylbenzene Chemical compound C1=CC(Br)=CC=C1C1=CC=CC=C1 PKJBWOWQJHHAHG-UHFFFAOYSA-N 0.000 description 1
- DTTDXHDYTWQDCS-UHFFFAOYSA-N 1-phenylcyclohexan-1-ol Chemical compound C=1C=CC=CC=1C1(O)CCCCC1 DTTDXHDYTWQDCS-UHFFFAOYSA-N 0.000 description 1
- YXADWCNDSYNYQT-UHFFFAOYSA-N 2-(2-chlorophenyl)cyclohexan-1-ol Chemical compound OC1CCCCC1C1=CC=CC=C1Cl YXADWCNDSYNYQT-UHFFFAOYSA-N 0.000 description 1
- FTDCRHPZMQFMID-UHFFFAOYSA-N 2-(2-methylphenyl)cyclohexan-1-ol Chemical compound CC1=CC=CC=C1C1C(O)CCCC1 FTDCRHPZMQFMID-UHFFFAOYSA-N 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000003182 bronchodilatating effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 230000003779 hair growth Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 210000002374 sebum Anatomy 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000849 selective androgen receptor modulator Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
- C07C29/10—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes
- C07C29/103—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes of cyclic ethers
- C07C29/106—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes of cyclic ethers of oxiranes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/04—Compounds containing oxirane rings containing only hydrogen and carbon atoms in addition to the ring oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/08—Compounds containing oxirane rings with hydrocarbon radicals, substituted by halogen atoms, nitro radicals or nitroso radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic System
- C07F1/02—Lithium compounds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00002—Chemical plants
- B01J2219/00004—Scale aspects
- B01J2219/00006—Large-scale industrial plants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Abstract
The invention discloses a method for preparing 2-aryl-1-cyclohexanol based on a continuous flow reaction technology. Which relates to a continuous flow process for lithium halide exchange. And pumping bromobenzene or derivatives thereof and n-butyllithium into a continuous flow reaction device according to a certain proportion, reacting for a period of time under a specific low temperature condition to perform lithium halide exchange, then pumping cyclohexene oxide to perform nucleophilic substitution reaction, and finally pumping boron trifluoride diethyl ether as a fourth component to perform ring opening reaction to obtain a 2-aryl-1-cyclohexanol product. The invention solves the problems of large energy consumption, amplification effect and the like of the traditional kettle type reaction by utilizing a continuous flow reaction technology under a low temperature condition; the dangerous coefficient of the active lithium reagent is reduced, the reaction obtains higher product purity under the controllable continuous condition, the reaction efficiency is improved, and the method has wide application prospect.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for preparing 2-aryl-1-cyclohexanol based on a continuous flow reaction technology.
Background
2-aryl-1-cyclohexanols are important intermediates for the synthesis of a wide variety of bioactive molecules, drugs, and other materials. For example: 4-cycloalkoxybenzonitrile is an androgen receptor modulator. Can effectively reduce sebum secretion and stimulate hair growth, thereby bringing good news to the patient suffering from alopecia; ketamine is a kind of intravenous general anesthetic, clinically used as general anesthetic or anesthetic inducer, and has bronchodilatory effect, so that it is also suitable for treating asthma patient, and can be used as dilator for cerebral blood vessel. 2- (2-methylphenyl) -2-nitrocyclohex-1-one has good effect in treating nervous system diseases. And 2-aryl-1-cyclohexanol is an important intermediate for synthesizing the above compounds, and thus has important significance for developing a rapid and efficient synthesis method therefor.
The 2-aryl-1-cyclohexanol compounds can be obtained with ideal yield under the action of metal lithium reagents (such as n-butyl lithium and tert-butyl lithium) by utilizing ternary epoxy compounds to oxidize cyclohexene and aryl bromine, and the method is an efficient means for synthesizing the compounds. For example, zhang Fumin and the like take o-chlorobromobenzene and cyclohexene oxide as raw materials, tertiary butyl lithium is adopted as a lithium reagent, 2- (2-chlorophenyl) cyclohexanol can be obtained by synthesis under the low temperature condition, and ketamine is finally synthesized; xue Tao 2- (2-methylphenyl) -2-nitrocyclohex-1-one was synthesized from 2- (2-methylphenyl) cyclohexanol, which has therapeutic effect on nervous system; tang Shizhong and the like, which are prepared by oxidizing phenylcyclohexanol as a raw material and then catalyzing the fluorination of a-diketone by PTSA, can be used for constructing a fluorinated quaternary carbon center.
