CN116836046A - Novel synthesis process of 4-biphenyl formaldehyde - Google Patents
Novel synthesis process of 4-biphenyl formaldehyde Download PDFInfo
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- CN116836046A CN116836046A CN202310604319.4A CN202310604319A CN116836046A CN 116836046 A CN116836046 A CN 116836046A CN 202310604319 A CN202310604319 A CN 202310604319A CN 116836046 A CN116836046 A CN 116836046A
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- 238000000034 method Methods 0.000 title claims abstract description 42
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 title claims abstract description 18
- 230000015572 biosynthetic process Effects 0.000 title abstract description 10
- 238000003786 synthesis reaction Methods 0.000 title abstract description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 93
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims abstract description 70
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 66
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims abstract description 60
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims abstract description 48
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 claims abstract description 33
- IWCVDCOJSPWGRW-UHFFFAOYSA-M magnesium;benzene;chloride Chemical compound [Mg+2].[Cl-].C1=CC=[C-]C=C1 IWCVDCOJSPWGRW-UHFFFAOYSA-M 0.000 claims abstract description 27
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims abstract description 24
- 230000018044 dehydration Effects 0.000 claims abstract description 19
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 19
- 239000004305 biphenyl Substances 0.000 claims abstract description 17
- 235000010290 biphenyl Nutrition 0.000 claims abstract description 17
- LMVCINGLGLOSPM-UHFFFAOYSA-N 2-(4-chlorophenyl)-1,3-dioxane Chemical compound C1=CC(Cl)=CC=C1C1OCCCO1 LMVCINGLGLOSPM-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 14
- -1 biphenyl acetal Chemical class 0.000 claims abstract description 13
- ISDBWOPVZKNQDW-UHFFFAOYSA-N 4-phenylbenzaldehyde Chemical compound C1=CC(C=O)=CC=C1C1=CC=CC=C1 ISDBWOPVZKNQDW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000002378 acidificating effect Effects 0.000 claims abstract description 8
- 125000003172 aldehyde group Chemical group 0.000 claims abstract description 8
- 239000007858 starting material Substances 0.000 claims abstract description 7
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 6
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 239000002841 Lewis acid Substances 0.000 claims abstract description 4
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 4
- 238000010511 deprotection reaction Methods 0.000 claims abstract 2
- 230000007062 hydrolysis Effects 0.000 claims abstract 2
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 117
- 230000002194 synthesizing effect Effects 0.000 claims description 19
- 229910021380 Manganese Chloride Inorganic materials 0.000 claims description 10
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 claims description 10
- 239000011565 manganese chloride Substances 0.000 claims description 10
- 235000002867 manganese chloride Nutrition 0.000 claims description 10
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 8
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000011592 zinc chloride Substances 0.000 claims description 4
- 235000005074 zinc chloride Nutrition 0.000 claims description 4
- 239000011968 lewis acid catalyst Substances 0.000 claims description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- 235000011147 magnesium chloride Nutrition 0.000 claims description 3
- 229940099607 manganese chloride Drugs 0.000 claims description 3
- LCRCBXLHWTVPEQ-UHFFFAOYSA-N 2-phenylbenzaldehyde Chemical compound O=CC1=CC=CC=C1C1=CC=CC=C1 LCRCBXLHWTVPEQ-UHFFFAOYSA-N 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 72
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 72
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- 239000012074 organic phase Substances 0.000 description 45
- 239000007788 liquid Substances 0.000 description 36
- 239000000243 solution Substances 0.000 description 34
- 238000003756 stirring Methods 0.000 description 33
- 238000010992 reflux Methods 0.000 description 28
- 239000002904 solvent Substances 0.000 description 26
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 26
- 238000010438 heat treatment Methods 0.000 description 25
- 239000000203 mixture Substances 0.000 description 25
- 238000001816 cooling Methods 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 24
- 230000007935 neutral effect Effects 0.000 description 24
- 239000008346 aqueous phase Substances 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 238000004809 thin layer chromatography Methods 0.000 description 18
- 239000012141 concentrate Substances 0.000 description 12
- 238000004821 distillation Methods 0.000 description 12
- 238000000605 extraction Methods 0.000 description 12
- 239000012071 phase Substances 0.000 description 12
- 238000005292 vacuum distillation Methods 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 239000012299 nitrogen atmosphere Substances 0.000 description 9
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 9
- 238000006467 substitution reaction Methods 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 230000003301 hydrolyzing effect Effects 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- GBVSONMCEKNESD-UHFFFAOYSA-N 1,1'-biphenyl;lithium Chemical compound [Li].C1=CC=CC=C1C1=CC=CC=C1 GBVSONMCEKNESD-UHFFFAOYSA-N 0.000 description 1
- AWEMQEXISNJHBN-UHFFFAOYSA-N 1,1'-biphenyl;magnesium Chemical compound [Mg].C1=CC=CC=C1C1=CC=CC=C1 AWEMQEXISNJHBN-UHFFFAOYSA-N 0.000 description 1
- PKJBWOWQJHHAHG-UHFFFAOYSA-N 1-bromo-4-phenylbenzene Chemical group C1=CC(Br)=CC=C1C1=CC=CC=C1 PKJBWOWQJHHAHG-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- NOKUWSXLHXMAOM-UHFFFAOYSA-N hydroxy(phenyl)silicon Chemical class O[Si]C1=CC=CC=C1 NOKUWSXLHXMAOM-UHFFFAOYSA-N 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- ODOPKAJVFRHHGM-UHFFFAOYSA-N phenyltin Chemical compound [Sn]C1=CC=CC=C1 ODOPKAJVFRHHGM-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/42—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydrolysis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/12—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/16—Radicals substituted by halogen atoms or nitro radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a novel synthesis process of 4-biphenylformaldehyde, which belongs to the technical field of biphenylformaldehyde preparation, and the specific scheme comprises the following two steps: adopting p-chlorobenzaldehyde as a starting material, adopting glycol as an aldehyde group protecting reagent, and adopting trimethyl orthoformate dehydration process or a water knockout drum dehydration process to synthesize an acetal intermediate (2- (4-chlorophenyl) -1, 3-dioxane); the phenyl magnesium chloride and the acetal intermediate form a biphenyl acetal intermediate under the action of Lewis acid, and finally, formyl is released by hydrolysis and deprotection under the acidic condition, so that the 4-biphenyl formaldehyde with high yield and purity is prepared.
