CN114736098A - Chloro compound and preparation method thereof - Google Patents
Chloro compound and preparation method thereof Download PDFInfo
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- CN114736098A CN114736098A CN202111483420.6A CN202111483420A CN114736098A CN 114736098 A CN114736098 A CN 114736098A CN 202111483420 A CN202111483420 A CN 202111483420A CN 114736098 A CN114736098 A CN 114736098A
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- -1 Chloro compound Chemical class 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims abstract description 80
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- 239000005051 trimethylchlorosilane Substances 0.000 claims abstract description 34
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000012044 organic layer Substances 0.000 claims abstract description 16
- 239000010410 layer Substances 0.000 claims abstract description 15
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 claims abstract description 15
- 238000001035 drying Methods 0.000 claims abstract description 14
- 238000010438 heat treatment Methods 0.000 claims abstract description 12
- 238000012544 monitoring process Methods 0.000 claims abstract description 10
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229940073608 benzyl chloride Drugs 0.000 claims abstract description 8
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical compound C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 claims abstract description 7
- ZDVDCDLBOLSVGM-UHFFFAOYSA-N [chloro(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(Cl)C1=CC=CC=C1 ZDVDCDLBOLSVGM-UHFFFAOYSA-N 0.000 claims abstract description 4
- MBXXQYJBFRRFCK-UHFFFAOYSA-N benzyl fluoride Chemical compound FCC1=CC=CC=C1 MBXXQYJBFRRFCK-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 125000006182 dimethyl benzyl group Chemical group 0.000 claims abstract description 4
- 125000006178 methyl benzyl group Chemical group 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims abstract description 4
- 125000006493 trifluoromethyl benzyl group Chemical group 0.000 claims abstract description 4
- 125000000524 functional group Chemical group 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 85
- 238000003756 stirring Methods 0.000 claims description 19
- 238000000605 extraction Methods 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000005086 pumping Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 abstract description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 5
- 150000001298 alcohols Chemical class 0.000 abstract description 5
- 238000005660 chlorination reaction Methods 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 3
- 238000004440 column chromatography Methods 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract 2
- 239000001257 hydrogen Substances 0.000 abstract 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 abstract 1
- 150000002500 ions Chemical class 0.000 abstract 1
- 239000003153 chemical reaction reagent Substances 0.000 description 35
- 239000012295 chemical reaction liquid Substances 0.000 description 12
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 11
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- 238000001228 spectrum Methods 0.000 description 11
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 8
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 238000010586 diagram Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- CHMJJIHXWABUHA-UHFFFAOYSA-N 1-(chloromethyl)-2,3-dimethylbenzene Chemical compound CC1=CC=CC(CCl)=C1C CHMJJIHXWABUHA-UHFFFAOYSA-N 0.000 description 4
- KVOKEUYGMDGQSP-UHFFFAOYSA-N 1-(chloromethyl)-2-fluoro-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C(F)=C1 KVOKEUYGMDGQSP-UHFFFAOYSA-N 0.000 description 4
- XGASTRVQNVVYIZ-UHFFFAOYSA-N 1-(chloromethyl)-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(CCl)=C1 XGASTRVQNVVYIZ-UHFFFAOYSA-N 0.000 description 4
- IZXWCDITFDNEBY-UHFFFAOYSA-N 1-(chloromethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CCl)C=C1 IZXWCDITFDNEBY-UHFFFAOYSA-N 0.000 description 4
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 4
- DMHZDOTYAVHSEH-UHFFFAOYSA-N 1-(chloromethyl)-4-methylbenzene Chemical compound CC1=CC=C(CCl)C=C1 DMHZDOTYAVHSEH-UHFFFAOYSA-N 0.000 description 4
- JQZAEUFPPSRDOP-UHFFFAOYSA-N 1-chloro-4-(chloromethyl)benzene Chemical compound ClCC1=CC=C(Cl)C=C1 JQZAEUFPPSRDOP-UHFFFAOYSA-N 0.000 description 4
- MSHFRERJPWKJFX-UHFFFAOYSA-N 4-Methoxybenzyl alcohol Chemical compound COC1=CC=C(CO)C=C1 MSHFRERJPWKJFX-UHFFFAOYSA-N 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- GEZMEIHVFSWOCA-UHFFFAOYSA-N (4-fluorophenyl)methanol Chemical compound OCC1=CC=C(F)C=C1 GEZMEIHVFSWOCA-UHFFFAOYSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- AJYOOHCNOXWTKJ-UHFFFAOYSA-N p-Chlorobenzhydrol Chemical compound C=1C=C(Cl)C=CC=1C(O)C1=CC=CC=C1 AJYOOHCNOXWTKJ-UHFFFAOYSA-N 0.000 description 3
