CN114805019A - 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
- Publication number
- CN114805019A CN114805019A CN202210438652.8A CN202210438652A CN114805019A CN 114805019 A CN114805019 A CN 114805019A CN 202210438652 A CN202210438652 A CN 202210438652A CN 114805019 A CN114805019 A CN 114805019A
- Authority
- CN
- China
- Prior art keywords
- continuous flow
- reaction
- flow reaction
- aryl
- solution
- 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.)
- Granted
Links
- 238000006243 chemical reaction Methods 0.000 title claims abstract description 74
- 238000000034 method Methods 0.000 title claims abstract description 40
- 230000002194 synthesizing effect Effects 0.000 title claims description 9
- 238000005516 engineering process Methods 0.000 title abstract description 10
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 26
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 20
- ZWAJLVLEBYIOTI-UHFFFAOYSA-N cyclohexene oxide Chemical compound C1CCCC2OC21 ZWAJLVLEBYIOTI-UHFFFAOYSA-N 0.000 claims abstract description 14
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohexene oxide Natural products O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 claims abstract description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 12
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 12
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 11
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 11
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 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
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 22
- 239000000463 material Substances 0.000 claims description 16
- 238000002474 experimental method Methods 0.000 claims description 15
- 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
- 238000003786 synthesis reaction Methods 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- -1 amino, hydroxyl Chemical group 0.000 claims description 10
- 238000005086 pumping Methods 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000001246 bromo group Chemical group Br* 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 150000007517 lewis acids Chemical group 0.000 claims description 5
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 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
- 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
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 2
- 238000012544 monitoring process Methods 0.000 claims description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 claims description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 claims description 2
- 238000012805 post-processing Methods 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
- 238000003556 assay 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 8
- 238000005265 energy consumption Methods 0.000 abstract description 5
- 230000003321 amplification Effects 0.000 abstract description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 abstract description 4
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 4
- 229910015900 BF3 Inorganic materials 0.000 abstract description 2
- 238000005112 continuous flow technique Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 21
- 239000000047 product Substances 0.000 description 19
- 238000004817 gas chromatography Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 239000004593 Epoxy Substances 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 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
- DTTDXHDYTWQDCS-UHFFFAOYSA-N 1-phenylcyclohexan-1-ol Chemical compound C=1C=CC=CC=1C1(O)CCCCC1 DTTDXHDYTWQDCS-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
- 150000001499 aryl bromides Chemical class 0.000 description 2
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzenecarbonitrile Natural products N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000007789 gas Substances 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
- 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
- 206010002091 Anaesthesia Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102400001284 Vessel dilator Human genes 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 108010090012 atrial natriuretic factor prohormone (31-67) Proteins 0.000 description 1
- 201000009267 bronchiectasis Diseases 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
- 238000010276 construction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 229940005494 general anesthetics Drugs 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
- 150000002576 ketones Chemical class 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
- 210000000653 nervous system Anatomy 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
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
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 Table
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing 2-aryl-1-cyclohexanol based on a continuous flow reaction technology. In which a lithium halide exchange continuous flow process is involved. The bromobenzene or the derivatives thereof and n-butyllithium are pumped into a continuous flow reaction device according to a certain proportion, the reaction is carried out for a period of time under a specific low temperature condition for lithium halogen exchange, then cyclohexene oxide is pumped for nucleophilic substitution reaction, and finally boron trifluoride ether as a fourth component is pumped for ring opening reaction to obtain a 2-aryl-1-cyclohexanol product. The invention utilizes the continuous flow reaction technology under the low temperature condition, solves the problems of large energy consumption, amplification effect and the like of the traditional kettle type reaction; the danger 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 biologically active molecules, drugs, and other materials. For example: 4-Cycloalkoxy benzonitrile is an androgen receptor modulator. Can effectively reduce sebum secretion and stimulate hair growth, thereby bringing good news to patients with alopecia; ketamine is a vein general anesthetic, is clinically used for general anesthetics or anesthesia inducers, has the effect of bronchiectasis, is also suitable for treating asthma patients, and can also be used as a cerebral vessel dilator. The 2- (2-methylphenyl) -2-nitrocyclohex-1-one has good effect on treating nervous system diseases. And 2-aryl-1-cyclohexanol is used as an important intermediate for synthesizing the compound, so that the method has important significance for developing a rapid and efficient synthesis method.