Description
Technical Field
The invention relates to the technical field related to biphenyl formaldehyde, in particular to a novel synthesis process of 4-biphenyl formaldehyde.
Background
The 4-biphenyl formaldehyde can show special physical and chemical properties due to the inherent conjugated structure, so the 4-biphenyl formaldehyde is widely applied to the fields of medicines, pesticides, photovoltaic materials, liquid crystal materials, dyes and the like, has important industrial application value, the synthesis method of the 4-biphenyl formaldehyde is focused in academia and industry, and the current synthesis method of the 4-biphenyl formaldehyde comprises the following steps:
1. the main raw materials of the method are p-halobenzaldehyde, phenylboric acid, phenyltin reagent, phenylsiloxane, grignard reagent and the like, and divalent or zero-valent palladium is used as a catalyst to synthesize biphenyl under alkaline conditions. The metal palladium catalyst used by the method is high in price and relatively large in dosage, and is not beneficial to industrial production and application. The specific synthetic route is
2. The second synthesis process directly uses biphenyl as a starting material to synthesize 4-biphenyl formaldehyde, wherein the biphenyl is brominated by liquid bromine to obtain a 4-bromobiphenyl intermediate, then a biphenyl magnesium reagent or a biphenyl lithium reagent is synthesized by Grignard reaction or lithium halogen exchange reaction, finally aldehyde group is introduced by reaction with N, N-Dimethylformamide (DMF), and finally 4-biphenyl formaldehyde is synthesized. The process uses biphenyl as a starting material, avoids the use of a noble metal catalyst, reduces the production cost to a certain extent, but has higher price of a lithium reagent, has severe synthesis conditions of the biphenyl-based metal reagent and unobvious yield of the reaction with DMF, and has certain difficulty in industrial production and application due to the reasons.
The synthesis process of 4-biphenyl formaldehyde with biphenyl as initial material
Therefore, the invention aims to provide a novel synthesis method of 4-biphenyl formaldehyde, which has the advantages of mild reaction conditions, low cost and high yield.
Disclosure of Invention
The invention aims to provide a novel process for synthesizing 4-biphenyl formaldehyde, which takes p-chlorobenzaldehyde as an initial raw material, adopts glycol as an aldehyde group protection reagent, and synthesizes an acetal intermediate by heating and refluxing under an acidic condition; and (3) forming a biphenyl acetal intermediate by using phenyl magnesium chloride and the acetal intermediate under the action of Lewis acid, and finally hydrolyzing and deprotecting to release formyl under an acidic condition to obtain the 4-biphenyl formaldehyde.
In order to achieve the above purpose, the present invention provides the following technical solutions: a preparation process of 4-biphenyl formaldehyde comprises the following two steps:
adopting p-chlorobenzaldehyde as a starting material, adopting glycol as an aldehyde group protecting reagent, and adopting trimethyl orthoformate dehydration process or a water knockout drum dehydration process to synthesize an acetal intermediate (2- (4-chlorophenyl) -1, 3-dioxane);
and finally, hydrolyzing and deprotecting the phenyl magnesium chloride and the acetal intermediate under the acidic condition to release formyl groups to prepare the 4-biphenyl formaldehyde.
Further, in the process for synthesizing the acetal intermediate by dehydrating trimethyl orthoformate, the molar ratio of p-chlorobenzaldehyde, ethylene glycol, trimethyl orthoformate and trifluoromethanesulfonic acid is 1: (1.1-10): (1.1-4): 0.1.
further, the process for synthesizing the acetal intermediate by dehydrating trimethyl orthoformate is adopted, and the reaction temperature is 30-110 ℃.
Further, in the process of synthesizing the acetal intermediate by dehydration through a water separator, the molar ratio of p-chlorobenzaldehyde, ethylene glycol and trifluoromethanesulfonic acid is 1: (1.1-3): 0.1.
further, the reaction temperature of the process for synthesizing the acetal intermediate by dehydration through a water separator is 50-130 ℃.
Further, the Lewis acid catalyst used for the reaction of the phenylmagnesium chloride and the acetal intermediate is one of zinc chloride, manganese chloride and magnesium chloride.
Further, the phenyl magnesium chloride reacts with the acetal intermediate to form a biphenyl acetal intermediate, the molar ratio between the 2- (4-chlorophenyl) -1, 3-dioxane, the phenyl magnesium chloride and the catalyst being 1: (1.05-2): (0-0.05).
Further, phenylmagnesium chloride reacts with the acetal intermediate to form a biphenyl acetal intermediate at a reaction temperature of-5 to 50 ℃.
The beneficial effects are that:
compared with synthesizing biphenyl metal reagent, the invention has milder generating condition and looser reaction condition. The p-chlorobenzaldehyde is adopted as the initial raw material, the ethylene glycol is adopted as the aldehyde group protecting reagent, the raw material cost is low, the dehydration process is relatively simple in operation, and the industrial production is facilitated.
Detailed Description
All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In the description of the present invention, it should be noted that the directions or positional relationships indicated by the terms "upper", "lower", "inner", "outer", "front", "rear", "both ends", "one end", "the other end", etc. are based on the directions or positional relationships shown in the drawings, are merely for convenience of describing the present invention and simplifying the description, and do not indicate or imply that the devices or elements referred to must have a specific direction, be configured and operated in the specific direction, and thus should not be construed as limiting the present invention. Furthermore, the terms "first," "second," and the like, are used for descriptive purposes only and are not to be construed as indicating or implying relative importance.