- ZQQIVMXQYUZKIQ-UHFFFAOYSA-N (2,3-dimethylphenyl)methanol Chemical compound CC1=CC=CC(CO)=C1C ZQQIVMXQYUZKIQ-UHFFFAOYSA-N 0.000 description 2
- AZYGOIQKPGPBTM-UHFFFAOYSA-N (2-fluoro-4-methoxyphenyl)methanol Chemical compound COC1=CC=C(CO)C(F)=C1 AZYGOIQKPGPBTM-UHFFFAOYSA-N 0.000 description 2
- PTHGDVCPCZKZKR-UHFFFAOYSA-N (4-chlorophenyl)methanol Chemical compound OCC1=CC=C(Cl)C=C1 PTHGDVCPCZKZKR-UHFFFAOYSA-N 0.000 description 2
- MCHDHQVROPEJJT-UHFFFAOYSA-N 1-(chloromethyl)-4-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=C(CCl)C=C1 MCHDHQVROPEJJT-UHFFFAOYSA-N 0.000 description 2
- MOOUWXDQAUXZRG-UHFFFAOYSA-N 4-(trifluoromethyl)benzyl alcohol Chemical compound OCC1=CC=C(C(F)(F)F)C=C1 MOOUWXDQAUXZRG-UHFFFAOYSA-N 0.000 description 2
- KMTDMTZBNYGUNX-UHFFFAOYSA-N 4-methylbenzyl alcohol Chemical compound CC1=CC=C(CO)C=C1 KMTDMTZBNYGUNX-UHFFFAOYSA-N 0.000 description 2
- BXEHKCUWIODEDE-UHFFFAOYSA-N [3-(trifluoromethyl)phenyl]methanol Chemical compound OCC1=CC=CC(C(F)(F)F)=C1 BXEHKCUWIODEDE-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- QILSFLSDHQAZET-UHFFFAOYSA-N diphenylmethanol Chemical compound C=1C=CC=CC=1C(O)C1=CC=CC=C1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- ALKWTKGPKKAZMN-UHFFFAOYSA-N 1-chloro-4-[chloro(phenyl)methyl]benzene Chemical compound C=1C=C(Cl)C=CC=1C(Cl)C1=CC=CC=C1 ALKWTKGPKKAZMN-UHFFFAOYSA-N 0.000 description 1
- YVBMXGVGOLXFFS-UHFFFAOYSA-N 6,8-dimethylbenzo[7]annulen-7-one Chemical compound C1=C(C)C(=O)C(C)=CC2=CC=CC=C21 YVBMXGVGOLXFFS-UHFFFAOYSA-N 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- DGUVYSKQPBATBX-UHFFFAOYSA-N benzylbenzene;hydrochloride Chemical compound Cl.C=1C=CC=CC=1CC1=CC=CC=C1 DGUVYSKQPBATBX-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- VOYMPSZBODLRKS-UHFFFAOYSA-N trimethylsilanylium Chemical compound C[Si+](C)C VOYMPSZBODLRKS-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B39/00—Halogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C22/00—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom
- C07C22/02—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings
- C07C22/04—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C22/00—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom
- C07C22/02—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings
- C07C22/04—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings containing six-membered aromatic rings
- C07C22/08—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings containing six-membered aromatic rings containing fluorine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
- C07C25/02—Monocyclic aromatic halogenated hydrocarbons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
- C07C25/02—Monocyclic aromatic halogenated hydrocarbons
- C07C25/13—Monocyclic aromatic halogenated hydrocarbons containing fluorine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
- C07C25/18—Polycyclic aromatic halogenated hydrocarbons
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
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Abstract
The invention provides a chloro compound and a preparation method thereof, wherein the preparation method comprises the following steps: mixing and heating an alcohol compound and trimethylchlorosilane to obtain a reaction solution, wherein a functional group in the alcohol compound is selected from benzyl, methoxybenzyl, methylbenzyl, benzyl chloride, trifluoromethylbenzyl, dimethylbenzyl, benzyl fluoride, chloro-diphenylmethane, fluoro-methoxybenzyl or diphenylmethane and the like; monitoring the reaction solution by liquid chromatography-mass spectrometry, extracting, separating liquid, extracting the water layer again, combining organic layers, and spin-drying; the trimethyl silicon positive ions in the trimethyl chlorosilane are equivalent to hydrogen ions with larger size, and the hydrogen ions are weaker in acidity relative to hydrochloric acid, but the reaction activity is not weakened, so that a great number of reactions which cannot use strong acid for chlorination can also safely, reliably and mildly generate chlorinated compounds from alcohol compounds, and the application range is enlarged; the preparation method disclosed by the invention is simple to operate, has no side reaction after reaction treatment, does not need column chromatography purification, and is high in yield, green and environment-friendly.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a chloro compound and a preparation method thereof.