Under the action of a metal lithium reagent (such as n-butyl lithium) by using cyclohexene oxide of a three-membered epoxy compound and aryl bromide, a 2-aryl-1-cyclohexanol compound can be obtained with a relatively ideal yield, and the method is an efficient means for synthesizing the compound. For example, Zhang assistor and the like can synthesize 2- (2-chlorophenyl) cyclohexanol and finally synthesize ketamine by using o-chloro bromobenzene and cyclohexene oxide as raw materials and tert-butyl lithium as a lithium reagent under a low-temperature condition; schopper et al synthesized 2- (2-methylphenyl) -2-nitrocyclohex-1-one from 2- (2-methylphenyl) cyclohexanol, and the medicine has the function of treating nervous system; tangshifai et al, which uses phenylcyclohexanol as a raw material, oxidizes the phenylcyclohexanol, and then uses PTSA to catalyze the fluorination of alpha-branched ketone, thereby being used for the construction of fluorinated quaternary carbon centers.
However, although the 2-aryl-1-cyclohexanol synthesized by the above reaction has high yield and relatively good effect, t-butyllithium/butyllithium with high risk needs to be used; in addition, the tert-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 danger of the reaction and the harsh requirements on temperature. At present, for the synthesis of 2-aryl-1-cyclohexanol, the prior art has a plurality of problems, including danger coefficient, large energy consumption, complex operation and the like. Therefore, the method has important research significance and application value in developing new synthesis technology for the compounds.
Disclosure of Invention
In order to solve the defects of the prior art, including danger coefficient, large 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 relies on the pressure of a nitrogen balance system, utilizes continuous flow experimental pump equipment to realize continuous production through continuous feeding and discharging, and prepares the product 2-aryl-1-cyclohexanol by taking a material 1 as a reactant and carrying out lithium halide exchange reaction, nucleophilic substitution reaction and Lewis acid ring-opening reaction.
The method of the invention utilizes bromobenzene, butyl lithium, epoxy and boron trifluoride diethyl etherate to synthesize the target product of 2-aryl-1-cyclohexanol by adopting a continuous flow chemical technology. The reaction is carried out by a sequential feeding mode, an aryl lithium intermediate is obtained through lithium halide exchange of butyl lithium and aryl bromide, nucleophilic substitution is further carried out on the aryl lithium intermediate and epoxy, ring opening is carried out under the action of boron trifluoride, and finally, water quenching reaction is carried out to obtain the target product 2-aryl-1-cyclohexanol.
The reaction route of the method is as follows:
wherein, R represents a substituent group which is any one or more of methyl, methoxy, halogen (fluorine, chlorine), alkyl, aryl, heteroaryl, alkoxy, amino, hydroxyl, trifluoromethyl and the like on any position except a bromine substituent on the aromatic ring.
The method comprises the following steps:
(1) lithium halide exchange
Filling a pipeline with tetrahydrofuran before the reaction starts, so that no air exists in the pipeline, pumping a 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-60 ℃ to-80 ℃ to perform lithium halide 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, pumping the cyclohexene oxide solution into the continuous flow reaction device in proportion, and reacting for 5-7 minutes in a second solvent at the temperature of-60 ℃ to-80 ℃ to perform nucleophilic substitution to generate an active intermediate 3;
(3) lewis acid ring opening
And (3) continuously introducing the active intermediate 3 generated in the step (2) into a continuous flow reaction device, pumping boron trifluoride diethyl etherate solution into the continuous flow reaction device according to a proportion, reacting for 8-10 minutes in a third solvent at the temperature of-70 ℃ to-85 ℃, and carrying out a ring-opening reaction to obtain a 2-aryl-1-cyclohexanol product.