In the description of the present invention, it should be noted that, unless explicitly specified and limited otherwise, the terms "mounted," "provided," "connected," and the like are to be construed broadly, and may be fixedly connected, detachably connected, or integrally connected, for example; can be mechanically or electrically connected; can be directly connected or indirectly connected through an intermediate medium, and can be communication between two elements. The specific meaning of the above terms in the present invention will be understood in specific cases by those of ordinary skill in the art.
Referring to the drawings, an embodiment of the present invention is: taking p-chlorobenzaldehyde as a starting material, adopting glycol as an aldehyde group protecting reagent, and heating and refluxing under an acidic condition to synthesize an acetal intermediate; and (3) forming a biphenyl acetal intermediate by using phenyl magnesium chloride and the acetal intermediate under the action of Lewis acid, and finally hydrolyzing and deprotecting to release formyl under an acidic condition to obtain the 4-biphenyl formaldehyde. The synthetic route is as follows:
a preparation process of 4-biphenyl formaldehyde comprises the following two steps:
adopting p-chlorobenzaldehyde as a starting material, adopting glycol as an aldehyde group protecting reagent, and adopting trimethyl orthoformate dehydration process or a water knockout drum dehydration process to synthesize an acetal intermediate (2- (4-chlorophenyl) -1, 3-dioxane);
and finally, hydrolyzing and deprotecting the phenyl magnesium chloride and the acetal intermediate under the acidic condition to release formyl groups to prepare the 4-biphenyl formaldehyde.
The process for synthesizing the acetal intermediate by adopting trimethyl orthoformate dehydration comprises the following steps of: (1.1-10): (1.1-4): 0.1.
the process for synthesizing the acetal intermediate by dehydrating trimethyl orthoformate is adopted, and the reaction temperature is 30-110 ℃.
The process for synthesizing the acetal intermediate by dehydration through a water separator comprises the following steps of: (1.1-3): 0.1.
the process for synthesizing the acetal intermediate by dehydration through a water separator has the reaction temperature of 50-130 ℃.
The Lewis acid catalyst used for the reaction of the phenyl magnesium chloride and the acetal intermediate is one of zinc chloride, manganese chloride and magnesium chloride.
The phenyl magnesium chloride reacts with the acetal intermediate to form a biphenyl acetal intermediate, the molar ratio between the 2- (4-chlorophenyl) -1, 3-dioxane, the phenyl magnesium chloride and the catalyst being 1: (1.05-2): (0-0.05).
Phenyl magnesium chloride reacts with the acetal intermediate to form a biphenyl acetal intermediate at a reaction temperature of-5 to 50 ℃.
Synthesis process 1 of acetal intermediate (trimethyl orthoformate is used as dehydration reagent)
Process for synthesizing acetal intermediate
Example 1
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (124 g), and trimethyl orthoformate (84.8 g). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, and heating to reflux reaction for 5h after the dripping is finished. And after the reaction is finished, the solvent is distilled and recovered under reduced pressure, and the recovered liquid is used for the next batch of reaction. After concentrating to near dryness, the concentrate temperature was controlled below 5 ℃ and PH was adjusted to neutral (ph=7) with 20% sodium hydroxide solution. Extraction with ethyl acetate three times, in amounts of (100mL+50mL+50mL), respectively, concentrating the combined organic phases to an oil, high vacuum distillation at 130℃and collection of the fraction with a steam temperature of 95℃gives the acetal intermediate as a colorless transparent liquid 31.3g (HPLC purity > 99%) in a yield of 84.8%.
Example 2
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (124 g), trifluoromethanesulfonic acid (3 g), and after cooling to 0 to 5℃with stirring, trimethyl orthoformate (84.8 g) was added. The temperature of the system is kept below 10 ℃, and the temperature is raised to reflux reaction for 5 hours after the dripping is finished. And after the reaction is finished, the solvent is distilled and recovered under reduced pressure, and the recovered liquid is used for the next batch of reaction. After concentrating to near dryness, the concentrate temperature was controlled below 5 ℃ and PH was adjusted to neutral (ph=7) with 20% sodium hydroxide solution. Extraction with ethyl acetate three times, in amounts of (100mL+50mL+50mL), respectively, concentrating the combined organic phases to an oil, high vacuum distillation at 130℃and collection of the fraction with a steam temperature of 95℃gives 29.3g of the acetal intermediate as a colorless transparent liquid (HPLC purity not less than 99%) in 79.4% yield.
Example 3
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (24.8 g), and trimethyl orthoformate (84.8 g). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, and heating to reflux reaction for 5h after the dripping is finished. And after the reaction is finished, the solvent is distilled and recovered under reduced pressure, and the recovered liquid is used for the next batch of reaction. After concentrating to near dryness, the concentrate temperature was controlled below 5 ℃ and PH was adjusted to neutral (ph=7) with 20% sodium hydroxide solution. Extraction with ethyl acetate three times, using amounts of (100mL+50mL+50mL), combining the organic phases, concentrating to an oil, high vacuum distillation at 130 ℃, and collecting the fraction with a steam temperature of 95 ℃ to obtain 28.96g (HPLC purity: 99%) of the acetal intermediate as colorless transparent liquid, with a yield of 78.5%.
Example 4
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (13.64 g), and trimethyl orthoformate (84.8 g). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, and heating to reflux reaction for 5h after the dripping is finished. And after the reaction is finished, the solvent is distilled and recovered under reduced pressure, and the recovered liquid is used for the next batch of reaction. After concentrating to near dryness, the concentrate temperature was controlled below 5 ℃ and PH was adjusted to neutral (ph=7) with 20% sodium hydroxide solution. Extraction with ethyl acetate three times, in amounts of (100mL+50mL+50mL), respectively, concentrating the combined organic phases to an oil, high vacuum distillation at 130℃and collection of the fraction with a steam temperature of 95℃gives 29.7g of the acetal intermediate as a colorless transparent liquid (HPLC purity not less than 99%) in 80.5% yield.