Background
With the rapid development of the new drug research and development field in China, the demand potential for the types of chemical reagents is huge, and halogenated compounds, especially chlorinated compounds, play a significant role in the synthesis of medical molecules. The chloro-compound is an organic compound intermediate with wide application, is suitable for the construction of complex drug molecules, and has good application value in substitution reaction, rearrangement reaction, ring closure reaction, coupling reaction and the like.
The development of new synthetic methods for chlorinated compounds is also under constant optimization. Generally, the chlorination reaction is carried out by alcohol compounds, and because raw materials are easy to obtain, the alcohol compounds containing hydroxyl groups are the series with the highest abundance in the current organic compounds. The synthesis method of chlorinated compounds mainly uses thionyl chloride and other strong acidic reagents to chlorinate hydroxyl groups, but thionyl chloride is dangerous when used, hydrogen chloride gas harmful to human bodies and the environment can be released in reaction, and alkali used for the aftertreatment of reaction liquid can release a large amount of heat and acidic gas after quenching thionyl chloride, so that great danger exists. Meanwhile, for some compounds with acid sensitive groups, protection reaction must be carried out firstly, and then chlorination is carried out. Greatly increasing the complexity of the reaction. Meanwhile, along with the green chemical concept of atom economic efficiency and atom conversion utilization rate, a more environment-friendly method is required to replace the concept.
Disclosure of Invention
Aiming at the defects in the prior art, the invention mainly aims to provide a preparation method of a chlorinated compound.
It is a secondary object of the present invention to provide the above chlorinated compounds.
In order to achieve the above primary object, the solution of the present invention is:
a preparation method of a chlorinated compound comprises the following steps:
(1) mixing and heating an alcohol compound and trimethylchlorosilane, and stirring to obtain a reaction solution;
(2) and monitoring the reaction solution by liquid chromatography-mass spectrometry, adding water and ethyl acetate for extraction, separating liquid, extracting a water layer by ethyl acetate again, combining organic layers, drying, spin-drying, and pumping by an oil pump at room temperature to obtain the chlorinated compound.
Preferably, in step (1), the functional group in the alcohol compound is selected from one or more of benzyl, methoxybenzyl, methylbenzyl, benzyl chloride, trifluoromethylbenzyl, dimethylbenzyl, benzyl fluoride, chloro-diphenylmethane, fluoro-methoxybenzyl or diphenylmethane.
Preferably, in step (1), the heating temperature is 25-60 ℃.
Preferably, in the step (1), the stirring time is 1-16 h.
Preferably, in step (2), the temperature for spin-drying is 35-42 ℃.
Preferably, in the step (2), the extraction time is 5-10 h.
To achieve the above secondary object, the solution of the present invention is:
a chloro compound obtained by the preparation method.
Due to the adoption of the scheme, the invention has the beneficial effects that:
the trimethylsilyl cation in the trimethylchlorosilane is equivalent to a hydrogen ion with a larger size, is weaker in acidity than hydrochloric acid, but the reaction activity is not weakened, so that a great number of reactions which cannot use strong acid chlorination can safely, reliably and mildly generate chlorinated compounds from alcohol compounds, and the application range is enlarged. In addition, the preparation method disclosed by the invention is simple in operation and treatment, simple in post-reaction treatment, single in reaction mechanism, free of side reaction, free of column chromatography purification in post-treatment, high in yield, green and environment-friendly, and accords with the concept of modern organic chemistry development.