In some embodiments, the steps of operating comprise 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, reacting for 5-8 min at-80 ℃ to perform lithium halide exchange, and continuously passing the generated active intermediate 2 through the continuous flow device; pumping the cyclohexene oxide solution into a continuous flow reaction device according to a certain proportion, and reacting for 5-7 min at-80 ℃ to perform nucleophilic substitution to generate an intermediate 3; and (3) 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-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 synthesis intermediate 2 is at least one of toluene, tetrahydrofuran and anhydrous 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;
the equivalence ratio of feed 1 to butyllithium in synthetic intermediate 2 was 1: 1-1.5 ℃, wherein the temperature is-60 ℃ to-80 ℃;
the reaction time of lithium halide exchange in the synthetic intermediate 2 is 5 min-8 min;
the organic lithium reagent is one of butyl lithium, sec-butyl lithium and tert-butyl lithium, and the flow rate is 4mL/min to 6 mL/min;
in the step (2), the second solvent used in the cyclohexene oxide solution in the synthesis of the intermediate 3 is at least one of toluene, tetrahydrofuran and anhydrous 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 the synthesis of intermediate 3 is 1: 0.9 to 1; the temperature is-60 ℃ to-80 ℃;
the reaction time of nucleophilic substitution in the synthesis of the intermediate 3 is 3 min-5 min;
in the step (3), the third solvent used in the boron trifluoride diethyl etherate solution used for 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;
when synthesizing the target product 4, the equivalent ratio of the material 1 to boron trifluoride diethyl etherate is 1: 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; the continuous flow reaction experiment pump is 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, the continuous flow reaction experiment 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 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 introduced into the pipeline, and the flow rate is 4mL/min to 6 mL/min;
the continuous flow reaction experiment pump 3 leads the tetrahydrofuran solution of cyclohexene oxide into the pipeline, the concentration of the tetrahydrofuran solution is 0.8-1.5 mol/L, and the flow rate is 5-8 mL/min;
the continuous flow reaction experiment pump 4 leads the toluene solution of boron trifluoride-diethyl ether into the pipeline, the concentration of the toluene solution is 1.2-2.0 mol/L, and the flow rate is 6.5-10.0 mL/min.
The reaction temperature is-80 ℃ on the whole, and the retention time of the reaction on the whole is 20-30 min.
The invention further comprises a post-processing step:
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 presence of a gas in the gas,
monitoring the product collected in the step 5) by GC, wherein the purity of the product is 80-90%.
The invention also provides an intermediate 2 shown as follows,
wherein, R represents a substituent group which is any one or more of methyl, methoxy, halogen (fluorine, chlorine), alkyl, aryl, heteroaryl, alkoxy, amino, hydroxyl, trifluoromethyl and the like on any position except a bromine substituent on the aromatic ring.
The invention also provides an intermediate 3, which has the following structure:
wherein, R represents a substituent group which is any one or more of methyl, methoxy, halogen (fluorine, chlorine), alkyl, aryl, heteroaryl, alkoxy, amino, hydroxyl, trifluoromethyl and the like on any position except a bromine substituent on the aromatic ring.
The invention has the advantages 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, an efficient, safe and low-cost process method is provided for synthesizing the 2-aryl-1-cyclohexanol, and the reaction can obtain a crude product with higher purity (the GC purity is 80-90%) and higher purity (the GC purity is 65-70%) than the kettle test under the controllable continuous condition. The method combines the good effect of heat and mass transfer of the continuous flow reaction, the continuous flow reaction has no amplification effect, the loss caused by the amplification effect is avoided, the continuous flow reaction has the advantages of simple operation, low danger coefficient and the like, and the continuous flow reaction device has the advantages of good heat and mass transfer, short reaction time, relatively less energy consumption and the like. The method for synthesizing the 2-aryl-1-cyclohexanol by using the continuous flow method has important significance and application value in the technical field of synthesis.