Example 5
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (124 g), and trimethyl orthoformate (25.5 g). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, and heating to reflux reaction for 5h after the dripping is finished. And after the reaction is finished, the solvent is distilled and recovered under reduced pressure, and the recovered liquid is used for the next batch of reaction. After concentrating to near dryness, the concentrate temperature was controlled below 5 ℃ and PH was adjusted to neutral (ph=7) with 20% sodium hydroxide solution. Extraction with ethyl acetate three times, in amounts of (100mL+50mL+50mL), respectively, concentrating the combined organic phases to an oil, high vacuum distillation at 130℃and collection of the fraction with a steam temperature of 95℃gives 28.78g of the acetal intermediate as a colorless transparent liquid (HPLC purity not less than 99%) in a yield of 78.0%.
Example 6
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (124 g), and trimethyl orthoformate (42.4 g). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, and heating to reflux reaction for 5h after the dripping is finished. And after the reaction is finished, the solvent is distilled and recovered under reduced pressure, and the recovered liquid is used for the next batch of reaction. After concentrating to near dryness, the concentrate temperature was controlled below 5 ℃ and PH was adjusted to neutral (ph=7) with 20% sodium hydroxide solution. Extraction with ethyl acetate three times, in amounts of (100mL+50mL+50mL), respectively, concentrating the combined organic phases to an oil, high vacuum distillation at 130℃and collecting the fraction with a steam temperature of 95℃to obtain the acetal intermediate as a colorless transparent liquid 31.47g (HPLC purity not less than 99%) in 85.3% yield.
Example 7
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (124 g), and trimethyl orthoformate (84.8 g). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, and heating to 30 ℃ for reaction for 5h after the dripping is finished. And after the reaction is finished, the solvent is distilled and recovered under reduced pressure, and the recovered liquid is used for the next batch of reaction. After concentrating to near dryness, the concentrate temperature was controlled below 5 ℃ and PH was adjusted to neutral (ph=7) with 20% sodium hydroxide solution. Extraction with ethyl acetate three times, in amounts of (100mL+50mL+50mL), respectively, concentrating the combined organic phases to an oil, high vacuum distillation at 130℃and collection of the fraction with a steam temperature of 95℃gives 26.3g of the acetal intermediate as a colorless transparent liquid (HPLC purity not less than 99%) in 71.3% yield.
Example 8
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (124 g), and trimethyl orthoformate (84.8 g). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, and heating to 40 ℃ for reaction for 5h after the dripping is finished. And after the reaction is finished, the solvent is distilled and recovered under reduced pressure, and the recovered liquid is used for the next batch of reaction. After concentrating to near dryness, the concentrate temperature was controlled below 5 ℃ and PH was adjusted to neutral (ph=7) with 20% sodium hydroxide solution. Extraction with ethyl acetate three times, in amounts of (100mL+50mL+50mL), respectively, concentrating the combined organic phases to an oil, high vacuum distillation at 130℃and collection of the fraction with a steam temperature of 95℃gives 26.7g of the acetal intermediate as a colorless transparent liquid (HPLC purity not less than 99%) in a yield of 72.6%.
Example 9
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (124 g), and trimethyl orthoformate (84.8 g). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, and heating to 50 ℃ for reaction for 5h after the dripping is finished. And after the reaction is finished, the solvent is distilled and recovered under reduced pressure, and the recovered liquid is used for the next batch of reaction. After concentrating to near dryness, the concentrate temperature was controlled below 5 ℃ and PH was adjusted to neutral (ph=7) with 20% sodium hydroxide solution. Extraction with ethyl acetate three times, in amounts of (100mL+50mL+50mL), respectively, concentration of the combined organic phases to an oil, high vacuum distillation at 130℃and collection of the fraction with a steam temperature of 95℃gave 29g (HPLC purity. Gtoreq.99%) of the acetal intermediate as a colorless transparent liquid, with a yield of 78.6%.
Example 10
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (124 g), and trimethyl orthoformate (84.8 g). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, and heating to 60 ℃ for reaction for 5h after the dripping is finished. And after the reaction is finished, the solvent is distilled and recovered under reduced pressure, and the recovered liquid is used for the next batch of reaction. After concentrating to near dryness, the concentrate temperature was controlled below 5 ℃ and PH was adjusted to neutral (ph=7) with 20% sodium hydroxide solution. Extraction with ethyl acetate three times, in amounts of (100mL+50mL+50mL), respectively, concentrating the combined organic phases to an oil, high vacuum distillation at 130℃and collecting the fraction with a steam temperature of 95℃to give the acetal intermediate as a colorless transparent liquid 29.9g (HPLC purity. Gtoreq.99%) in a yield of 81.2%.
Example 11
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (124 g), and trimethyl orthoformate (84.8 g). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, and heating to reflux reaction for 4h after the dripping is finished. And after the reaction is finished, the solvent is distilled and recovered under reduced pressure, and the recovered liquid is used for the next batch of reaction. After concentrating to near dryness, the concentrate temperature was controlled below 5 ℃ and PH was adjusted to neutral (ph=7) with 20% sodium hydroxide solution. Extraction with ethyl acetate three times, in amounts of (100mL+50mL+50mL), respectively, concentrating the combined organic phases to an oil, high vacuum distillation at 130℃and collection of the fraction with a steam temperature of 95℃gives 29.2g of the acetal intermediate as a colorless transparent liquid (HPLC purity not less than 99%) with a yield of 79.3%.