Drawings
FIG. 1 is a NMR spectrum of benzyl chloride in example 1 of the present invention.
FIG. 2 is a GCMS diagram of benzyl chloride in example 1 of the present invention.
FIG. 3 is the NMR spectrum of 4-methoxybenzyl chloride in example 2 of the present invention.
FIG. 4 is a GCMS chart of 4-methoxybenzyl chloride in example 2 of the present invention.
FIG. 5 is the NMR spectrum of 4-methylbenzyl chloride in example 3 of the present invention.
FIG. 6 is a GCMS plot of 4-methylbenzyl chloride in example 3 of the present invention.
FIG. 7 is the NMR spectrum of 4-chlorobenzyl chloride in example 4 of the present invention.
FIG. 8 is a GCMS diagram of 4-chlorobenzyl chloride in example 4 of the present invention.
FIG. 9 shows the NMR spectrum of 3-trifluoromethylbenzyl chloride in example 5 of the present invention.
FIG. 10 is a GCMS diagram of 3-trifluoromethylbenzyl chloride in example 5 of the present invention.
FIG. 11 is a NMR chart of 4- (trifluoromethyl) chlorobenzyl in example 6 of the present invention.
FIG. 12 is a GCMS plot of 4- (trifluoromethyl) chlorobenzyl in example 6 of this invention.
FIG. 13 is a NMR spectrum of 2, 3-dimethylbenzyl chloride in example 7 of the present invention.
FIG. 14 is a GCMS plot of 2, 3-dimethylbenzyl chloride in example 7 of the present invention.
FIG. 15 is a NMR spectrum of 4-fluorobenzyl chloride in example 8 of the present invention.
FIG. 16 is a GCMS diagram of 4-fluorobenzyl chloride in example 8 of the present invention.
FIG. 17 is a NMR chart of 4-chlorobenzhydryl chloride in example 9 of the present invention.
FIG. 18 is a GCMS diagram of 4-chlorodiphenylchloromethane in example 9 of the present invention.
FIG. 19 is a NMR spectrum of 2-fluoro-4-methoxybenzyl chloride in example 10 of the present invention.
FIG. 20 shows the GCMS pattern of 2-fluoro-4-methoxybenzyl chloride in example 10 of the present invention.
FIG. 21 is a NMR chart of diphenylmethane chloride in example 11.
FIG. 22 is a GCMS diagram of chlorinated diphenylmethane in example 11 of the present invention.
Detailed Description
The invention provides a chloro compound and a preparation method thereof.
< method for producing chlorinated Compound >
The reaction formula of the preparation method of the chloro compound is as follows:
wherein R is selected from more than one of benzyl, methoxybenzyl, methylbenzyl, benzyl chloride, trifluoromethyl benzyl, dimethylbenzyl, benzyl fluoride, chloro-diphenylmethane, fluoro-methoxybenzyl or diphenylmethane.
The method specifically comprises the following steps:
(1) adding 1.0eq alcohol compound into a bottle, then adding 5.0eq trimethylchlorosilane (TMSCl), mixing and heating, and stirring to obtain a reaction solution;
(2) and monitoring the reaction solution by liquid chromatography-mass spectrometry, adding water and ethyl acetate for extraction, separating liquid, extracting a water layer by ethyl acetate again, combining organic layers, drying, spin-drying, and finally extracting by an oil pump at room temperature to obtain the chlorinated compound, wherein the yield is 85-95% and the purity is 95-98%.
Wherein, in the step (1), the trimethylchlorosilane is used as a solvent and a reactant; and has mild property. The amount of the added trimethylchlorosilane depends on the speed of the reaction and the dissolution degree of alcohol compounds in the system, and if a large amount of raw materials are input, the amount of the trimethylchlorosilane can be properly reduced. When the molar mass of the alcohol compound is large, the relative mass decreases by charging 5 equivalents (eq.) of trimethylchlorosilane. The molar ratio of trimethylchlorosilane to the alcohol compound can be limited to 4 to 8, i.e., the amount of trimethylchlorosilane to be charged is 4 to 8eq.