However, the above reaction for synthesizing 2-aryl-1-cyclohexanol has a high yield and a relatively good effect, but it is necessary to use tert-butyllithium/butyllithium which is highly dangerous; in addition, the tertiary butyl lithium and boron trifluoride diethyl etherate solution adopted in the system is sensitive to water and air, and the reaction needs to be carried out at low temperature of minus 80 ℃ and the like, so that the requirement on the reaction operation is high. At the same time, the reaction is difficult to scale up due to the dangers of the reaction and the severe temperature requirements. At present, the prior art has a plurality of problems for synthesizing 2-aryl-1-cyclohexanol, including dangerous coefficient, larger energy consumption, complex operation and the like. Therefore, the development of new synthesis technology for the compounds has important research significance and application value.
Disclosure of Invention
In order to solve the defects of the prior art, including large risk coefficient, high energy consumption, complex operation and the like, the invention provides a method for rapidly preparing 2-aryl-1-cyclohexanol based on a continuous flow reaction technology and application thereof.
The invention provides a method for rapidly preparing 2-aryl-1-cyclohexanol based on a continuous flow reaction technology, which utilizes nitrogen balance system pressure, utilizes continuous flow experimental pump equipment to realize continuous production through continuous feeding and discharging, takes material 1 as a reactant, and prepares the product 2-aryl-1-cyclohexanol through lithium halogen exchange reaction, nucleophilic substitution reaction and Lewis acid ring opening reaction.
The method of the invention utilizes bromobenzene, butyllithium, epoxy and boron trifluoride diethyl etherate to synthesize the 2-aryl-1-cyclohexanol target product by adopting a continuous flow chemical technology. The reaction is carried out by sequentially feeding, exchanging lithium halogen of butyl lithium and aryl bromine to obtain aryl lithium intermediate, nucleophilic substituting with epoxy, opening ring under action of boron trifluoride, and water quenching to obtain final product 2-aryl-1-cyclohexanol.
The reaction route of the method is as follows:
wherein R represents any one or more of methyl, methoxy, halogen (fluorine, chlorine), alkyl, aryl, heteroaryl, alkoxy, amino, hydroxy, trifluoromethyl and other substituents at any position on the aromatic ring except bromine substituent.
The method comprises the following steps:
(1) Lithium halide exchange
Before the reaction starts, filling a pipeline with tetrahydrofuran to ensure that no air exists in the pipeline, pumping the material 1 and a lithium reagent into a continuous flow reaction device according to an equivalent proportion under the protection of nitrogen, and reacting for 5-8 minutes in a first solvent at the temperature of minus 60 ℃ to minus 80 ℃ to perform lithium halogen exchange to generate an intermediate 2;
(2) Nucleophilic substitution
Continuously introducing the active intermediate 2 generated in the step (1) into a continuous flow reaction device, then pumping cyclohexene oxide solution into the continuous flow reaction device in proportion, and carrying out nucleophilic substitution in a second solvent at the temperature of minus 60 ℃ to minus 80 ℃ for 5-7 minutes to generate an active intermediate 3;
(3) Ring opening of Lewis acids
Continuously introducing the active intermediate 3 generated in the step (2) into a continuous flow reaction device, then pumping boron trifluoride diethyl etherate solution into the continuous flow reaction device in proportion, and reacting for 8-10 minutes in a third solvent at the temperature of minus 70 ℃ to minus 85 ℃ to perform ring opening reaction to obtain a 2-aryl-1-cyclohexanol product.
In some embodiments, the operating steps include the following:
filling a pipeline with tetrahydrofuran to ensure that no air exists in the pipeline, pumping the material 1 and butyl lithium into a continuous flow reaction device according to a certain equivalent ratio under the protection of nitrogen, and reacting for 5-8 min at the temperature of minus 80 ℃ to perform lithium halide exchange, wherein the generated active intermediate 2 continuously passes through the continuous flow device; pumping cyclohexene oxide solution into a continuous flow reaction device according to a certain proportion, and reacting for 5-7 min at-80 ℃ to carry out nucleophilic substitution to generate an intermediate 3; and continuously introducing the generated active intermediate 3 into a continuous flow reaction device, pumping boron trifluoride diethyl etherate solution into the continuous flow reaction device according to a certain proportion, reacting for 8-10 min at the temperature of minus 80 ℃, and carrying out Lewis acid ring opening to obtain the 2-aryl-1-cyclohexanol.