Example 12
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (124 g), and trimethyl orthoformate (84.8 g). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, and heating to reflux reaction for 6h after the dripping is finished. And after the reaction is finished, the solvent is distilled and recovered under reduced pressure, and the recovered liquid is used for the next batch of reaction. After concentrating to near dryness, the concentrate temperature was controlled below 5 ℃ and PH was adjusted to neutral (ph=7) with 20% sodium hydroxide solution. Extraction with ethyl acetate three times, in amounts of (100mL+50mL+50mL), respectively, concentrating the combined organic phases to an oil, high vacuum distillation at 130℃and collection of the fraction with a steam temperature of 95℃gives the acetal intermediate as a colorless transparent liquid 31.07g (HPLC purity > 99%) in a yield of 84.2%.
Process 2 for synthesizing an acetal intermediate (dehydration using a water separator)
Example 13
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (24.8 g), and toluene (150 mL). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, installing a water separator and a reflux condensing device, heating to reflux for 5h until no new water drops are generated in the water separator, and separating out a water phase generated in the system. After the reaction, the temperature of the system was controlled to be lower than 5 ℃, and the PH was adjusted to be neutral (ph=7) with a 5% sodium hydroxide solution. The organic phase was separated and the aqueous phase was extracted twice with toluene in the amount of 50mL+50mL respectively, the combined organic phases were concentrated to an oil, distilled at 130℃under high vacuum and the distillation was carried out at a vapor temperature of 95℃to give 31.9g of the acetal intermediate as a colorless transparent liquid (HPLC purity. Gtoreq.99%) in 86.5% yield.
Example 14
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (14.9 g), and toluene (150 mL). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, installing a water separator and a reflux condensing device, heating to reflux for 5h until no new water drops are generated in the water separator, and separating out a water phase generated in the system. After the reaction, the temperature of the system was controlled to be lower than 5 ℃, and the PH was adjusted to be neutral (ph=7) with a 5% sodium hydroxide solution. The organic phase was separated and the aqueous phase was extracted twice with toluene in the amount of 50mL+50mL respectively, the combined organic phases were concentrated to an oil, distilled at 130℃under high vacuum and the distillation was carried out at a vapor temperature of 95℃to give 27.9g of the acetal intermediate as a colorless transparent liquid (HPLC purity: 99%) in a yield of 75.6%.
Example 15
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (18.6 g), and toluene (150 mL). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, installing a water separator and a reflux condensing device, heating to reflux for 5h until no new water drops are generated in the water separator, and separating out a water phase generated in the system. After the reaction, the temperature of the system was controlled to be lower than 5 ℃, and the PH was adjusted to be neutral (ph=7) with a 5% sodium hydroxide solution. The organic phase was separated and the aqueous phase was extracted twice with toluene in the amount of 50mL+50mL respectively, the combined organic phases concentrated to an oil, distilled at 130℃under high vacuum and the distillation at 95℃steam was collected to give 29.37g of the acetal intermediate as a colorless transparent liquid (HPLC purity. Gtoreq.99%) in 79.6% yield.
Example 16
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (37.2 g), and toluene (150 mL). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, installing a water separator and a reflux condensing device, heating to reflux for 5h until no new water drops are generated in the water separator, and separating out a water phase generated in the system. After the reaction, the temperature of the system was controlled to be lower than 5 ℃, and the PH was adjusted to be neutral (ph=7) with a 5% sodium hydroxide solution. The organic phase was separated and the aqueous phase was extracted twice with toluene in the amount of 50ml +50ml respectively, the combined organic phases concentrated to an oil, distilled at 130 c under high vacuum and the distillation at 95 c steam was collected to give the acetal intermediate as a colorless transparent liquid 31.8g (HPLC purity > 99%) in 86.4% yield.
Example 17
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (24.8 g), and toluene (150 mL). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, installing a water separator and a reflux condensing device, heating to 50 ℃ for reaction for 5h until no new water drops are generated in the water separator, and separating out a water phase generated in the system. After the reaction, the temperature of the system was controlled to be lower than 5 ℃, and the PH was adjusted to be neutral (ph=7) with a 5% sodium hydroxide solution. The organic phase was separated and the aqueous phase was extracted twice with toluene in the amount of 50ml +50ml respectively, the combined organic phases concentrated to an oil, distilled at 130 c under high vacuum and the distillation at 95 c steam was collected to give 20.0g of the acetal intermediate as a colorless transparent liquid (HPLC purity > 99%) in 54.2% yield.
Example 18
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (24.8 g), and toluene (150 mL). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, installing a water separator and a reflux condensing device, heating to 60 ℃ for reaction for 5h until no new water drops are generated in the water separator, and separating out a water phase generated in the system. After the reaction, the temperature of the system was controlled to be lower than 5 ℃, and the PH was adjusted to be neutral (ph=7) with a 5% sodium hydroxide solution. The organic phase was separated and the aqueous phase was extracted twice with toluene in the amount of 50ml +50ml respectively, the combined organic phases concentrated to an oil, distilled at 130 c under high vacuum and the distillation at 95 c steam was collected to give 25.2g of the acetal intermediate as a colorless transparent liquid (HPLC purity > 99%) in a yield of 68.3%.
Example 19
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (24.8 g), and toluene (150 mL). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, installing a water separator and a reflux condensing device, heating to 70 ℃ for reaction for 5h until no new water drops are generated in the water separator, and separating out a water phase generated in the system. After the reaction, the temperature of the system was controlled to be lower than 5 ℃, and the PH was adjusted to be neutral (ph=7) with a 5% sodium hydroxide solution. The organic phase was separated and the aqueous phase was extracted twice with toluene in the amount of 50ml +50ml respectively, the combined organic phases concentrated to an oil, distilled under high vacuum at 130 c and the distillation was carried out with a steam temperature of 95 c to give 27g of the acetal intermediate as a colorless transparent liquid (HPLC purity > 99%) in 73.2% yield.