In step (1), the heating temperature may be 25 to 60 ℃, preferably 25 ℃. Because the heating energy accelerates the collision among molecules in the reaction system, the reaction process is accelerated.
In step (1), the stirring time may be 1 to 16 hours, preferably 2 hours.
In step (2), the work-up requires only a simple extraction with ethyl acetate to give the pure product, while other impurities are dissolved in the aqueous phase.
< chlorinated Compound >
The chlorinated compound of the present invention is obtained by the above-mentioned preparation method.
In fact, the chlorinated compound of the invention may be specifically of the following structural formula:
the technical content of the present invention will be further described with reference to examples. The following examples are illustrative and not intended to be limiting, and are not intended to limit the scope of the invention. The experimental procedures used in the following examples are all conventional procedures unless otherwise specified. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1:
the preparation method of benzyl chloride of this example includes the following steps:
(1) 20g of benzyl alcohol is weighed and added into a 250mL single-neck bottle, 100.5g of trimethylchlorosilane (TMSCl) is added and stirred, then the mixture is heated to 25 ℃, and stirring is continued for 2 hours, so as to obtain reaction liquid.
(2) After the LC-MS monitoring reaction liquid is finished, 100mL of water and 100mL of ethyl acetate are added for extraction, liquid separation is carried out, an aqueous layer is extracted again by using ethyl acetate 50mLx2, organic layers are combined, and spin drying is carried out to obtain 22g of benzyl chloride as colorless transparent liquid, the yield is 94%, and the purity is 98%. The details of the reaction reagents are shown in Table 1. The spectra are shown in FIGS. 1 and 2.
Wherein the reaction equation is as follows:
TABLE 1 parameters of the reagents
| Reagent | Molecular formula | Molecular weight | Feed amount | Batch charging ratio |
| Benzyl alcohol | C7H8O | 108.14 | 20g | 1.0eq. |
| Trimethylchlorosilane | C3H9ClSi | 108.64 | 100.5g | 5.0eq. |
Example 2:
the preparation method of 4-methoxybenzyl chloride of this example includes the following steps:
(1) weighing 10g of 4-methoxybenzyl alcohol, adding into a 100mL single-neck bottle, adding 39.4g of trimethylchlorosilane (TMSCl), stirring, heating to 50 ℃, and continuously stirring for 6 hours to obtain a reaction solution.
(2) After the LC-MS monitoring reaction liquid is finished, 100mL of water and 100mL of ethyl acetate are added for extraction, liquid separation is carried out, an aqueous layer is extracted again by using ethyl acetate 50mLx2, organic layers are combined, and the obtained 4-methoxybenzyl chloride is colorless transparent liquid after rotary drying, the yield is 89%, and the purity is 97%. The details of the reaction reagents are shown in Table 2. The spectra are shown in FIGS. 3 and 4.
Wherein the reaction equation is as follows:
TABLE 2 parameters of the reagents
| Reagent | Molecular formula | Molecular weight | Feed amount | Batch charging ratio |
| 4-methoxy benzyl alcohol | C8H10O2 | 138.16 | 10g | 1.0eq. |
| Trimethylchlorosilane | C3H9ClSi | 108.64 | 39.4g | 5.0eq. |
Example 3:
the preparation method of 4-methylbenzyl chloride of this example includes the following steps:
(1) 50g of 4-methylbenzyl alcohol is weighed and added into a 500mL single-neck bottle, 220g of trimethylchlorosilane (TMSCl) is added and stirred, then the mixture is heated to 45 ℃, and stirring is continued for 16 hours, so that reaction liquid is obtained.
(2) After the LC-MS monitoring reaction liquid is finished, 200mL of water and 200mL of ethyl acetate are added for extraction, liquid separation is carried out, an aqueous layer is extracted again by using ethyl acetate 100mLx2, organic layers are combined, and the organic layers are dried in a spinning mode to obtain 54g of 4-methylbenzyl chloride which is colorless or light yellow transparent liquid, the yield is 95%, and the purity is 98%. The details of the reaction reagents are shown in Table 3. The spectra are shown in FIGS. 5 and 6.