In the step (1), the first solvent used in the solution of the material 1 in the synthetic intermediate 2 is at least one of toluene, tetrahydrofuran and anhydrous diethyl ether, the concentration of the first solvent is 0.8-1.5 mol/L, and the flow rate is 6.0-10.0 mL/min;
equivalent ratio 1 of material 1 to butyllithium in synthetic intermediate 2: 1 to 1.5, wherein the temperature is-60 ℃ to-80 ℃;
the reaction time of lithium halide exchange in the synthesized intermediate 2 is 5-8 min;
the organic lithium reagent is one of butyl lithium, sec-butyl lithium and tert-butyl lithium, and the flow rate is 4 mL/min-6 mL/min;
in the step (2), the second solvent used in the cyclohexene oxide solution in the synthesis intermediate 3 is at least one of toluene, tetrahydrofuran and anhydrous diethyl ether, the concentration of the second solvent is 0.8-1.5 mol/L, and the flow rate is 5-8 mL/min;
the equivalent ratio of material 1 to cyclohexene oxide in synthetic intermediate 3 is 1:0.9 to 1; the temperature is-60 ℃ to-80 ℃;
the reaction time of nucleophilic substitution in the synthesized intermediate 3 is 3-5 min;
in the step (3), the third solvent used in the boron trifluoride diethyl etherate solution used in synthesizing the target product 4, namely the product 2-aryl-1-cyclohexanol, is at least one of toluene, tetrahydrofuran and anhydrous diethyl ether, the concentration of the third solvent is 1.2-2.0 mol/L, and the flow rate is 6.5-10.0 mL/min;
the equivalent ratio of the material 1 to the boron trifluoride diethyl etherate is 1 when the target product 4 is synthesized: 1.5-2, wherein the temperature is-70 ℃ to-85 ℃;
the reaction time of the Lewis ring opening reaction is 5 min-10 min when the target product 4 is synthesized.
In the method of the present invention, the continuous flow reaction apparatus comprises: the continuous flow reaction pipeline is a PTFE Teflon pipe or a 316L stainless steel pipe; a micro-mixer; a temperature control system; a continuous flow reaction experiment pump connected with the inlet of the reactant; the continuous flow reaction pressure stabilizing device is connected with the outlet of the product; and the continuous flow product collecting device is connected with the outlet of the pressure stabilizing device.
In the method of the invention, the continuous flow reaction experimental pump comprises a pump 1-a pump 4; wherein,
the continuous flow reaction experiment pump 1 leads tetrahydrofuran and toluene solution of the material 1 to be introduced into a pipeline, wherein the concentration of the solution is 0.5-1 mol/L, and the flow rate is 6.0-10.0 mL/min;
the continuous flow reaction experiment pump 2 leads the lithium reagent to be led into a pipeline, and the flow speed is 4 mL/min-6 mL/min;
the continuous flow reaction experiment pump 3 leads the tetrahydrofuran solution of cyclohexene oxide to be led into a pipeline, the concentration of the tetrahydrofuran solution is 0.8 mol/L-1.5 mol/L, and the flow rate is 5 mL/min-8 mL/min;
the continuous flow reaction experiment pump 4 leads toluene solution of boron trifluoride-diethyl etherate to be introduced into a pipeline, the concentration of the toluene solution is 1.2 mol/L-2.0 mol/L, and the flow rate is 6.5-10.0 mL/min.
The overall reaction temperature of the reaction is-80 ℃, and the overall reaction retention time is 20-30 min.
The invention further comprises the post-treatment steps of:
step 4) extracting and separating the product to obtain an organic phase, then drying the organic phase by using anhydrous sodium sulfate, and spin-drying the organic phase by using a rotary evaporator to obtain a white waxy solid; and/or the number of the groups of groups,
the product collected in step 5) was 80-90% pure as monitored by GC.