Drawings
FIG. 1 is a schematic process flow diagram of the process for the synthesis of 2-aryl-1-cyclohexanols according to the invention: wherein 1, 2, 3 and 4 are prepared materials; 5, 6, 7 and 8 are continuous flow experiment pumps; 9, 10, 11 and 12 are precooling pipes; 13, 16 and 19 are micro-mixing devices; 14, 17 and 20 are detection points of the temperature control device; 15, 18 and 21 are reaction tubes for reaction; 22 a pressure stabilizing device of the system; 23 is a receiving device of the system.
Fig. 2 and 3 are process flow diagrams.
Detailed Description
The invention is further described in detail with reference to the following specific examples and the accompanying drawings. The procedures, conditions, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
Example 1
As shown in FIG. 1, THF solution of bromobenzene was charged into three-necked flask 1, nBuLi was charged into three-necked flask 2, THF solution of cyclohexene oxide was charged into three-necked flask 3, toluene solution of boron trifluoride etherate was charged into three-necked flask 4, temperature control device was set at-60 deg.C, THF solution of bromobenzene and nBuLi were fed by continuous flow experiment pumps 5 and 6, respectively, and lithium halide exchange was performed in reaction tube 15 for 6 min; then, nucleophilic substitution is carried out on the obtained intermediate 2 and the THF solution of cyclohexene oxide in a reaction tube 18 for 4 min; finally, the intermediate 3 obtained in the second step and a toluene solution of boron trifluoride ethyl ether are subjected to ring opening in a reaction tube 21, and the retention time is 7 min; then introducing the reactant into 23 (an ice-water mixture containing 1/3) for quenching, then separating the reaction liquid, washing with saline water once, drying, and performing analysis by GC (gas chromatography) in a rotary drying manner to obtain a crude product with the purity of 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 synthetic process is the same as that of the embodiment 1 of the invention, except that bromobenzene is changed into 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 synthetic process is the same as that of the embodiment 2 of the invention, except that 2-methylbromobenzene is changed into 3-methylbromobenzene; 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 synthetic process is the same as that of the embodiment 1 of the invention, except that bromobenzene is replaced by 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 synthetic 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 of the invention, except that the temperature control device for replacing bromobenzene by 2-chlorobromobenzene is set to-78 ℃; the purity of the obtained product is 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 synthetic process is the same as that of the embodiment 1 of the invention, except that bromobenzene is changed into 4-phenylborobenzene, and the temperature control device is set to be-82 ℃; the purity of the obtained product is 83.7 percent
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 which may occur to those skilled in the art, without departing from the spirit and scope of the inventive concept, may be indicated by the appended claims.
Claims (10)
1. A method for synthesizing 2-aryl-1-cyclohexanol based on continuous flow reaction is characterized in that continuous production is achieved by means of continuous feeding and discharging through continuous flow experiment pump equipment by means of nitrogen balance system pressure, and a product 2-aryl-1-cyclohexanol is prepared through lithium halide exchange reaction, nucleophilic substitution reaction and Lewis acid ring opening reaction in sequence by taking a material 1 as a reactant; the reaction scheme of the method is as follows:
wherein, R represents a substituent group which is any one or more of methyl, methoxy, halogen, alkyl, aryl, heteroaryl, alkoxy, amino, hydroxyl and trifluoromethyl on any position except a bromine substituent on an aromatic ring.
2. The method of claim 1, wherein the method comprises the steps of:
(1) lithium halide exchange
Filling a pipeline with tetrahydrofuran before the reaction starts, so that no air exists in the pipeline, pumping a 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-60 ℃ to-80 ℃ to perform lithium halide exchange to generate an active intermediate 2;
(2) nucleophilic substitution
Continuously introducing the active intermediate 2 generated in the step (1) into a continuous flow reaction device, pumping the cyclohexene oxide solution into the continuous flow reaction device in proportion, and reacting for 5-7 minutes in a second solvent at the temperature of-60 ℃ to-80 ℃ to perform nucleophilic substitution to generate an active intermediate 3;
(3) lewis acid ring opening
And (3) continuously introducing the active intermediate 3 generated in the step (2) into a continuous flow reaction device, pumping boron trifluoride diethyl etherate solution into the continuous flow reaction device according to a proportion, reacting for 8-10 minutes in a third solvent at the temperature of-70 ℃ to-85 ℃, and carrying out a ring-opening reaction to obtain a 2-aryl-1-cyclohexanol product.