Wherein the reaction equation is as follows:
TABLE 3 parameters of the reagents
| Reagent | Molecular formula | Molecular weight | Feed amount | Batch charging ratio |
| 4-methylbenzyl alcohol | C8H10O | 122.16 | 50g | 1.0eq. |
| Trimethylchlorosilane | C3H9ClSi | 108.64 | 220g | 5.0eq. |
Example 4:
the preparation method of 4-chlorobenzyl chloride of this example comprises the following steps:
(1) 20g of p-chlorobenzyl alcohol is weighed and added into a 250mL single-mouth bottle, 76.2g of trimethylchlorosilane (TMSCl) is added and stirred, then the mixture is heated to 60 ℃ and stirred continuously for 5 hours, and reaction liquid is obtained.
(2) After the LC-MS monitoring reaction liquid is finished, 100mL of water and 100mL of ethyl acetate are added for extraction, liquid separation is carried out, an aqueous layer is extracted again by using ethyl acetate 80mLx2, organic layers are combined, and spin drying is carried out to obtain 20g of 4-chlorobenzyl chloride as colorless transparent liquid, the yield is 89%, and the purity is 95%. The details of the reaction reagents are shown in Table 4. The spectra are shown in FIGS. 7 and 8.
Wherein the reaction equation is as follows:
TABLE 4 parameters of the reagents
| Reagent | Molecular formula | Molecular weight | Feed amount | Batch charging ratio |
| P-chlorobenzyl alcohol | C7H7ClO | 142.58 | 20g | 1.0eq. |
| Trimethylchlorosilane | C3H9ClSi | 108.64 | 76.2g | 5.0eq. |
Example 5:
the preparation method of 3-trifluoromethyl benzyl chloride of this example includes the following steps:
(1) 10g of 3-trifluoromethylbenzyl alcohol is weighed and added into a 100mL single-neck bottle, 32g of trimethylchlorosilane (TMSCl) is added and stirred, then the mixture is heated to 55 ℃, and stirring is continued for 6 hours, so as to obtain a reaction solution.
(2) After the reaction solution was monitored by LC-MS, 100mL of water and 100mL of ethyl acetate were added for extraction, liquid separation was performed, the aqueous layer was extracted again with ethyl acetate 50mL of X2, the organic layers were combined, and spin-dried to obtain 10.3g of 3-trifluoromethyl benzyl chloride as a colorless transparent liquid with a yield of 93% and a purity of 95%. Details of the reaction reagents are shown in Table 5. The spectra are shown in FIGS. 9 and 10.
Wherein the reaction equation is as follows:
TABLE 5 parameters of the reagents
| Reagent | Molecular formula | Molecular weight | Feed amount | Batch charging ratio |
| 3-trifluoromethyl benzyl alcohol | C8H7F3O | 176.14 | 10g | 1.0eq. |
| Trimethylchlorosilane | C3H9ClSi | 108.64 | 32g | 5.0eq. |
Example 6:
the preparation method of 4- (trifluoromethyl) benzyl chloride of the embodiment comprises the following steps:
(1) 10g of p-trifluoromethylbenzyl alcohol was weighed and added into a 100mL single-neck flask, and 32g of trimethylchlorosilane (TMSCl) was added and stirred, and then heated to 55 ℃ and stirred continuously for 6 hours to obtain a reaction solution.
(2) After the LC-MS monitoring reaction liquid is finished, 100mL of water and 100mL of ethyl acetate are added for extraction, liquid separation is carried out, an aqueous layer is extracted again by using ethyl acetate 50mLx2, organic layers are combined, and spin drying is carried out to obtain 10g of 4- (trifluoromethyl) benzyl chloride as a colorless transparent liquid, the yield is 90%, and the purity is 98%. Details of the reaction reagents are shown in Table 6. The spectra are shown in FIGS. 11 and 12.
Wherein the reaction equation is as follows:
TABLE 6 parameters of the reagents
| Reagent | Molecular formula | Molecular weight | Feed amount | Batch charging ratio |
| P-trifluoromethyl benzyl alcohol | C8H7F3O | 176.14 | 10g | 1.0eq. |
| Trimethylchlorosilane | C3H9ClSi | 108.64 | 32g | 5.0eq. |
Example 7:
the preparation method of 2, 3-dimethylbenzyl chloride of the embodiment comprises the following steps:
(1) 30g of 2, 3-dimethylbenzyl alcohol is weighed and added into a 500mL single-mouth bottle, 120g of trimethylchlorosilane (TMSCl) is added and stirred, then the mixture is heated to 30 ℃, and stirring is continued for 3 hours, so as to obtain reaction liquid.