The present invention also proposes intermediate 2 as shown below,
wherein R represents any one or more of methyl, methoxy, halogen (fluorine, chlorine), alkyl, aryl, heteroaryl, alkoxy, amino, hydroxy, trifluoromethyl and other substituents at any position on the aromatic ring except bromine substituent.
The invention also provides an intermediate 3, which has the structure as follows:
wherein R represents any one or more of methyl, methoxy, halogen (fluorine, chlorine), alkyl, aryl, heteroaryl, alkoxy, amino, hydroxy, trifluoromethyl and other substituents at any position on the aromatic ring except bromine substituent.
The invention has the innovative beneficial effects that the synthesis path with low cost is combined with the continuous flow technology, the amplification effect of the kettle test reaction is solved, the dangerous operation coefficient of the active lithium reagent is reduced, the energy consumption required by the reaction is reduced, the cost is saved, and the invention provides a high-efficiency, safe and low-cost process method for synthesizing the 2-aryl-1-cyclohexanol, so that the reaction can obtain a crude product with higher purity (GC purity is 80% -90%) under the controllable continuous condition, and the purity is higher than the purity of the kettle test (GC purity is 65% -70%). The method combines the good heat and mass transfer effects of the continuous flow reaction, has no amplification effect, avoids the loss caused by the amplification effect, has the advantages of simple operation, low risk coefficient and the like, and comprises the advantages of good heat and mass transfer, short reaction time, relatively less energy consumption and the like of the continuous flow reaction device. The method for synthesizing the 2-aryl-1-cyclohexanol by using the continuous flow method provided by the invention has important significance and application value in the technical field of synthesis.
Drawings
FIG. 1 is a schematic process flow diagram of the method of the invention for synthesizing 2-aryl-1-cyclohexanol: wherein 1,2,3,4 are the prepared materials; 5,6,7,8 are continuous flow experimental pumps; 9, 10, 11, 12 are pre-cooling tubes; 13 16, 19 are micro-mixing devices; 14 17, 20 are temperature control device detection points; 15 18, 21 are reaction tubes for the reaction; 22 a voltage stabilizing device of the system; 23 is the receiving means of the system.
Fig. 2 and 3 are process flow diagrams.
Detailed Description
The invention will be described in further detail with reference to the following specific examples and drawings. The procedures, conditions, experimental methods, etc. for carrying out the present invention are common knowledge and common knowledge in the art, except for the following specific references, and the present invention is not particularly limited.
Example 1
As shown in fig. 1, a THF solution of bromobenzene was filled into a three-necked flask 1, nBuLi was filled into a three-necked flask 2, a THF solution of cyclohexene oxide was filled into a three-necked flask 3, a toluene solution of boron trifluoride diethyl ether was filled into a three-necked flask 4, a temperature control device was set to-60 ℃, and THF solution of bromobenzene and nBuLi were fed into the reaction tube 15 by continuous flow experimental pumps 5 and 6, respectively, so that lithium halide exchange was performed for 6min; then nucleophilic substitution is carried out on the intermediate 2 and cyclohexene oxide THF solution obtained in the above in the reaction tube 18 for 4min; finally, ring-opening the intermediate 3 obtained in the second step and toluene solution of boron trifluoride diethyl etherate in a reaction tube 21, wherein the retention time is 7min; then the reactant is led into 23 (the ice-water mixture with 1/3 of the water) for quenching, then the reaction liquid is separated, washed once by brine, dried and spin-dried for analysis by GC, and the purity of the crude product is 90.3%;
1 HNMR(400MHz,CDCl 3 )δ7.32(t,J＝7.5Hz,2H),7.24(dd,J＝7.6,2.6Hz,3H),3.65(td,J＝10.0,4.2Hz,1H),2.41(m,1H),2.14-2.05(m,1H),1.85(dd,J＝12.2,3.4Hz,2H),1.79-1.70(m,1H),1.59-1.27(m,6H).
example 2
The specific synthesis process is the same as that of the embodiment 1 of the invention, only the bromobenzene is replaced by 2-methyl bromobenzene, and the temperature control device is set to be-65 ℃; the purity of the obtained product is 87.2%;
1 HNMR(400MHz,CDC1 3 )δ7.27-7.23(m,1H),7.22-7.14(m,2H),7.13-7.08(m,1H),3.83-3.71(m,1H),2.83-2.68(m,1H),2.36(s,3H),2.18-2.07(m,1H),1.94-1.70(m,3H),1.69-1.59(m,1H),1.51-1.27(m,4H).