Example 20
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (24.8 g), and toluene (150 mL). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, installing a water separator and a reflux condensing device, heating to 80 ℃ for reaction for 5h until no new water drops are generated in the water separator, and separating out a water phase generated in the system. After the reaction, the temperature of the system was controlled to be lower than 5 ℃, and the PH was adjusted to be neutral (ph=7) with a 5% sodium hydroxide solution. The organic phase was separated and the aqueous phase was extracted twice with toluene in the amount of 50ml +50ml respectively, the combined organic phases concentrated to an oil, distilled under high vacuum at 130 c and the distillation was carried out with a steam temperature of 95 c to give 27.6g of the acetal intermediate as a colorless transparent liquid (HPLC purity > 99%) in 75% yield.
Example 21
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (24.8 g), and toluene (150 mL). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, installing a water separator and a reflux condensing device, heating to 90 ℃ for reaction for 5h until no new water drops are generated in the water separator, and separating out a water phase generated in the system. After the reaction, the temperature of the system was controlled to be lower than 5 ℃, and the PH was adjusted to be neutral (ph=7) with a 5% sodium hydroxide solution. The organic phase was separated and the aqueous phase was extracted twice with toluene in the amount of 50mL+50mL respectively, the combined organic phases were concentrated to an oil, distilled at 130℃under high vacuum and the distillation was carried out at a vapor temperature of 95℃to give 28.4g of the acetal intermediate as a colorless transparent liquid (HPLC purity. Gtoreq.99%) in 77.1% yield.
Example 22
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (24.8 g), and toluene (150 mL). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, installing a water separator and a reflux condensing device, heating to 100 ℃ for reaction for 5h until no new water drops are generated in the water separator, and separating out a water phase generated in the system. After the reaction, the temperature of the system was controlled to be lower than 5 ℃, and the PH was adjusted to be neutral (ph=7) with a 5% sodium hydroxide solution. The organic phase was separated and the aqueous phase was extracted twice with toluene in the amount of 50ml +50ml respectively, the combined organic phases concentrated to an oil, distilled at 130 c under high vacuum and the distillation at 95 c steam was collected to give 29.59g of the acetal intermediate as a colorless transparent liquid (HPLC purity > 99%) in 80.2% yield.
Example 23
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (24.8 g), and toluene (150 mL). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, installing a water separator and a reflux condensing device, heating to reflux reaction for 4h until no new water drops are generated in the water separator, and separating out a water phase generated in the system. After the reaction, the temperature of the system was controlled to be lower than 5 ℃, and the PH was adjusted to be neutral (ph=7) with a 5% sodium hydroxide solution. The organic phase was separated and the aqueous phase was extracted twice with toluene in the amount of 50ml+50ml respectively, the combined organic phases concentrated to an oil, distilled under high vacuum at 130℃and the distillation cut at 95℃was collected to give 29.9g of the acetal intermediate as a colorless transparent liquid (HPLC purity not less than 99%) in 81% yield.
Example 24
To a 500mL three-necked flask at room temperature was successively added p-chlorobenzaldehyde (28.1 g), ethylene glycol (24.8 g), and toluene (150 mL). Stirring and cooling to 0-5 ℃, adding 3g of trifluoromethanesulfonic acid, keeping the system temperature below 10 ℃, installing a water separator and a reflux condensing device, heating to reflux for 6h until no new water drops are generated in the water separator, and separating out a water phase generated in the system. After the reaction, the temperature of the system was controlled to be lower than 5 ℃, and the PH was adjusted to be neutral (ph=7) with a 5% sodium hydroxide solution. The organic phase was separated and the aqueous phase was extracted twice with toluene in the amount of 50ml +50ml respectively, the combined organic phases concentrated to an oil, distilled at 130 c under high vacuum and the distillation at 95 c steam was collected to give 31.88g of the acetal intermediate as a colorless transparent liquid (HPLC purity > 99%) in 86.4% yield.
Synthesis process of 4-biphenylcarbaldehyde
Synthesis process of 4-biphenylcarbaldehyde
Example 25
2- (4-chlorophenyl) -1, 3-dioxane (36.9 g) was weighed out, dried anhydrous manganese dichloride (1.25 g) was added to a dry 500mL three-necked round bottom flask under nitrogen atmosphere, dried tetrahydrofuran (230 mL) was added, after the addition was completed, nitrogen substitution was again performed, and stirring was performed at room temperature until the solid was dissolved. After the reaction system is cooled to minus 5 ℃ to minus 10 ℃, the phenylmagnesium chloride solution (105 mL, the concentration is 2 mol/L) is added dropwise, the reaction is carried out for 5 hours at the temperature of minus 5 ℃ to 0 ℃ after the dropwise addition, and the reaction (thin layer chromatography, TLC) is monitored until the reaction is complete. After the reaction, 6mol/L HCl aqueous solution is slowly added dropwise to the system until the pH=1-2, the mixture is stirred for 1 hour, then the mixture is stood for layering, the aqueous phase is extracted twice by adding ethyl acetate (150+50 mL), the organic phases are combined, the saturated saline solution is washed twice, dried by anhydrous sodium sulfate, filtered, the filtrate is distilled under reduced pressure to remove the solvent, and then the solvent is purified by column chromatography to obtain 23.74g (purity 98%) of off-white solid, and the yield is 65.2%.
Example 26
2- (4-chlorophenyl) -1, 3-dioxane (36.9 g) was weighed into a dry 500mL three-necked round bottom flask, dry tetrahydrofuran (230 mL) was added under nitrogen atmosphere, after the addition was completed, nitrogen substitution was again performed, and stirring was performed at room temperature until the solid was dissolved. After the reaction system is cooled to minus 5 ℃ to minus 10 ℃, the phenylmagnesium chloride solution (105 mL, the concentration is 2 mol/L) is added dropwise, the reaction is carried out for 5 hours at the temperature of minus 5 ℃ to 0 ℃ after the dropwise addition, and the reaction (thin layer chromatography, TLC) is monitored until the reaction is complete. After the reaction, 6mol/L HCl aqueous solution is slowly added dropwise to the system until the pH=1-2, the mixture is stirred for 1 hour, then the mixture is stood for layering, the aqueous phase is extracted twice by adding ethyl acetate (150+50 mL), the organic phases are combined, the saturated saline water is washed twice, the mixture is dried by anhydrous sodium sulfate and filtered, the filtrate is distilled under reduced pressure to remove the solvent, and then the white solid is purified by column chromatography to obtain 12.8g (purity 98%) with the yield of 35.3%.