3. The method of claim 2,
in the step (1), the first solvent used in the material 1 solution is at least one of toluene, tetrahydrofuran and anhydrous ether; in the step (2), the second solvent used in the cyclohexene oxide solution is at least one of toluene, tetrahydrofuran and anhydrous 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;
the lithium reagent is an organic lithium reagent and is one of butyl lithium, sec-butyl lithium and tert-butyl lithium.
4. The method of synthesis according to claim 2,
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 boron trifluoride ethyl ether is 1: 1.5 to 2.
5. The method of claim 2, wherein the continuous flow reaction device comprises:
the continuous flow reaction pipeline is a PTFE Teflon pipe or a 316L stainless steel pipe;
a micro-mixer;
a temperature control system;
the continuous flow reaction experiment pump is 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.
6. The method of claim 1, wherein the continuous flow reaction assay pump comprises pump 1-pump 4;
wherein,
the continuous flow reaction experiment pump 1 leads tetrahydrofuran and toluene solution of the material 1 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 introduced into the pipeline, and the flow rate is 4mL/min to 6 mL/min;
the continuous flow reaction experiment pump 3 leads the tetrahydrofuran solution of cyclohexene oxide into the pipeline, the concentration of the tetrahydrofuran solution is 0.8-1.5 mol/L, and the flow rate is 5-8 mL/min;
the continuous flow reaction experiment pump 4 leads the toluene solution of boron trifluoride-diethyl ether into the pipeline, the concentration of the toluene solution is 1.2-2.0 mol/L, and the flow rate is 6.5-10.0 mL/min.
7. The process according to claim 1, wherein the reaction temperature as a whole is-80 ℃ and the residence time of the reaction as a whole is 20 to 30 min.
8. The method according to claim 1 or 2, further comprising the following post-processing steps:
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 monitoring the product collected in the step 5) by GC, wherein the purity of the product is 80-90%.
9. An intermediate 2 having the structure:
wherein, R represents a substituent group which is any one or more of methyl, methoxy, halogen, alkyl, aryl, heteroaryl, alkoxy, amino, hydroxyl, trifluoromethyl and the like on any position except a bromine substituent on an aromatic ring.
10. An intermediate 3 having the structure:
wherein, R represents a substituent group which is any one or more of methyl, methoxy, halogen, alkyl, aryl, heteroaryl, alkoxy, amino, hydroxyl, trifluoromethyl and the like on any position except a bromine substituent on an aromatic ring.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210438652.8A CN114805019B (en) | 2022-04-25 | 2022-04-25 | Method for synthesizing 2-aryl-1-cyclohexanol based on continuous flow reaction technology |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210438652.8A CN114805019B (en) | 2022-04-25 | 2022-04-25 | Method for synthesizing 2-aryl-1-cyclohexanol based on continuous flow reaction technology |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114805019A true CN114805019A (en) | 2022-07-29 |
| CN114805019B CN114805019B (en) | 2024-03-12 |
Family
ID=82506792
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210438652.8A Active CN114805019B (en) | 2022-04-25 | 2022-04-25 | Method for synthesizing 2-aryl-1-cyclohexanol based on continuous flow reaction technology |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114805019B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116212764A (en) * | 2023-02-20 | 2023-06-06 | 上海荟银化学技术有限公司 | Method for industrially synthesizing 2, 2-diphenyl ethanol by using continuous flow equipment |
| CN116283506A (en) * | 2023-02-20 | 2023-06-23 | 上海荟银化学技术有限公司 | Method for preparing 3,4, 5-trifluorophenol based on continuous flow reaction technology |