example 3
The specific synthesis process is the same as that of the embodiment 2 of the invention, except that 2-methyl bromobenzene is changed into 3-methyl bromobenzene; the purity of the obtained product is 85.9%;
1 HNMR(400MHZ,CDC1 3 )δ7.26-7.18(m,1H),7.09-7.01(m,3H),3.70--3.58(m,1H),2.43-2.35(m,1H),2.34(s,3h),2.14-2.06(m,1h),1.88-1.71(m,3H),1.68-1.60(m,1H),1.56-1.28(m,4h).
example 4
The specific synthesis process is the same as that of the embodiment 1 of the invention, only the bromobenzene is changed into 2-fluorobromobenzene, and the purity of the obtained product is 88.7%;
1 H NMR(400MHz,CDC1 3 ),δ7.28(m,1H),7.20(m,1H),7.12(m,1H),7.04(m,1H),3.79(m,1H),2.83(m,1H),2.17-2.10(m,1H),1.94-1.81(m,2H),1.81-1.69(m,1H),1.66-1.18(m,4H),0.93-0.79(m,1H).
example 5
The specific synthesis process is the same as that of the embodiment 4 of the invention, except that 2-fluorobromobenzene is changed into 3-fluorobromobenzene; the purity of the obtained product is 89.8%;
1 H NMR(400MHz,CDC1 3 )δ87.32-7.27(m,1H),7.03(d,J＝7.5Hz,1H),6.94(dd J＝16.8,9.1Hz,2H)、3.64(td,J＝9.9,4.2Hz,1H),2.49-2.38(m,1H),2.12(d,J＝8.0Hz,1H)，1.86(d,J＝10.2Hz,2H)
example 6
The specific synthesis process is the same as that of the embodiment 1, except that the temperature control device for changing bromobenzene into 2-chlorobromobenzene is set to be-78 ℃; the purity of the obtained product was 82.3%.
1 H NMR(400MHz,CDCl 3 )δ7.39(d,J＝8.0Hz,1H),7.33(d,J＝7.8Hz,1H),7.26(q,J＝8.0,7.5Hz,2H),7.21–7.10(m,2H),3.90–3.78(m,1H),3.12(m,1H),2.36(m,1H),2.16(m,1H),1.97–1.65(m,4H),1.55–1.18(m,4H).
Example 7
The specific synthesis process is the same as that of the embodiment 1 of the invention, only the bromobenzene is replaced by 4-phenyl bromobenzene, and the temperature control device is set to be-82 ℃; the purity of the obtained product is 83.7%
1 H NMR(400MHz,CDCl 3 ):δ7.61-7.68(m,4H),7.48-7.05(m,2H),7.37-7.44(m,3H),3.70-3.78(m,1H),2.50-2.58(m,1H),2.17-2.21(m,1H),1.93-1.98(m,2H),1.85(s,2H),1.38-1.67(m,4H).
The protection of the present invention is not limited to the above embodiments. Variations and advantages that would occur to those skilled in the art, and that simple technical modifications and equivalents to the invention may be resorted to without departing from the spirit and scope of the inventive concepts, are intended to be encompassed by the invention as defined by the appended claims.