Example 27
2- (4-chlorophenyl) -1, 3-dioxane (36.9 g) was weighed out, dried anhydrous manganese dichloride (1.25 g) was added to a dry 500mL three-necked round bottom flask under nitrogen atmosphere, dried tetrahydrofuran (230 mL) was added, after the addition was completed, nitrogen substitution was again performed, and stirring was performed at room temperature until the solid was dissolved. After the reaction system is cooled to minus 5 ℃ to minus 10 ℃, the phenylmagnesium chloride solution (150 mL, concentration 2 mol/L) is added dropwise, the reaction is carried out for 5 hours at the temperature of minus 5 ℃ to 0 ℃ after the dropwise addition, and the reaction (thin layer chromatography, TLC) is monitored until the reaction is complete. After the reaction, 6mol/L HCl aqueous solution is slowly added dropwise to the system until the pH=1-2, the mixture is stirred for 1 hour, then the mixture is stood for layering, the aqueous phase is extracted twice by adding ethyl acetate (150+50 mL), the organic phases are combined, the saturated saline water is washed twice, the mixture is dried by anhydrous sodium sulfate and filtered, the filtrate is distilled under reduced pressure to remove the solvent, and then the solvent is purified by column chromatography to obtain 18.57g (purity 98%) of off-white solid, and the yield is 51%.
Example 28
2- (4-chlorophenyl) -1, 3-dioxane (36.9 g) was weighed out, dried anhydrous manganese dichloride (1.25 g) was added to a dry 500mL three-necked round bottom flask under nitrogen atmosphere, dried tetrahydrofuran (230 mL) was added, after the addition was completed, nitrogen substitution was again performed, and stirring was performed at room temperature until the solid was dissolved. After the reaction system is cooled to minus 5 ℃ to minus 10 ℃, the phenylmagnesium chloride solution (200 mL, concentration 2 mol/L) is added dropwise, the reaction is carried out for 5 hours at the temperature of minus 5 ℃ to 0 ℃ after the dropwise addition, and the reaction (thin layer chromatography, TLC) is monitored until the reaction is complete. After the reaction, 6mol/L HCl aqueous solution is slowly added dropwise to the system until the pH=1-2, the mixture is stirred for 1 hour, then the mixture is stood for layering, the aqueous phase is extracted twice by adding ethyl acetate (150+50 mL), the organic phases are combined, the saturated saline water is washed twice, the mixture is dried by anhydrous sodium sulfate and filtered, the filtrate is distilled under reduced pressure to remove the solvent, and 17.04g (purity 98%) of off-white solid is obtained after column chromatography purification, and the yield is 46.8%.
Example 29
2- (4-chlorophenyl) -1, 3-dioxane (36.9 g) was weighed out, dried anhydrous manganese dichloride (1.25 g) was added to a dry 500mL three-necked round bottom flask under nitrogen atmosphere, dried tetrahydrofuran (230 mL) was added, after the addition was completed, nitrogen substitution was again performed, and stirring was performed at room temperature until the solid was dissolved. After the reaction system is cooled to 5 to minus 10 ℃, the phenyl magnesium chloride solution (105 mL with the concentration of 2 mol/L) is added dropwise, the reaction is carried out for 5 hours at the temperature of 5 to 10 ℃ after the dropwise addition, and the reaction (thin layer chromatography, TLC) is monitored until the reaction is complete. After the reaction, 6mol/L HCl aqueous solution is slowly added dropwise to the system until the pH=1-2, the mixture is stirred for 1 hour, then the mixture is stood for layering, the aqueous phase is extracted twice by adding ethyl acetate (150+50 mL), the organic phases are combined, the saturated saline solution is washed twice, dried by anhydrous sodium sulfate, filtered, the filtrate is distilled under reduced pressure to remove the solvent, and then the solvent is purified by column chromatography to obtain 21.96g of off-white solid (purity 98%), and the yield is 60.3%.
Example 30
2- (4-chlorophenyl) -1, 3-dioxane (36.9 g) was weighed out, dried anhydrous manganese dichloride (1.25 g) was added to a dry 500mL three-necked round bottom flask under nitrogen atmosphere, dried tetrahydrofuran (230 mL) was added, after the addition was completed, nitrogen substitution was again performed, and stirring was performed at room temperature until the solid was dissolved. After the reaction system is cooled to 5 to minus 10 ℃, the phenyl magnesium chloride solution (105 mL, concentration 2 mol/L) is added dropwise, the reaction is carried out for 5 hours at 15 to 20 ℃ after the dropwise addition, and the reaction (thin layer chromatography, TLC) is monitored until the reaction is complete. After the reaction, 6mol/L HCl aqueous solution is slowly added dropwise to the system until the pH=1-2, the mixture is stirred for 1 hour, then the mixture is stood for layering, the aqueous phase is extracted twice by adding ethyl acetate (150+50 mL), the organic phases are combined, the saturated saline water is washed twice, the mixture is dried by anhydrous sodium sulfate and filtered, the filtrate is distilled under reduced pressure to remove the solvent, and then the white solid is purified by column chromatography to obtain 19.74g (purity 98%), and the yield is 54.2%.