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 |
|---|
| B. JURASEK ET AL.: "Synthesis of methoxetamine, its metabolites and deuterium labelled analog as analytical standards and their HPLC and chiral capillary electrophoresis separation", 《RSC ADV》, vol. 7, pages 56691 - 56696 * |
| LANCE T. LEPOVITZ ET AL.: "Diversity-Oriented Synthesis of Bioactive Azaspirocycles", 《TETRAHEDRON》, pages 1 - 10 * |
| NAVENDU JANA ET AL.: "Promoting Reductive Tandem Reactions of Nitrostyrenes with Mo(CO)6 and a Palladium Catalyst To Produce 3H‑Indoles", 《J. AM. CHEM. SOC》, vol. 137, pages 6738 - 6741 * |
| 鄢明: "铜盐催化氧化环己烯的开环加成反应", 化学通报, no. 06, 18 June 2004 (2004-06-18), pages 452 - 460 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116212764A (en) * | 2023-02-20 | 2023-06-06 | 上海荟银化学技术有限公司 | Method for industrially synthesizing 2, 2-diphenyl ethanol by using continuous flow equipment |
| CN116283506A (en) * | 2023-02-20 | 2023-06-23 | 上海荟银化学技术有限公司 | Method for preparing 3,4, 5-trifluorophenol based on continuous flow reaction technology |
| CN116212764B (en) * | 2023-02-20 | 2024-06-21 | 上海荟银化学技术有限公司 | Method for industrially synthesizing 2, 2-diphenyl ethanol by using continuous flow equipment |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114805019B (en) | 2024-03-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114805019B (en) | Method for synthesizing 2-aryl-1-cyclohexanol based on continuous flow reaction technology | |
| CN102924301B (en) | Preparation method of N,N-bis(2-hydroxyethyl)isopropanolamine | |
| US11708321B2 (en) | Method for preparing (dimethylaminomethylene) malononitrile using a micro reaction system | |
| CN109096328A (en) | A kind of method of the continuous synthesizing phosphorous acid diethylester of micro passage reaction | |
| CN107473949A (en) | A kind of synthesis technique of the pentanone of 3,5 dichloro 2 | |
| CN108409516A (en) | A kind of method of continuous current micro-reactor synthesis benzophenone derivates | |
| CN102304024B (en) | Method for synthesizing difluoroethanol | |
| CN108774189A (en) | Yi Zhong oxazine phenylate derivatives and preparation method thereof | |
| CN110382470B (en) | Preparation method of efavirenz | |
| CN110627754B (en) | Method for preparing 2-oxo-2-furyl acetic acid by using continuous flow microchannel reactor | |
| CN114702460B (en) | Method for synthesizing 2H-1, 3-oxazine compound by utilizing micro-channel reaction device | |
| CN103408413B (en) | Method for preparing deuterated chloroform by using hexachloroacetone as intermediate | |
| CN109485541B (en) | Method for preparing 1H,1H, 2H-perfluoro-1-octene | |
| CN106167459B (en) | A method of synthesis alkenyl thiocyanates derivative | |
| CN106045827B (en) | A kind of preparation method of arylprop ketone compounds | |
| CN105523915A (en) | Method for high-yield gas-phase catalytic cracking preparation of difluoroacetyl fluoride | |
| CN101328113A (en) | Industrialized production method of hexafluoroacetone | |
| CN113511954B (en) | Continuous flow preparation method of 1,2, 3-trichloropropane | |
| CN109970601A (en) | 2- (bicyclic [2.2.1] the hept- 2- subunit of 3,3- dimethyl) acetaldoxime-O- benzylic ether and preparation method | |
| CN108822060B (en) | 3-aryl substituted oxetane and preparation method thereof | |
| CN103880709B (en) | A kind of preparation method of the fluoro-2-butylene nitrile of 4,4,4-tri- | |
| CN103848756B (en) | Preparation method of teriflunomide and intermediate thereof | |
| CN102584905B (en) | Method for preparing chloromethyl methyl ether ferrocene | |
| CN115142077B (en) | Application of electrochemical microchannel reaction device in 1, 2-alkynyl migration reaction | |
| CN106748643A (en) | A kind of preparation method of 1 adamantanol |
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 |