Claims (4)
1. A method for synthesizing 2-aryl-1-cyclohexanol based on continuous flow reaction is characterized in that the method relies on nitrogen balance system pressure, continuous flow experimental pump equipment is utilized to realize continuous production through continuous feeding and discharging, material 1 is used as a reactant, and the product 2-aryl-1-cyclohexanol is prepared through lithium halogen exchange reaction, nucleophilic substitution reaction and Lewis acid ring opening reaction in sequence; the reaction route of the method is as follows:
wherein R represents an alkyl group, an aryl group, fluorine or chlorine;
the method comprises the following steps:
(1) Lithium halide exchange
Before the reaction starts, filling a pipeline with tetrahydrofuran to ensure that no air exists in the pipeline, pumping the material 1 and a lithium reagent into a continuous flow reaction device according to an equivalent proportion under the protection of nitrogen, and reacting for 5-8 minutes in a first solvent at the temperature of minus 60 ℃ to minus 80 ℃ to perform lithium halogen exchange to generate an active intermediate 2; the lithium reagent is an organolithium reagent, and is n-butyllithium;
(2) Nucleophilic substitution
Continuously introducing the active intermediate 2 generated in the step (1) into a continuous flow reaction device, then pumping cyclohexene oxide solution into the continuous flow reaction device in proportion, and carrying out nucleophilic substitution in a second solvent at the temperature of minus 60 ℃ to minus 80 ℃ for 5-7 minutes to generate an active intermediate 3;
(3) Ring opening of Lewis acids
Continuously introducing the active intermediate 3 generated in the step (2) into a continuous flow reaction device, then pumping boron trifluoride diethyl etherate solution into the continuous flow reaction device in proportion, and reacting for 8-10 minutes in a third solvent at the temperature of-70 ℃ to-85 ℃ to perform ring opening reaction to obtain a 2-aryl-1-cyclohexanol product;
the continuous flow reaction apparatus comprises:
the continuous flow reaction pipeline is a PTFE Teflon pipe or a 316L stainless steel pipe;
a micro-mixer;
a temperature control system;
a continuous flow reaction experiment pump connected with the inlet of the reactant; the continuous flow reaction experimental pump comprises a pump 1-a pump 4; wherein,
the continuous flow reaction experiment pump 1 leads tetrahydrofuran and toluene solution of the material 1 to be introduced into a pipeline, wherein the concentration of the solution is 0.5-1 mol/L, and the flow rate is 6.0-10.0 mL/min;
the continuous flow reaction experiment pump 2 leads the lithium reagent to be led into a pipeline, and the flow speed is 4 mL/min-6 mL/min;
the continuous flow reaction experiment pump 3 leads the tetrahydrofuran solution of cyclohexene oxide to be led into a pipeline, the concentration of the tetrahydrofuran solution is 0.8 mol/L-1.5 mol/L, and the flow rate is 5 mL/min-8 mL/min;
the continuous flow reaction experiment pump 4 leads toluene solution of boron trifluoride-diethyl etherate into a pipeline, the concentration of the toluene solution is 1.2 mol/L-2.0 mol/L, and the flow rate is 6.5-10.0 mL/min;
the continuous flow reaction pressure stabilizing device is connected with the outlet of the product;
and the continuous flow product collecting device is connected with the outlet of the pressure stabilizing device.
2. The method of claim 1, wherein the step of determining the position of the substrate comprises,
in the step (1), the first solvent used in the solution of the material 1 is at least one of toluene, tetrahydrofuran and anhydrous diethyl ether;
in the step (2), the second solvent used in the cyclohexene oxide solution is at least one of toluene, tetrahydrofuran and anhydrous diethyl ether;
in the step (3), the third solvent used in the boron trifluoride diethyl etherate solution is at least one of toluene, tetrahydrofuran and anhydrous diethyl ether.
3. The method of claim 1, wherein the step of determining the position of the substrate comprises,
in the step (1), the equivalent ratio of the material 1 to the lithium reagent is 1:1 to 1.5;
in the step (2), the equivalent ratio of the material 1 to cyclohexene oxide is 1:0.9 to 1;
in the step (3), the equivalent ratio of the material 1 to the boron trifluoride diethyl etherate is 1:1.5 to 2.
4. The method of claim 1, further comprising the post-processing step of:
step 4) extracting and separating the product to obtain an organic phase, then drying the organic phase by using anhydrous sodium sulfate, and spin-drying the organic phase by using a rotary evaporator to obtain a white waxy solid;
and/or the product collected in step 5) is monitored by GC and has a purity of 80 to 90%.