Example 31
2- (4-chlorophenyl) -1, 3-dioxane (36.9 g) was weighed out, dried anhydrous manganese dichloride (1.25 g) was added to a dry 500mL three-necked round bottom flask under nitrogen atmosphere, dried tetrahydrofuran (230 mL) was added, after the addition was completed, nitrogen substitution was again performed, and stirring was performed at room temperature until the solid was dissolved. After the reaction system is cooled to 5 to minus 10 ℃, the phenyl magnesium chloride solution (105 mL, concentration 2 mol/L) is added dropwise, the reaction is carried out for 5 hours at the temperature of 25 to 30 ℃ after the dropwise addition, and the reaction (thin layer chromatography, TLC) is monitored until the reaction is complete. After the reaction, 6mol/L HCl aqueous solution is slowly added dropwise to the system until the pH=1-2, the mixture is stirred for 1 hour, then the mixture is stood for layering, the aqueous phase is extracted twice by adding ethyl acetate (150+50 mL), the organic phases are combined, the saturated saline water is washed twice, the mixture is dried by anhydrous sodium sulfate and filtered, the filtrate is distilled under reduced pressure to remove the solvent, and then the solvent is purified by column chromatography to obtain 18.2g (purity 98%) of off-white solid, and the yield is 50%.
Example 29
2- (4-chlorophenyl) -1, 3-dioxane (36.9 g) was weighed out, dried anhydrous manganese dichloride (1.25 g) was added to a dry 500mL three-necked round bottom flask under nitrogen atmosphere, dried tetrahydrofuran (230 mL) was added, after the addition was completed, nitrogen substitution was again performed, and stirring was performed at room temperature until the solid was dissolved. After the reaction system is cooled to 5 to minus 10 ℃, the phenyl magnesium chloride solution (105 mL, concentration 2 mol/L) is added dropwise, the reaction is carried out for 5 hours at the temperature of 35 to 45 ℃ after the dropwise addition, and the reaction (thin layer chromatography, TLC) is monitored until the reaction is complete. After the reaction, 6mol/L HCl aqueous solution is slowly added dropwise to the system until the pH=1-2, the mixture is stirred for 1 hour, then the mixture is stood for layering, the aqueous phase is extracted twice by adding ethyl acetate (150+50 mL), the organic phases are combined, the saturated saline water is washed twice, the mixture is dried by anhydrous sodium sulfate and filtered, the filtrate is distilled under reduced pressure to remove the solvent, and then the white solid is purified by column chromatography to obtain 15.3g (purity 98%) with the yield of 42%.
Example 30
2- (4-chlorophenyl) -1, 3-dioxane (36.9 g) was weighed out, dried anhydrous zinc chloride (2.5 g) was added to a dry 500mL three-necked round bottom flask under nitrogen atmosphere, dried tetrahydrofuran (230 mL) was added, after the addition was completed, nitrogen substitution was again performed, and stirring was performed at room temperature until the solid was dissolved. After the reaction system is cooled to minus 5 ℃ to minus 10 ℃, the phenylmagnesium chloride solution (105 mL, the concentration is 2 mol/L) is added dropwise, the reaction is carried out for 5 hours at the temperature of minus 5 ℃ to 0 ℃ after the dropwise addition, and the reaction (thin layer chromatography, TLC) is monitored until the reaction is complete. After the reaction, 6mol/L HCl aqueous solution is slowly added dropwise to the system until the pH=1-2, the mixture is stirred for 1 hour, then the mixture is stood for layering, the aqueous phase is extracted twice by adding ethyl acetate (150+50 mL), the organic phases are combined, the saturated saline water is washed twice, the mixture is dried by anhydrous sodium sulfate and filtered, the filtrate is distilled under reduced pressure to remove the solvent, and then the solvent is purified by column chromatography to obtain 23.63g (purity 98%) of off-white solid, and the yield is 64.9%.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference signs in the claims shall not be construed as limiting the claim concerned.
Claims (8)
1. A preparation process of 4-biphenyl formaldehyde is characterized in that: the preparation process comprises the following two steps:
adopting p-chlorobenzaldehyde as a starting material, adopting glycol as an aldehyde group protecting reagent, and adopting trimethyl orthoformate dehydration process or a water knockout drum dehydration process to synthesize an acetal intermediate (2- (4-chlorophenyl) -1, 3-dioxane);
the phenyl magnesium chloride and the acetal intermediate form a biphenyl acetal intermediate under the action of Lewis acid, and finally, formyl is released by hydrolysis and deprotection under the acidic condition, so that the 4-biphenyl formaldehyde with high yield and purity is prepared.
2. The novel process for synthesizing 4-biphenylcarbaldehyde as claimed in claim 1, wherein: the process for synthesizing the acetal intermediate by adopting trimethyl orthoformate dehydration comprises the following steps of: (1.1-10): (1.1-4): 0.1.
3. the novel process for synthesizing 4-biphenylcarbaldehyde as claimed in claim 2, wherein: the process for synthesizing the acetal intermediate by dehydrating trimethyl orthoformate is adopted, and the reaction temperature is 30-110 ℃.
4. A novel process for synthesizing 4-biphenylcarbaldehyde as defined in claim 3, wherein: the process for synthesizing the acetal intermediate by dehydration through a water separator comprises the following steps of: (1.1-3): 0.1.
5. the process for producing 4-biphenylcarbaldehyde as defined in claim 4, wherein: the process for synthesizing the acetal intermediate by dehydration through a water separator has the reaction temperature of 50-130 ℃.
6. The process for producing 4-biphenylcarbaldehyde as defined in claim 5, wherein: the Lewis acid catalyst used for the reaction of the phenyl magnesium chloride and the acetal intermediate is one of zinc chloride, manganese chloride and magnesium chloride.
7. The method for preparing 4-biphenylcarbaldehyde as defined in claim 6, wherein: the phenyl magnesium chloride reacts with the acetal intermediate to form a biphenyl acetal intermediate, the molar ratio between the 2- (4-chlorophenyl) -1, 3-dioxane, the phenyl magnesium chloride and the catalyst being 1: (1.05-2): (0-0.05).
8. The method for preparing 4-biphenylcarbaldehyde as defined in claim 7, wherein: phenyl magnesium chloride reacts with the acetal intermediate to form a biphenyl acetal intermediate at a reaction temperature of-5 to 50 ℃.
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