(2) After the LC-MS monitoring reaction liquid is finished, 200mL of water and 200mL of ethyl acetate are added for extraction, liquid separation is carried out, an aqueous layer is extracted again by using ethyl acetate 80mLx2, organic layers are combined, and spin drying is carried out to obtain 29g of 2, 3-dimethylbenzyl chloride as white solid powder, the yield is 85%, and the purity is 97%. Details of the reaction reagents are shown in Table 7. The spectra are shown in FIGS. 13 and 14.
Wherein the reaction equation is as follows:
TABLE 7 parameters of the reagents
| Reagent | Molecular formula | Molecular weight | Feed amount | |
| 2, 3-dimethyl benzyl alcohol | C9H12O | 136.19 | 30g | 1.0eq. |
| Trimethylchlorosilane | C3H9ClSi | 108.64 | 120g | 5.0eq. |
Example 8:
the preparation method of 4-fluorobenzyl chloride of the present example comprises the following steps:
(1) weighing 15g of p-fluorobenzyl alcohol, adding the p-fluorobenzyl alcohol into a 250mL single-neck bottle, adding 65g of trimethylchlorosilane (TMSCl), stirring, heating to 45 ℃, and continuously stirring for 5 hours to obtain a reaction solution.
(2) After the reaction solution was monitored by LC-MS, 150mL of water and 100mL of ethyl acetate were added for extraction, liquid separation was performed, the aqueous layer was extracted again with ethyl acetate 80mL of X2, the organic layers were combined, and spin-dried to obtain 15g of 4-fluorobenzyl chloride as a colorless transparent liquid with a yield of 88% and a purity of 98%. Details of the reaction reagents are shown in Table 8. The spectra are shown in FIGS. 15 and 16.
Wherein the reaction equation is as follows:
TABLE 8 parameters of the reagents
| Reagent | Molecular formula | Molecular weight | Feed amount | Batch charging ratio |
| P-fluorobenzyl alcohol | C7H7FO | 126.13 | 15g | 1.0eq. |
| Trimethylchlorosilane | C3H9ClSi | 108.64 | 65g | 5.0eq. |
Example 9:
the preparation method of 4-chlorodiphenylchloromethane of this example includes the following steps:
(1) weighing 20g of 4-chlorobenzhydrol, adding the 4-chlorobenzhydrol into a 250mL single-neck bottle, adding 50g of trimethylchlorosilane (TMSCl), stirring, heating to 60 ℃, and continuously stirring for 15 hours to obtain a reaction solution.
(2) After the reaction solution was monitored by LC-MS, 150mL of water and 150mL of ethyl acetate were added for extraction, liquid separation was performed, the water layer was extracted again with ethyl acetate 80mLx2, the organic layers were combined, and spin-dried to give 18.8g of 4-chlorodiphenylchloromethane as a colorless to pale yellow liquid with a yield of 87% and a purity of 95%. The details of the reaction reagents are shown in Table 9. The spectra are shown in FIGS. 17 and 18.
Wherein the reaction equation is as follows:
TABLE 9 parameters of the reagents
| Reagent | Molecular formula | Molecular weight | Feed amount | Batch charging ratio |
| 4-Chlorodiphenylmethanol | C13H11ClO | 218.68 | 20g | 1.0eq. |
| Trimethylchlorosilane | C3H9ClSi | 108.64 | 50g | 5.0eq. |
Example 10:
the preparation method of 2-fluoro-4-methoxybenzyl chloride of this example includes the following steps:
(1) weighing 10g of 2-fluoro-4-methoxybenzyl alcohol, adding into a 100mL single-neck bottle, adding 35g of trimethylchlorosilane (TMSCl), stirring, heating to 45 ℃, and continuously stirring for 5 hours to obtain a reaction solution.
(2) After the reaction solution was monitored by LC-MS, 100mL of water and 100mL of ethyl acetate were added for extraction, liquid separation was performed, the water layer was extracted again with ethyl acetate 50mL of X2, the organic layers were combined, and spin-dried to obtain 10.1g of 2-fluoro-4-methoxybenzyl chloride as a colorless transparent liquid with a yield of 90% and a purity of 96%. The details of the reaction reagents are shown in Table 10. The spectra are shown in FIGS. 19 and 20.