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004024663A1 (en) * | 2002-08-31 | 2004-03-25 | Clariant Gmbh | Method for the organometallic production of organic intermediate products by halogen-metal exchange reactions |
| JP2006241065A (en) * | 2005-03-03 | 2006-09-14 | Fujifilm Finechemicals Co Ltd | Method for producing organic compound using halogen-lithium exchange reaction |
| CN105073114A (en) * | 2013-03-14 | 2015-11-18 | 第一三共株式会社 | Drug for respiratory diseases |
| CN106478367A (en) * | 2016-09-30 | 2017-03-08 | 兰州大学 | A kind of synthesis midbody compound of ketamine and the synthetic method of ketamine |
| CN110343050A (en) * | 2018-04-04 | 2019-10-18 | 上海键合医药科技有限公司 | Aromatic compounds and its preparation method and application |
| CN110835292A (en) * | 2019-10-12 | 2020-02-25 | 北京海美桐医药科技有限公司 | Method for preparing 2-fluoro-6-trifluoromethylbenzaldehyde by adopting continuous flow reaction device |
| ES2837446A1 (en) * | 2019-12-31 | 2021-06-30 | Laboratorios Vinas S A | MANUFACTURING PROCEDURES FOR BROMOMETHYL CYCLOPROPYLKETONE, CYCLOPROPYLCARBONYLMETHYLTRIPHENYLPHOSPHONIUM BROMIDE, CYCLOPROPYLCARBONYL METHYLENETHRIPHENYLPHOSPHORANE, VITAMIN D DERIVATIVES AND CALCIPOTRIOL (Machine-translation by Google Translate, not legally binding) |
| CN113264819A (en) * | 2021-05-25 | 2021-08-17 | 都创(上海)医药开发有限公司 | Method for rapidly synthesizing 3-bromo-2-fluorobenzaldehyde based on continuous flow reaction technology |
| CN113549042A (en) * | 2021-07-23 | 2021-10-26 | 安庆奇创药业有限公司 | Preparation method of dapagliflozin |
-
2022
- 2022-04-25 CN CN202210438652.8A patent/CN114805019B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004024663A1 (en) * | 2002-08-31 | 2004-03-25 | Clariant Gmbh | Method for the organometallic production of organic intermediate products by halogen-metal exchange reactions |
| JP2006241065A (en) * | 2005-03-03 | 2006-09-14 | Fujifilm Finechemicals Co Ltd | Method for producing organic compound using halogen-lithium exchange reaction |
| CN105073114A (en) * | 2013-03-14 | 2015-11-18 | 第一三共株式会社 | Drug for respiratory diseases |
| CN106478367A (en) * | 2016-09-30 | 2017-03-08 | 兰州大学 | A kind of synthesis midbody compound of ketamine and the synthetic method of ketamine |
| CN110343050A (en) * | 2018-04-04 | 2019-10-18 | 上海键合医药科技有限公司 | Aromatic compounds and its preparation method and application |
| CN110835292A (en) * | 2019-10-12 | 2020-02-25 | 北京海美桐医药科技有限公司 | Method for preparing 2-fluoro-6-trifluoromethylbenzaldehyde by adopting continuous flow reaction device |
| ES2837446A1 (en) * | 2019-12-31 | 2021-06-30 | Laboratorios Vinas S A | MANUFACTURING PROCEDURES FOR BROMOMETHYL CYCLOPROPYLKETONE, CYCLOPROPYLCARBONYLMETHYLTRIPHENYLPHOSPHONIUM BROMIDE, CYCLOPROPYLCARBONYL METHYLENETHRIPHENYLPHOSPHORANE, VITAMIN D DERIVATIVES AND CALCIPOTRIOL (Machine-translation by Google Translate, not legally binding) |
| CN113264819A (en) * | 2021-05-25 | 2021-08-17 | 都创(上海)医药开发有限公司 | Method for rapidly synthesizing 3-bromo-2-fluorobenzaldehyde based on continuous flow reaction technology |
| CN113549042A (en) * | 2021-07-23 | 2021-10-26 | 安庆奇创药业有限公司 | Preparation method of dapagliflozin |
Non-Patent Citations (4)
| Title |
|---|
| Diversity-Oriented Synthesis of Bioactive Azaspirocycles;Lance T. Lepovitz et al.;《Tetrahedron》;第1-10页 * |
| Promoting Reductive Tandem Reactions of Nitrostyrenes with Mo(CO)6 and a Palladium Catalyst To Produce 3H‑Indoles;Navendu Jana et al.;《J. Am. Chem. Soc》;第137卷;第6738-6741页、Supporting InformationS5页 * |
| Synthesis of methoxetamine, its metabolites and deuterium labelled analog as analytical standards and their HPLC and chiral capillary electrophoresis separation;B. Jurasek et al.;《RSC Adv》;第7卷;第56691-56696页 * |
| 铜盐催化氧化环己烯的开环加成反应;鄢明;化学通报;20040618(06);452-460 * |
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