Wherein the reaction equation is as follows:
TABLE 10 parameters of the reagents
| Reagent | Molecular formula | Molecular weight | Feed amount | Batch charging ratio |
| 2-fluoro-4-methoxybenzyl alcohol | C8H9FO2 | 156.15 | 10g | 1.0eq. |
| Trimethylchlorosilane | C3H9ClSi | 108.64 | 35g | 5.0eq. |
Example 11:
the preparation method of chlorinated diphenylmethane of this example includes the following steps:
(1) 30g of benzhydrol is weighed and added into a 2500mL single-neck bottle, 90g of trimethylchlorosilane (TMSCl) is added and stirred, then the mixture is heated to 50 ℃, and stirring is continued for 3 hours, so as to obtain reaction liquid.
(2) After the reaction solution was monitored by LC-MS, 200mL of water and 150mL of ethyl acetate were added for extraction, liquid separation was performed, the aqueous layer was extracted again with ethyl acetate 100mL of X2, the organic layers were combined, and spin-dried to obtain 29.5g of chlorinated diphenylmethane as a pale yellow transparent liquid with a yield of 89% and a purity of 97%. The details of the reaction reagents are shown in Table 11. The spectra are shown in FIGS. 21 and 22.
Wherein the reaction equation is as follows:
TABLE 11 parameters of the reagents
| Reagent | Molecular formula | Molecular weight | Feed amount | Batch charging ratio |
| Diphenyl carbinols | C13H12O | 184.23 | 30g | 1.0eq. |
| Trimethylchlorosilane | C3H9ClSi | 108.64 | 90g | 5.0eq. |
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. It will be readily apparent to those skilled in the art that various modifications to these embodiments and the generic principles defined herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments. Those skilled in the art should appreciate that many modifications and variations are possible in light of the above teaching without departing from the scope of the invention.
Claims (7)
1. A preparation method of chlorinated compounds is characterized in that: the method comprises the following steps:
(1) mixing and heating an alcohol compound and trimethylchlorosilane, and stirring to obtain a reaction solution;
(2) and monitoring the reaction solution by liquid chromatography-mass spectrometry, adding water and extracting with ethyl acetate, separating the solution, extracting the water layer with ethyl acetate again, combining the organic layers, drying, spin-drying, and pumping by an oil pump at room temperature to obtain the chlorinated compound.
2. The method for preparing chlorinated compounds according to claim 1, characterized in that: in the step (1), the functional group in the alcohol compound is selected from one or more of benzyl, methoxybenzyl, methylbenzyl, benzyl chloride, trifluoromethyl benzyl, dimethyl benzyl, benzyl fluoride, chloro-diphenylmethane, fluoro-methoxybenzyl or diphenylmethane.
3. The method for preparing chlorinated compounds according to claim 1, characterized in that: in the step (1), the heating temperature is 25-60 ℃.
4. The method for preparing chlorinated compounds according to claim 1, characterized in that: in the step (1), the stirring time is 1-16 h.
5. The method for preparing chlorinated compounds according to claim 1, characterized in that: in the step (2), the temperature of the spin drying is 35-42 ℃.
6. The method for preparing chlorinated compounds according to claim 1, characterized in that: in the step (2), the extraction time is 5-10 h.
7. A chlorinated compound characterized by: which is obtained by the production method according to any one of claims 1 to 6.
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| CN108473438A (en) * | 2015-09-25 | 2018-08-31 | 耶鲁大学 | The fully synthetic and thus obtained compound of Glucosepane |
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| CN102690175A (en) * | 2012-06-18 | 2012-09-26 | 潍坊杜得利化学工业有限公司 | Preparation method of 3-methoxybenzyl chloride |
| CN103113193A (en) * | 2013-03-05 | 2013-05-22 | 华东师范大学 | Synthetic method of 2-chlorine-5-trifluoromethyl benzyl alcohol |
| CN108473438A (en) * | 2015-09-25 | 2018-08-31 | 耶鲁大学 | The fully synthetic and thus obtained compound of Glucosepane |
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